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Non-pharmaceutical medications and approaches to glaucoma (all articles)

    Submitted by rritch on Wed, 09/15/2010 - 9:33am

    The blog post contains several articles. Keep scrolling down past the references at the end of each article to read the next article.

    Section Leaders: Makoto Araie, Robert Ritch, Clement Tham

    Contributors: Makoto Aihara, Aiko Iwase, Sandra Fernando, Michael S Kook, Simon Law, Robert Nussenblatt, Vincenzo Parisi, Nathan Radcliffe, Douglas Rhee, Kwok-Fai So, Raymond Chuen-Chung CHANG, He Wei, Lori Ventura

    Consensus points

    • Plant extracts have been used medicinally throughout history. Every society has plants used medicinally
    • Even dogs eat grass when sick, while chimpanzees consume a variety of non-food plants medicinally. This is learned behavior
    • Our modern pharmacopoiea of drugs were originally synthesized from plants used medicinally. These include vitamin C, digitalis, penicillin, and pilocarpine.
    • Chinese traditional medicine in its written form dates back 5000 years.
    • Technically speaking, vitamins fall into this category. We depend on essential vitamins from food for survival. There is a fine line between nutrition and medicinal uses of plants.
    • It was only in the 20th century, with the advent of single molecule products synthesized and patented by pharmaceutical companies and U.S. medical school philosophiesthat other non-pharmaceutical traditional medications came under attack, leading often to their being ridiculed and held in contempt.Thus, in order to get away from this view, we prefer the term “non-pharmaceutical therapy” to “alternative” or “complementary”
    • Many available natural compounds used as “non-pharmaceutical therapy” have been reported to show beneficial effects on circulation, the immune system, and neuroprotective activities in vitro and in vivo.
    • The mechanism of action of neuroprotection most common to natural compounds is antioxidant/free radical scavenging activity. However, many other actions are present and some extracts, such as Gingko biloa and curcumin have widespread activity on a number of enzyme systems.
    • Comment: Some of these compounds reportedly modify expression of enzymes relating to excitotoxicity, apoptosis, inflammation, lipid peroxidation, or immune stimulation. Some of these compounds have undergone clinical trials to evidence their effects on systemic diseases, including neurodegenerative disorders.

    Comment: There have been several randomized trials with the majority showing a clinical benefit of n-acetyl cysteine therapy of chronic obstructive pulmonary disease. There are currently 33 NIH-sponsored trials involving curcumin.

    • There is a relative paucity of clinical trials examining neuroprotective effects of these compounds on ocular diseases, including glaucoma, and most of them were case series.
    • Bioavailability of these natural compounds have not been well studied.
    • Exercise reduces intraocular pressure (IOP) and influences ocular blood flow. It also protects against Alzheimer’s and cardiovascular disease.

    Comment: Stress may also influence IOP and ocular blood flow.

    • Acupuncture influences IOP and ocular blood flow, but the reported results are not consistent.
    • Clinical trials on many of these extracts and compounds are warranted.

    Comment: Funding is a problem, since these compounds are mostly in the pubic domain and not patentable. In addition, end points are seriously inadequate. We need methods of reducing detection of endpoints to months instead of years and reducing the numbers of patients required for clinical trials.


    Quercetin and quercetin glycosides

    Makoto Aihara, MD., PhD.



    Flavonoids comprise a large family of plant-derived compounds widely distributed in fruits and vegetables.(Heim et al. 2002)(Ross & Kasum 2002) There is growing evidence from human nutrition studies that the absorption and bioavailability of specific flavonoids is much higher than originally believed.(Ross & Kasum 2002)(Manach et al. 2005) Flavonoids are believed to exert protective and/or beneficial effects on multiple disease states, including cancer, cardiovascular disease, and neurodegenerative disorders.(Middleton 1998; Middleton et al. 2000)(Ross & Kasum 2002) These physiological benefits of flavonoids are generally thought to be derived from their antioxidant activity and free radical scavenging. (Ishige et al. 2001).

    Quercetin is an important flavonoid and is ordinarily present bound to a sugar as a glycoside. For example, quercetin 3-O-rutinoside (rutin) is one of the quercetin glycosides, which is rich in buckwheat and tartary buckwheat, commonly ingested in Japan and other Asian countries, and amazingly accounting for as high as 1% of the total weight of buckwheat and tartary buckwheat.(Kim et al. 2009)(Fabjan et al. 2003)

    RGC death in glaucoma is believed to be induced by apoptotic mechanisms triggered by multiple stimuli, including ischemia, oxidative stress, or elevation of glutamate levels.(Quigley 1999)(Wax & Tezel 2002) Numerous studies have demonstrated that excessive glutamate induces RGC death in vitro and in vivo,(Sucher et al. 1997) and that the glutamate receptor antagonists MK801 or memantine can ameliorate RGC death caused by elevated intraocular pressure.(Lipton 2003)(Chaudhary et al. 1998)(Hare et al. 2004)(Lagrèze et al. 1998)(WoldeMussie et al. 2002) Oxidative stress induced either by increased levels of reactive oxygen species (ROS) or mitochondrial dysfunction is also implicated in glaucomatous, ischemic, and hereditary optic neuropathies.(Carelli et al. 2009)(Tezel 2006) Accordingly, flavonoids including quercetin may also have neuroprotective potential in glaucoma.


    Neuroprotection in non-retinal neurons


    In in vitro culture studies, Quercetin showed an ameliorating effect on oxidative stress-induced PC12 cell death (Dajas et al. 2003) or midbrain culture of rat,(Mercer et al. 2005) and also other kinds of stress-induced cell death, such as beta-amyloid induced PC12 cell death(Zhu et al. 2007) or kainite/NMDA induced rat neuronal death.(Silva et al. 2008) Quercetin also induced neuroprotective effect by modulating inflammatory responses in astroglia by IL1beta.(Sharma et al. 2007) In vivo, quercetin was effective in rat brain trauma model(Schultke et al. 2005) and cerebrovascular insults.(Ossola et al. 2009)


    Neuroprotection in retinal neurons


    Only five studies describing the potential effects of flavonoids on RGC death induced by oxidative stress or pressure stress using RGC-5 transgenic cell lines or in vivo rodent models have been reported.(Zhang et al. 2007)(Maher & Hanneken 2008)(Maher & Hanneken 2005)(Jung et al. 2008)(Liu et al. 2007) Liu et al reported a neuroprotective effect of quercetin on pressure-induced RGC-5 death.(Liu et al. 2007)


    Drug delivery of quercetin and quercetin glycoside


    A few reports have indicated that repeated intake of several hundred milligrams of quercetin-rutinoside resulted in a plasma concentration of 100nM or higher.(Boyle et al. 2000)(Erlund et al. 2000)(Graefe et al. 2001) Moreover, flavonoids can penetrate into the central nervous system through the blood-brain barrier.(Youdim et al. 2004) Interestingly, quercetin itself may not be effective in neurodegenerative disease such as Parkinson disease model rat,(Zbarsky et al. 2005) because it penetrates the blood brain barrier less efficiently than quercetin glycosides.(Ossola et al. 2009) This may be the reason for its beneficial effects in rat brain trauma or cerebrovascular insults.(Ossola et al. 2009)(Schultke et al. 2005)


    Mechanism of neuroprotective action

    Although the precise mechanism of action remains unclear, the beneficial activity of flavonoids is generally attributed to their antioxidative efficacy.(Schultke et al. 2005)(Silva et al. 2008)(Ishige et al. 2001) The antioxidant capacity of flavonoids depends on the arrangement of functional groups surrounding the flavonol nucleus, which may directly affect glutathione metabolism, antioxidant capacity, or the ability to maintain low Ca2+ levels despite high levels of reactive oxygen species. (Heim et al. 2002)(Ishige et al. 2001)



    Quercetin and its glycosides have neuroprotective effect and may be effective on glaucomatous optic neuropathy. However there was no clinical evidence to use them as a neuroprotective agent. The major concerns of quercetin intake as a supplement are its poor penetration into the retina(Ossola et al. 2009)(Youdim et al. 2004) and its specific inhibitory effect on HSP72 induction,(Kretz et al. 2006)(Kwong et al. 2003) which may lead to deteriorate neuroprotective effect by HSP72. Further studies are needed using glaucoma animal model and human studies.



    Boyle SP, VL Dobson, SJ Duthie & et al (2000): Bioavailability and efficiency of rutin as an antioxidant: a human supplementation study. Eur J Clin Nutr 54: 774-782.

    Carelli V, C La Morgia, ML Valentino & et al (2009): Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders. Biochim Biophys Acta 1787: 518-528.

    Chaudhary P, F Ahmed & S Sharma (1998): MK801-a neuroprotectant in rat hypertensive eyes. Brain Res 792: 154-158.

    Dajas F, F Rivera, F Blasina & et al (2003): Cell culture protection and in vivo neuroprotective capacity of flavonoids. Neurotox Res 5: 425-432.

    Erlund I, T Kosonen, G Alfthan & et al (2000): Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers. Eur J Clin Pharmacol 56: 545-553.

    Fabjan N, J Rode, IJ Kosir & et al (2003): Tartary buckwheat (Fagopyrum tataricum Gaertn.) as a source of dietary rutin and quercitrin. J Agric Food Chem 51: 6452-6455.

    Graefe EU, J Wittig, S Mueller & et al (2001): Pharmacokinetics and bioavailability of quercetin glycosides in humans. J Clin Pharmacol 41: 492-499.

    Hare WA, E WoldeMussie, RK Lai & et al (2004): Efficacy and safety of memantine treatment for reduction of changes associated with experimental glaucoma in monkey, I: Functional measures. Invest Ophthalmol Vis Sci 45: 2625-2639.

    Heim KE, AR Tagliaferro & D Bobilya (2002): Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem 13: 572-584.

    Ishige K, D Schubert & Y Sagara (2001): Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic Biol Med. 30: 433-446.

    Jung SH, KD Kang, D Ji & et al (2008): The flavonoid baicalin counteracts ischemic and oxidative insults to retinal cells and lipid peroxidation to brain membranes. Neurochem Int 53: 325-337.

    Kim DW, IK Hwang, SS Lim & et al (2009): Germinated buckwheat extract decreases blood pressure and nitrotyrosine immunoreactivity in aortic endothelial cells in spontaneously hypertensive rats. Phytother Res 23: 993-998.

    Kretz A, C Schmeer, S Tausch & SS Isenmann (2006): Simvastatin promotes heat shock protein 27 expression and Akt activation in the rat retina and protects axotomized retinal ganglion cells in vivo. Neurobiol Dis 21: 421-430.

    Kwong JM, TT Lam & J Caprioli (2003): Hyperthermic pre-conditioning protects retinal neurons from N-methyl-D-aspartate (NMDA)-induced apoptosis in rat. Brain Res 970: 119-130.

    Lagrèze WA, R Knörle, M Bach & TJ Feuerstein (1998): Memantine is neuroprotective in a rat model of pressure-induced retinal ischemia. Invest Ophthalmol Vis Sci 39: 1063-1066.

    Lipton SA (2003): Possible role for memantine in protecting retinal ganglion cells from glaucomatous damage. Surv Ophthalmol 48 Suppl 1: S38-46.

    Liu Q, WK Ju, JG Crowston & et al (2007): Oxidative stress is an early event in hydrostatic pressure induced retinal ganglion cell damage. Invest Ophthalmol Vis Sci 48: 4580-9.

    Maher P & A Hanneken (2005): Flavonoids protect retinal ganglion cells from oxidative stress-induced death. Invest Ophthalmol Vis Sci 46: 4796-4803.

    Maher P & A Hanneken (2008): Flavonoids protect retinal ganglion cells from ischemia in vitro. Exp Eye Res 86: 366-374.

    Manach C, G Williamson, C Morand & et al (2005): Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr; 81: 230S-242S.

    Mercer LD, BL Kelly, MK Horne & P Beart (2005): Dietary polyphenols protect dopamine neurons from oxidative insults and apoptosis: investigations in primary rat mesencephalic cultures. Biochem Pharmacol 69: 339-345.

    Middleton E, ]. Jr., (1998): Effect of plant flavonoids on immune and inflammatory cell function. Adv Exp Med Biol 439: 175-182.

    Middleton EJ, C Kandaswami & TC Theoharides (2000): The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 52: 673-751.

    Ossola B, TM Kaariainen & PT Mannisto (2009): The multiple faces of quercetin in neuroprotection. Expert Opin Drug Saf 8: 397-409.

    Quigley HA (1999): Neuronal death in glaucoma. Prog Retin Eye Res 18: 39-57.

    Ross JA & CM Kasum (2002): Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr 22: 19-34.

    Schultke E, H Kamencic, M Zhao & et al (2005): Neuroprotection following fluid percussion brain trauma: a pilot study using quercetin. J Neurotrauma 22: 1475-1484.

    Sharma V, M Mishra, S Ghosh & et al (2007): Modulation of interleukin-1beta mediated inflammatory response in human astrocytes by flavonoids: implications in neuroprotection. Brain Res Bull 73: 55-63.

    Silva B, PJ Oliveira, A Dias & J Malva (2008): Quercetin, kaempferol and biapigenin from Hypericum perforatum are neuroprotective against excitotoxic insults. Neurotox Res 13: 265-279.

    Sucher NJ, SA Lipton & EB Dreyer (1997): Molecular basis of glutamate toxicity in retinal ganglion cells. Vision Res 37: 3483-3494.

    Tezel G (2006): Oxidative stress in glaucomatous neurodegeneration: mechanisms and consequences. Prog Brain Res 25: 490-513.

    Wax MB & G Tezel (2002): Neurobiology of glaucomatous optic neuropathy: diverse cellular events in neurodegeneration and neuroprotection. Mol Neurobiol 26: 45-55.

    WoldeMussie E, E Yoles, M Schwartz & et al (2002): Neuroprotective effect of memantine in different retinal injury models in rats. J Glaucoma 11: 474-480.

    Youdim KA, MZ Qaiser, DJ Begley & et al (2004): Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radic Biol Med. 36: 592-604.

    Zbarsky V, KP Datla, S Parkar & et al (2005): Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson's disease. Free Radic Res 39: 1119-25.

    Zhang B, R Safa, D Rusciano & NN Osborne (2007): Epigallocatechin gallate, an active ingredient from green tea, attenuates damaging influences to the retina caused by ischemia/reperfusion. Brain Res 1159: 40-53.

    Zhu JT, RC Choi, GK Chu & et al (2007): Flavonoids possess neuroprotective effects on cultured pheochromocytoma PC12 cells: a comparison of different flavonoids in activating estrogenic effect and in preventing beta-amyloid-induced cell death. J Agric Food Chem 55: 2438-2445.




    Makoto Aihara, MD., PhD.




    Methylcobalamin is an active form of Vitamin B12 (cyanocobalamin). Vitamin B12 deficiency is well known to cause megaloblastic anemia and neuropathy. Humans have two vitamin B12-dependent enzymes (i.e., methionine synthase and methylmalonyl coenzyme mutase). Neuropathy occurs because of lack of methionine synthase and not by a lack of activity by methylmalonyl coenzyme mutase. Methylcobalamin is effective to enhance myelinization in neural axons. Several reports have indicated enhancement of axonal regeneration or post-synaptic field potentials.(Yamazaki et al. 1994; Ikeuchi & Nishizaki 1995; Nishikawa et al. 1996) In rat cultured cortical neurons, methylcobalamin protected against glutamate-induced cell death.(Akaike et al. 1993) Vitamin B12 has until now been used primarily for diabetic neuropathy and peripheral neuropathy in humans.


    Ocular studies


    In eyes, vitamin B12 deficiency induced optic nerve atrophy in monkeys.(Chester et al. 1980) Also, in a patient with methionine synthase deficiency resembling methylcobalamine deficiency, the visual system was disturbed.(Poloschek et al. 2005) Thus, methylcobalamin may have a neuroprotective effect on optic neuropathy, including glaucoma. However, only a few studies have been reported in ophthalmology. In rat retinal culture, methylcobalamin protected against glutamate-induced cell death.(Kikuchi et al. 1997)(Kikuchi et al. 1997) In in vivo experiments, only one report showed methylcobalamine to ameliorate optic nerve degeneration in the optic nerve crush rat model. (Kong et al. 2004) There was no evidence of a beneficial effect of methylcobalamin in glaucomatous optic neuropathy.




    Akaike A, Tamura Y, Sato Y & T Yokota (1993): Protective effects of a vitamin B12 analog, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons. Eur J Pharmacol 241: 1-6.

    Chester EM, DP Agamanolis, JW Harris & et al (1980): Optic atrophy in [Kong, 2004 #16490] experimental vitamin B12 deficiency in monkeys. Acta Neurol Scand 61: 9-26.

    Ikeuchi Y & T Nishizaki (1995): Methylcobalamin induces a long-lasting enhancement of the postsynaptic field potential in hippocampal slices of the guinea pig. Neurosci Lett 192: 113-116.

    Kikuchi M, S Kashii, Y Honda & et al (1997): Protective effects of methylcobalamin, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture. Invest Ophthalmol Vis Sci 38: 848-854.

    Kong X, X Sun & J Zhang (2004): The protective role of Mecobalamin following optic nerve crush in adult rats. Yan Ke Xue Bao 20: 171-177.

    Nishikawa Y, S Shibata, T Shimazoe & S Watanabe (1996): Methylcobalamin induces a long-lasting enhancement of the field potential in rat suprachiasmatic nucleus slices. Neurosci Lett 220: 199-202.

    Poloschek CM, B Fowler, R Unsold & B Lorenz (2005): Disturbed visual system function in methionine synthase deficiency. Graefes Arch Clin Exp Ophthalmol 243: 497-500.

    Yamazaki K, K Oda, C Endo, T Kikuchi & T Wakabayashi (1994): Methylcobalamin (methyl-B12) promotes regeneration of motor nerve terminals degenerating in anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mouse. Neurosci Lett 170: 195-197.





    Makoto Araie, MD., Ph.D.



    1) Pharmacological basis of curcumin

    Curcumin is a yellow coloring agent present in the commonly used spice, turmeric (cucuma longa), which has been used in Indian cusine to add color and as a presenvative and also in traditional medicine to treat various common diseases (Singh, 2007). In 1815, Vogel and Pelletier first isolated curcumine and in 1910 Milobedzka and Lampe determined its chemical structure, diferuloylmethane [1,7-bis (4-hydroxy-3-methoxyphenyl) -1, 6-heptadiene-3,5dione] (Figure 1).


    Figure 1


    Studies of curcumin have increasied exponentially in recent years and over 2000 papers have been published since 2000 (Aggarwal and Sung, 2009). These studies demonstrated that curcumin has antioxidant, antibacterial, antiviral, antifungal, anti-inflammatory and antiproliferative and pro-apoptotic effects (Aggarwal et al., 2007). Potential therapeutic effects of this compound on various diseases, including neurodegenerative, cardiovascular, pulmonary, metabolic or immune-related diseases, malignancies and infectious diseases, including AIDS, have been suggested (Aggarwal and Harikumar, 2009; Hsu and Cheng, 2007; Bengmark, 2006; Cole et al., 2007) Diseases for which there are ongoing clinical trials with curcumin include Alzheimer’s disease (AD), psoriasis vulgaris, multiple myeloma, parcreatic cancer, familial adenomatous polyposis, and sporadic adenomatous polyps of the colon (Hsu and Cheng, 2007).

    The biology of the effects of curcumin has been under intensive study and curcumin is now known to have numerous molecular targets. Reported targets with which curcumin directly interacts are glycogen synthase kinase (GSK)-3ß, β-amyloid, toll-like receptor (TLR) 4, 5-lipoxygenase (LOX) of which binding constants (IC50) to curcumin are at nanomolar levels, cycloxgenase (COX)-2, xanthine oxidase, phosphorylase-3 kinase, N-aminopeptidase, DNA polymerase, autophosphorylation activated protein kinase, focal adhesion kinase (FAK), thioredoxin reductase (Trx R), topoisomerase II, ubiquitin isopeptidase, pp60 src tyrosine kinase, albumin, glutathione, tubulin, P glycoprotein or human α1-acid glycoprotein (Aggarwal and Sung, 2009). Further, curcumin binds with divalent metal ions such as Fe, Cu, Mn and Zn with relatively high affinity to Fe and Cu with dissociation constants of micromolar levels. Molecular targets of which activity curcumin reportedly modulates indirectly or secondarily include transcription factors such as NF-B, p53 or CHOP, enzymes such as glutathione reductase or protein kinase, growth factors such as EGFR, antiapoptotic proteins such as Bcl-2 or Bcl-xL, inflammatory mediators such as TNF-, IL-1 or IL-6, invasion and angiogenesis biomarkers such as MMP-9 or VEGF, some of chemokines and chemokine receptors or cell-cycle regulatory proteins (Aggarwal and Sung, 2009).


    2) Open angle glaucoma and curcumin

    Open angle glaucoma (OAG) is a neurodegenerative disease characterized by characteristic structural change of the optic nerve head and slowly progressive death of retinal ganglion cells mainly by apoptosis (Quigley, 1999). In addition to mechanical insult caused by elevated intraocular pressure (IOP), several mechanisms are thought to be involved in the development and progression of OAG which could be targets for pharmacological intervention (Chidlow et al., 2007). Such possibly interrelated mechanisms include ischemia/hypoxia due to insufficient perfusion (Flammer, 1994; Osborne et al., 2001; Flammer et al., 2002), oxidative stress (Mozaffarieh et al., 2008; Aslan et al., 2008), local or systemic abnormalities in the nitric oxide system (Aslan et al., 2008; Polak et al., 2007), primary or secondary mitochondrial dysfunction (Osborne, 2008; Kong et al., 2009), excitotoxicity (Casson, 2006), aberrant immunoregulation in which heat shock proteins may play an important role (Grus et al., 2008; Wax and Tezel, 2009; Wax et al., 2008; Tezel et al., 2004), neurotrophin deprivation (Johnson et al., 2009) or abnormal TNF- signaling (Tezel, 2008).

    It is interesting to note that curcumin has shown possible beneficial effects in most of the above mechanisms (Aggarwal and Sung, 2009; Cole et al., 2007). Beneficial effects of curcumin at various doses (30 – 300 mg/kg, i.p., 1 – 2 mg/kg, i.v., or 30 mg/kg, p.o.) on focal cerebral ischemia in rats have been reported (Ghoneim et al., 2002; Thiyagarajan and Sharma, 2004; Wang et al., 2005; Al-Omar et al., 2006; Jiang et al., 2007; Zhao et al., 2008; Shukla et al., 2008). These effects were thought to be primarily attributable to its potent anti-oxidative effects (Rajakumar and Rao, 1994; Selvam et al., 1995; Zbarsky et al., 2005; Wu et al., 2006) and partly to protection against hypoxia-induced decrease in beta-III tubulin content (Shen and Yu, 2008). Antioxidant activity of curcumin reportedly includes several mechanisms, i.e., upregulation of defensive genes and proteins such as HO-1 or catalase (Scapagnini et al., 2006; Rajeswari, 2006; Lavoie et al., 2009; Guangwei et al., 2009), inhibition of heavy metal-catalyzed lipid peroxidation by chelating toxic metals (Sreejayan and Rao, 1994; Daniel et al., 2004; Eybl et al., 2006), or reduction of nitrite levels (Jiang et al., 2007; Kumar et al., 2007; Rastogi et al., 2008). In vitro studies demonstrated that curcumin at relatively high concentrations (10 – 100 M) inhibited lipopolysaccharide (LPS)-induced NO synthase activity (Jung et al., 2006; Brouet and Ohshima, 1995; Onoda and Inano, 2000) by suppressing activation of NF-B (Pan et al., 2000). Curcumin also attenuates mitochondrial dysfunction by reducing reactive oxygen species (Zhu et al., 2004; Mythri et al., 2007; Sivalingam et al., 2008). Further, curcumin was reported to inhibit mitochondrial proton F0F1-ATPase/ATP synthase at a relatively high concentration. (45 M) (Zheng and Ramirez, 2000).

    Curcumin was reported to be effective in the kainic acid-induced hippocampal cell death in mice (Shin et al., 2007) and in the NMDA-induced damage of cultured retinal cells (Matteucci et al., 2005). Manganese complex curcumin may be more effective than the parent compound, curcumin, in reducing kainic acid-induced damage in hippocampal cells in the rat (Sumanont et al., 2006). Curcumin was also reported to be effective against glutamate toxicity in rat cerebral cortical neurons, attributed to increased brain-derived neurotropic factor (BDNF) levels and activation of Trk B (Wang et al., 2008). Oral administration of curcumin (10 – 20 mg/kg) increased hippocampal neurogenesis in chronically stressed rats probably by preventing stress-induced decrease in BDNF and 5-HT (1A) expression in the hippocampal subfields (Xu et al., 2007). Curcumin also increased viability of cultured rodent cortical neurons by up-regulating the BDNF/Trk B pathway (Wang et al., 2009).

    Effects of curcumin on pro-inflammatory cytokines have been well documented. (2) Curcumin reportedly inhibits effects of high glucose on lipid peroxication and secretion of cytokines such as TNF-, IL-6, IL-8 or MCP-1 by cultured monocytes at 0.01 – 1.0 M; pretreatment with curcumin (100 mg/kg) decreased blood levels of TNF-, IL-6 or MCP-1 in streptozosin (STZ)-induced diabetic rats (Jain et al., 2009). Tumor-induced oxidative stress is thought to play a role in loss of proper cell-mediated immunity and reduced effector T-cell population and thymic atrophy. Curcumin was reported to prevent tumor-induced thymic atrophy by restoring the perturbed activity of NF-B and TNF- signaling pathway (Bhattacharyya et al., 2007). Further, curcumin is known to have various immunomodulatory effects such as those on lympoid cell populations, antigen presentation, humoral and cell-mediated immunity and cytokine production (Gautam et al., 2007; Sharma et al., 2007). Cryopreservation of islets with curcumin at 10 M resulted in better islet viability and functionality associated with heat shock protein (Hsp) 90 and HO-1 (Kanitkar and Bhonde et al., 2008).

    In Alzheimer’s disease (AD), a neurodegenerative disorder of the elderly characterized by deposition of -amyloid plaque, NF-B and apolipoprotein E are involved in the associated neuroinflammation, while reactive oxygen species and activated microglial cells contribute to neural loss (Aggarwal and Harikumar, 2009; Cole et al., 2007; Ray and Lahiri, 2009). It is interesting to note that a possible link between glaucoma and AD has been suggested (Janciauskiene and Krakau, 2001; Tatton et al., 2003; Yoneda et al., 2005; Guo et al., 2007; Wostyn et al., 2009).

    Curcumin affects -amyloid peptide, suppressing oxidative damage and inflammatory signaling pathways (Aggarwal and Harikumar, 2009; Cole et al., 2007). Age adjusted AD prevalence and incidence in an area with high curcumin (rural India) was much lower than in western countries, including the USA (Chandra et al., 2001), Curcumin may also be effective in other neurodegenerative conditions, such as Parkinson’s disease, Huntington’s disease, tauopathies, cerebrovascular disease, head trauma, alcohol-induced neurotoxicity or aging of the brain (Aggarwal and Harikumar, 2009; Cole et al., 2007). It is possible that some of the mechanisms of action of curcumin in these neurodegenerative disorders also apply to OAG, and this field of investigation deserves study.

    Although curcumin is thought to be safe, biphasic responses to it must be kept in mind. In tumor cells, curcumin suppresses survival and proliferation and activates apoptosis (Aggarwal and Sung, 2009). Examples are its pro-apoptotic effects on human hepatoma G2 cells or cervical carcinoma cells (Cao et al., 2007; Singh M and Singh N, 2009) or those on N18 mouse-rat hybrid retinal ganglion cells (Lu et al., 2009a; Lu et al., 2009b).


    3) Effects of curcumin in ocular tissues

    Effects of curcumin have been examined in corneal epithelial cells, lens and retina. Corneal epithelial cells cultured in a hyperosmolic medium as a model for dry eye disease increased production of IL-1β, IL-6, while TNF-α levels and p38 MAP kinase, JNK MAP kinase and NF-κB were also activated. Pretreatment with 5μM curcumin abolished phosphorylation of p38 MAP kinase, increased activation of NF-κB and increased production of IL-1β, suggesting its usefulness in ameliorating inflammatory processes in the ocular surface in dry eye disease (Chen et al., 2010). Curcumin also suppressed IL-1β or TNF-α-induced disruption of simian virus 40-transformed human corneal epithelial barrier function by inhibiting NF-κB activity (Kimura et al., 2009; Kimura et al., 2008), and inhibited the angiogenic response induced by implantation of an FGF-2 pellet in the rabbit cornea by inhibiting expression of gelatinase B (Mohan et al., 2000).

    Curcumin at a dose of 75mg/kg in vivo or at 200 μM in vitro was reported to ameliorate cataract formation in rats caused by selenium-induced oxidative stress, probably by preventing free-radical-induced accumulation of Ca2+ in the lens (Manikandan et al., 2010; Manikandan et al., 2009). It was also reported that the lens removed from the rat treated with curcumin at a dose of 75mg/kg for 14 days was much more resistant to cataractgenesis by a product of lipid peroxidation, 4-hydroxy-2-trans-nonenal (4-HME,) than controls (Awasthi et al., 1996). Rats treated with naphthalene and kept on a diet supplemented with 0.005% curcumin showed significantly less lens opacification than controls treated only with naphthalene (Pandya et al., 2000).

    This effect was attributed to attenuation of apoptosis caused by naphthalene-induced oxidative stress. A diet supplemented with 0.002% curcumin was also reported to be effective against cataract induced by galactose or STZ-induced hyperglycemia in rats (Suryanarayana et al., 2003; Kumar et al., 2005). The effect of curcumin against STZ-induced cataract was attributed to prevention of the loss of chaperone-like activity of -crystallin (Kumar et al., 2005).

    A diet supplemented with curcumin was also reported effective in ameliorating retinal damage caused by diabetes. In STZ-induced diabetic rats kept on a diet supplemented with 0.05% curcumin, diabetes-induced decrease in the antioxidant capacity of the retinal tissue and increase in the oxidatively modified DNA and nitrotyrosine were prevented and diabetes-induced increase in the IL-1, VEGF and NF-B levels were inhibited (Kowluru and Kanwar, 2007). VEGF levels were reported to be inhibited at lower dose of curcumin, that is, 0.01% curcumin supplement (Mrudula et al., 2007). On the other hand, a higher dose of supplemental curcumin (0.2% in diet) was suggested to be necessary to protect retinal cells from light-stress-induced damage, the mechanism of which involves inhibition of NF-B activation and down-regulation of cellular inflammatory genes (Mandal et al., 2009). Pretreatment with curcumin also protected cells of retina-derived cell lines from H2O2-induced damage by up-regulating cellular protective mechanisms such as HO-1 and thioredoxin (Mandal et al., 2009). As briefly mentioned above, curcumin was also effective against NMDA-induced damage in rat retinal cell cutures at 15 M, but not 1 or 5 M. This effect against NMDA-mediated excitotoxic damage was associated with decrease in NMDA-induced Ca2+ rise and reduction in the level of phosphorylated NR1 subunit of the NMDA receptor, suggesting curcumin-induced modulation of NMDA receptor activity (Matteucci et al., 2005). On the other hand, curcumin was reported to cause DNA damage and inhibited expression of DNA repair genes such as ATM or DNA-PK and induced apoptosis through intrinsic pathway and caspase-3-dependent and –independent pathways in mouse-rat hybrid retinal ganglion cell line N18 cells at concentrations of 10 M or higher (Lu et al., 2009; Lu et al., 2009b).


    4) Bioavailability of curcumin

    Oral curcumin has poor bioavailability due to poor absorption attributable to high hydrophilicity, rapid metabolism and rapid systemic elimination (Anand et al., 2007; Sharma et al., 2007). Curcumin is thought to be metabolized through conjugation leading to the formation of curcumin glucuroride and sulfates and reduction leading to the formation of tetra-, hexa- or octa hydrocurcumin (Garcea et al., 2005; Ireson et al., 2002), and these metabolites are also biologically effective (Sandur et al., 2007). In one study, 15 patients with advanced colorectal cancer received oral doses of curcumin extract of 440 to 2200mg/day containing 36 to 180mg curcumin for up to 4 months (Sharma et al., 2007). Although oral extract was well tolerated without significant toxicity, neither curcumin nor its metabolites were detected in blood or urine, while curcumin was recovered from feces. In another study in 25 patients with high-risk or pre-malignant lesions, oral curcumin was given at a starting dose of 500mg and the dose was increased to another level in the order of 1000, 2000, 4000, 8000 and 12000mg/day. There was no curcumin-related toxicity up to 8000mg/day and the concentration of curcumin in the serum peaked at 1-2 hours, averaging 0.51, and 1.77μM after oral intake of 4000 and 8000mg of curcumin, respectively (Cheng et al., 2001). It was also reported that a daily oral dose of 3600mg of curcumin resulted in detectable levels in colorectal tissue which might be sufficient to be pharmacologically active (Garcea et al., 2005; Sharma et al., 2004).

    In spite of its lower bioavailability, effects of diet supplemented with curcumin have been documented in various rat models as described above, and an epidemiological study also suggested effectiveness of dietary curcumin in preventing Alzheimer’s disease (Chandra et al., 2001). Thus, enhanced bioavailability of curcumin in the near future may bring more promising results (Sharma et al., 2007). Bioavailability of curcumin may be increased by concomitant administration of curcumin with piperine (Shoba et al., 1998), by making curcumin nanoparticles, liposomes or phspholipid complexes (Bisht et al., 2007; Li et al., 2005; Maiti et al., 2007; Marczylo et al., 2007). Bis-0-demethylatedcurcumin, which has more potency than curcumin due to a higher number of phenolic groups, is reported to be safe in rats and this compound may also deserve future studies (Krishnaraju et al., 2009).

    Although curcumin is thought to be safe in animals and humans in spite of its numerous pharmacological effects (Hsu, 2007), and it is “generally regarded as safe” according to FDA (Aggarwal and Harikumar, 2009), its long-term use in rats at high doses was not free from toxicity. According to the evaluation of National Toxicology Program, daily administration of 2600 mg/kg of turmeric oleoresin containing about 80 % curcumin in rats caused moderate toxicological effects including relative increase in liver weight or stained fur at 13 weeks, and severe toxicological effects such as ulcers, hyperplasia of the cecum or intestinal cancer at 2 years (NTP, 1993).





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    Robert Ritch, MD.


    Ginkgo biloba extract contains over 60 known bioactive compounds, about 30 of which are found nowhere else in nature. The standardized extract used most widely in clinical research, EGb 761 (Dr Willmar Schwabe GmbH & Co, Karlsruhe, Germany), contains 24% ginkgo flavone glycosides (flavonoids), 6% terpene lactones (ginkgolides and bilobalide), approximately 7% proanthocyanidines, and other, uncharacterized compounds.(De Feudis 1991)

    GBE has been claimed effective in a variety of disorders associated with aging, including cerebrovascular disease, peripheral vascular disease, dementia, tinnitus, bronchoconstriction, and sexual dysfunction. GBE appears to have many properties applicable to the treatment of non-IOP-dependent risk factors for glaucomatous damage.(Ritch 2000) GBE exerts significant protective effects against free radical damage and lipid peroxidation in various tissues and experimental systems. Its antioxidant potential is comparable to water soluble antioxidants such as ascorbic acid and glutathione and lipid soluble ones such as alpha-tocopherol and retinol acetate.(Köse & Dogan 1995) The antioxidant properties of are due to its direct free radical scavenging activity. Proteasome inhibitory properties of anthocyanins may contribute to their antioxidative, anti-inflammatory and neuroprotective activities, rationalizing their use in neurodegenerative disorders.(Dreiseitel et al. 2008)

    GBE preserves mitochondrial metabolism and ATP production in various tissues and partially prevents morphologic changes and indices of oxidative damage associated with mitochondrial aging.(Pierre et al. 1999; Janssens et al. 2000; Sastre et al. 2002; Eckert et al. 2003; Eckert et al. 2005) In contrast to other antioxidants, gingko has the capacity to enter the inner mitochondrial membrane, thus making it an effective antioxidant at the mitochondrial level.(Hirooka et al. 2004) It can scavenge nitric oxide(Marcocci et al. 1994) and possibly inhibit its production.(Kobuchi et al. 1997)

    Substantial experimental evidence exists to support the view that GBE has neuroprotective properties in conditions such as hypoxia/ischemia, seizure activity, cerebral edema, and peripheral nerve damage.(Smith et al. 1996; Ahlemeyer & Krieglstein 2003) GBE protects against glutamate toxicity.(Chandrasekaran et al. 2002; Chandrasekaran et al. 2003) It can reduce glutamate-induced elevation of calcium concentrations(Zhu et al. 1997) and can reduce oxidative metabolism in both resting and calcium-loaded neurons.(Oyama et al. 1994) Neurons in tissue culture are protected from a variety of toxic insults by GBE, which inhibits apoptosis.(Ahlemeyer et al. 1999; Zhou & Zhu 2000; Guidetti et al. 2001; Lu et al. 2006)

    GBE improves both peripheral and cerebral blood flow. It is effective in treating Raynaud’s disease, which is strongly associated with normal-tension glaucoma.(Muir et al. 2002; Choi et al. 2009) It has been reported to protect myocardium against hypoxia and ischemia-reperfusion injury(Haramaki et al. 1994; Punkt et al. 1995) and to relax blood vessel walls.(Satoh & Nishida 2004) GBE is a strong inhibitor of platelet activating factor.(Koch 2005) There is mixed evidence for functional improvement in patients with Alzheimer’s-type and multi-infarct dementias. Preliminary data suggest that GBE may increase the probability of survival in the elderly population.(Dartigues et al. 2007)

    It has been suggested that alterations in systemic NO and ET-1 activity (endothelial dysfunction) are involved in vascular dysregulation in glaucoma.(Nicolela et al. 2003; Grieshaber & Flammer 2005; Henry et al. 2006; Su et al. 2006) Ginkgo biloba extract reportedly attenuates endothelial dysfunction(Zhou et al. 2006) and improvement of peripheral circulation by GBE is at least partly attributable to its effects on the NO-pathway or endothelium-dependent vasodilation.(Chen et al. 1997; Wu & Zhu 1999) Further studies of GBE on the ocular circulation and progression of normal-tension glaucoma are warranted.

    In the eye, GBE may have a protective effect against the progression of diabetic retinopathy(Droy-Lefaix et al. 1996) and reduces ischemia-reperfusion injury in rat retina.(Szabo et al. 1993) GBE protects retinal photoreceptors against light-induced damage by preventing oxidative stress in the retina.(Ranchon et al. 1999; Xie et al. 2007) Chloroquine-induced ERG changes were prevented by simultaneous treatment with GBE.(Meyniel et al. 1992) In a rat model of central retinal artery occlusion, GBE reduced edema and necrosis and blocked the reduction in b-wave amplitude.(Droy-Lefaix et al. 1993)

    Jia et al found that GBE suppressed dexamethasone-induced IOP elevation in rabbits.(Jia et al. 2008) It reduced the dexamethasone-associated accumulation of extracellular materials within the cribriform layers of the trabecular meshwork and achieved better meshwork cellularity. In cultured human trabecular cells, GBE substantially reduced dexamethasone-induced myocilin expression.(Jia et al. 2008) Ma et al(Ma et al. 2009) investigated the dosage dependence of intragastral GBE versus saline on RGC survival in the rat optic nerve crush model. The mean survival rate increased significantly (P<0.001) from 58.4±9.0% in the saline group to 74.2±6.8% in the high-dosage GBE group. The same group found that intraperitoneal administration gave similar results.(Ma et al. 2009)

    GBE has been reported to improve automated visual field indices.(Raabe et al. 1991; Quaranta et al. 2003) In one clinical cross-over study of low-dose, short-term treatment in normal volunteers, GBE increased ophthalmic artery blood flow by a mean of 24%.(Chung et al. 1999) A more recent study, however, failed to confirm these results.(Wimpissinger et al. 2007)

    A systematic review of case reports concluded that ‘‘the causality

    between ginkgo intake and bleeding is unlikely’’.(Ernst et al. 2005) A systematic review of eight randomized controlled trials concluded that the ‘‘available evidence does not demonstrate that GBE causes significant changes in blood coagulation parameters’’.(Savovic´ et al. 2005) The idea that the combination of ginkgo and anticoagulant or antiplatelet drugs might represent a serious health risk is based on several case reports but not supported by clinical trials.(Izzo & Ernst 2009)


    Ahlemeyer B & J Krieglstein (2003): Pharmacological studies supporting the therapeutic use of Ginkgo biloba extract for Alzheimer's disease. Pharmacopsychiatry 36 Suppl 1: S8-14.

    Ahlemeyer B, A Mowes & J Krieglstein (1999): Inhibition of serum deprivation- and staurosporine-induced neuronal apoptosis by Ginkgo biloba extract and some of its constituents. Eur J Pharmacol 367: 423-430.

    Chandrasekaran K, Z Mehrabian, B Spinnewyn & et al (2002): Bilobalide, a component of the Ginkgo biloba extract (EGb 761), protects against neuronal death in global brain ischemia and in glutamate-induced excitotoxicity. Cell Mol Biol 48: 663-670.

    Chandrasekaran K, Z Mehrabian, B Spinnewyn & et al (2003): Neuroprotective effects of bilobalide, a component of Ginkgo biloba extract (EGb 761) in global brain ischemia and in excitotoxicity-induced neuronal death. Pharmacopsychiatry 36 Suppl 1: S89-94.

    Chen X, S Salwinski & TJF Lee (1997): Extracts of Ginkgo biloba and ginsenosides exert cerebral vasorelaxation via a nitric oxide pathway. Clin Exp Pharmacol Physiol 24: 958-959.

    Choi WS, CJ Choi, KS Kim & et al (2009): To compare the efficacy and safety of nifedipine sustained release with Ginkgo biloba extract to treat patients with primary Raynaud's phenomenon in South Korea; Korean Raynaud study (KOARA study). Clin Rheumatol 28: 553-9.

    Chung HS, A Harris, JK Kristinsson, T Ciulla, C Kagemann & R Ritch (1999): Ginkgo biloba extract increases ocular blood flow velocity. J Ocular Pharmacol Therap 15: 233-240.

    Dartigues JF, L Carcaillon, C Helmer & et al (2007): Vasodilators and nootropics as predictors of dementia and mortality in the PAQUID cohort. J Am Geriatr Soc 55: 395-9.

    De Feudis FV (1991): Ginkgo biloba Extract (EGb 761): Pharmacological activities and clinical applications. Paris. Elsevier: Pages.

    Dreiseitel A, P Schreier, A Oehme & et al (2008): Inhibition of proteasome activity by anthocyanins and anthocyanidins. Biochem Biophys Res Comm 372: 57-61.

    Droy-Lefaix MT, ME Szabo & MN Doly (1993): Ischaemia and reperfusion-induced injury in the retina obtained form normotensive and spontaneously hypertensive rats: effects of free radical scavengers. Int J Tissue React 15: 85-91.

    Droy-Lefaix MT, ME Szabo-Tosaki & MN Doly (1996): Free radical scavenger properties of EGb 761 on functional disorders induced by experimental diabetic retinopathy. In: RG Cutler, L Packe, J Bertram and A Mori(eds.)| Book Title|. City|. Publisher|: Pages|.

    Eckert A, U Keil, S Kressmann & et al (2003): Effects of EGb 761 Ginkgo biloba extract on mitochondrial function and oxidative stress. Pharmacopsychiatry 36 Suppl 1: S15-23.

    Eckert A, U Keil, I Scherping & et al (2005): Stabilization of mitochondrial membrane potential and improvement of neuronal energy metabolism by Ginkgo biloba extract EGb 761. Ann NY Acad. Sci 1056: 474- 485.

    Ernst E, PH Canter & JT Coon (2005): Does Ginkgo biloba increase the risk of bleeding? A systemic review of case reports. Perfusion 18: 52-6.

    Grieshaber MC & J Flammer (2005): Blood flow in glaucoma. Curr Opin Ophthalmol 16: 79-83.

    Guidetti C, S Paracchini, S Lucchini & et al (2001): Prevention of neuronal cell damage induced by oxidative stress in vitro: effect of different Ginkgo biloba extracts. J Pharmacy Pharmacol 53: 387-392.

    Haramaki N, S Aggarwal, T Kawabata, MT Droy-Lefaix & L Packer (1994): Effects of natural antioxidant Ginkgo biloba extract (EGb 761). on myocardial ischemia-reperfusion injury. Free Radic Biol Med 16: 789-794.

    Henry E, DE Newby, DJ Webb, PW Hadoke & CJ O'Brien (2006): Altered endothelin-1 vasoreactivity in patients with untreated normal-pressure glaucoma. Invest Ophthalmol Vis Sci 47: 2528-32.

    Hirooka K, M Tokuda, O Miyamoto & et al (2004): The Ginkgo biloba extract (EGb 761) provides neuroprotective effect on retinal ganglion cells in a rat model of chronic glaucoma. Curr Eye Res 28: 153-157.

    Izzo AA & E Ernst (2009): Interaction between herbal medicines and prescribed drugs. An updated systematic review. Drugs 69: 1777-1798.

    Janssens D, E Delaive, J Remacle & C Michiels (2000): Protection by bilobalide of the ischaemia-induced alterations of the mitochondrial respiratory activity. Fundam Clin Pharmacol 14: 193-201.

    Jia LY, L Sun, DS Fan & et al (2008): Effect of topical Ginkgo biloba extract on steroid-induced changes in the trabecular meshwork and intraocular pressure. Arch Ophthalmol 126: 1700-1706.

    Kobuchi H, MT Droy-Lefaix, Y Christen & L Packer (1997): Ginkgo biloba extract (EGb 761): Inhibitory effect on nitric oxide production in the macrophage cell line RAW 264.7. Biochem Pharmacol 53: 897-904.

    Koch E (2005): Inhibition of platelet activating factor (PAF)-induced aggregation of human thrombocytes by ginkgolides: considerations on possible bleeding complications

    after oral intake of Ginkgo biloba extracts. Phytomedicine 12: 10-16.

    Köse K & P Dogan (1995): Lipoperoxidation induced by hydrogen peroxide in human erythrocyte membranes. 2. Comparison of the antioxidant effect of Ginkgo biloba extract (EGb 761) with those of water-soluble and lipid-soluble antioxidants. J Int Med Res 23: 9-18.

    Lu G, Y Wu, YT Mak & et al (2006): Molecular evidence of the neuroprotective effect of Ginkgo biloba (EGb761) using bax/bcl-2 ratio after brain ischemia in senescence-accelerated mice, strain-prone 8. Brain Res 1090: 23-8.

    Ma K, L Xu, H Zha & et al (2009): Dosage dependence of the effect of Ginkgo biloba on the rat retinal ganglion cell survival after optic nerve crush. Eye 23: 1598-1604.

    Ma K, L Xu, H Zhang & et al (2009): The effect of ginkgo biloba on the rat retinal ganglion cell survival in the optic nerve crush model. Acta Ophthalmol Epub Aug 14.

    Marcocci L, JJ Maguire, MT Droy-Lefaix & L Packer (1994): The nitric oxide-scavenging properties of Ginkgo biloba extract (EGb 761). Biochem Biophys Res Commun 201: 748-755.

    Meyniel G, M Doly, M Millerin & P Braquet (1992): Involvement of PAF (Platelet-Activating Factor) in chloroquine-induced retinopathy. C R Acad Sci III 314: 61-5.

    Muir AH, R Robb, M McLaren, F Daly & JJ Belch (2002): The use of Ginkgo biloba in Raynaud's disease: a double-blind placebo-controlled trial. Vasc Med 7: 265-7.

    Nicolela MT, SN Ferrier, CA Morrison & et al (2003): Effects of cold-induced vasospasm in glaucoma: the role of endothelin-1. Invest Ophthalmol Vis Sci 44: 2565-72.

    Oyama Y, PA Fuchs, N Katayama & K Noda (1994): Myricetin and quercetin, the flavonoid constituents of Ginkgo biloba extract, greatly reduce oxidative metabolism in both resting and Ca(2+)-loaded brain neurons. Brain Res 635: 125-129.

    Pierre S, I Jamme, MT Droy-Lefaix & et al (1999): Ginkgo biloba extract (EGb 761) protects NaK-ATPase activity during cerebral ischemia in mice. NeuroReport 10: 47-51.

    Punkt K, K Welt & L Schaffranietz (1995): Changes of enzyme activities in the rat myocardium caused by experimental hypoxia with and without ginkgo biloba extract EGb 761 pretreatment. A cytophotometrical study. Acta Histochem 97: 67-79.

    Quaranta L, S Bettelli, MG Uva & et al (2003): Effect of Ginkgo biloba extract on pre-existing visual field damage in normal tension glaucoma. Ophthalmology 110: 359-364.

    Raabe A, M Raabe & P Ihm (1991): Therapeutic follow-up using automatic perimetry in chronic cerebroretinal ischemia in elderly patients. Prospective double-blind study with graduated dose Ginkgo biloba treatment. Klin Monatsbl Augenheilkd 199: 432-438.

    Ranchon I, JM Gorrand, J Cluzel, MT Droy-Lefaix & M Doly (1999): Functional protection of photoreceptors from light-induced damage by dimethylthiourea and Ginkgo biloba extract. Invest Ophthalmol Vis Sci 40: 1191-1199.

    Ritch R (2000): A potential role for Ginkgo biloba extract in the treatment of glaucoma. Medical Hypotheses 54: 221-235.

    Sastre J, A Lloret, C Borras & et al (2002): GBE EGb 761 protects against mitochondrial aging in the brain and in the liver. Cell Mol Biol 48: 685-692.

    Satoh H & S Nishida (2004): Electropharmacological actions of Ginkgo biloba extract on vascular smooth and heart muscles. Clin Chim Acta 342: 13--22.

    Savovic´ J, B Wider & E Ernst (2005): Effects of Ginkgo biloba on blood coagulation parameters: a systematic review of randomised clinical trials. Evid Based Integrative Med 2: 167-76.

    Smith PF, K Maclennan & CL Darlington (1996): The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationshiop to platelet-activating factor (PAF). J Ethnopharmacol 50: 131-139.

    Su WW, ST Cheng, TS Hsu & WJ Ho (2006): Abnormal flow-mediated vasodilation in normal-tension glaucoma using a noninvasive determination for peripheral endothelial dysfunction. Invest Ophthalmol Vis Sci 47: 3390-4.

    Szabo ME, MT Droy-Lefaix, M Doly & P Braquet (1993): Modification of ischemia/reperfusion-induced ion shifts (Na+, K+, Ca2+ and Mg2+ by free radical scavengers in the rat retina. Ophthalmic Res 25: 1.

    Wimpissinger B, F Berisha, G Garhoefer & et al (2007): Influence of Gingko biloba on ocular blood flow. Acta Ophthalmol Scand 85: 445-9.

    Wu WR & XZ Zhu (1999): Involvement of monoamine oxidase inhibition in neuroprotective and neurorestorative effects of Ginkgo biloba extract against MPTP-induced nigrostriatal dopaminergic toxicity in C57 mice. Life Sci 65: 157-164.

    Xie Z, X Wu, Y Gong & et al (2007): Intraperitoneal injection of Ginkgo biloba extract enhances antioxidation ability of retina and protects photoreceptors after light-induced retinal damage in rats. Curr Eye Res 32: 471-9.

    Zhou LJ & XZ Zhu (2000): Reactive oxygen species-induced apoptosis in PC12 cells and protective effect of bilobalide. J Pharmacol Exp Ther 293: 982-988.

    Zhou W, H Chai, A Courson & et al (2006): Ginkgolide A attenuates homocysteine-induced endothelial dysfunction in porcine coronary arteries. J Vasc Surg 44: 853-62.

    Zhu L, J Wu, H Liao, J Gao, XN Zhao & ZX Zhang (1997): Antagonistic effects of extract from leaves of Ginkgo biloba on glutamate neurotoxicity. Acta Pharmacol Sinica 18: 344-347.





    Robert Ritch, MD.



    Grape seed proanthocyanidins have a broad spectrum of pharmacological

    and medicinal properties against oxidative stress. Grape seed proanthocyanidin extract (GSE) provides excellent protection against free radicals in both in vitro and in vivo models.(Bagchi et al. 2002) GSE-induced improvement in myocardial ischemia-reperfusion injury in vitro has been reported.(Pataki et al. 2002; Bagchi et al. 2003; Shao et al. 2003) Activin, a new generation antioxidant derived from grape seed proanthocyanidins, reduces plasma levels of oxidative stress and adhesion molecules (ICAM-1, VCAM-1 and E-selectin) in patients with systemic sclerosis.(Kalin et al. 2002) Supplementation of a meal with GSE minimizes postprandial oxidative stress by increasing the antioxidant levels in plasma, and, as a consequence, enhancing the resistance to oxidative modification of low density lipoproteins.(Natella et al. 2002) Grape seed proanthocyanidins have also been reported to have activity against HIV-1 entry into cells.(Nair et al. 2002) Grape seed extract has recently been shown to inhibit the growth of prostate cancer cells in mice.(Raina et al. 2007) In the eye, GSE inhibits key components of cataractogenesis by reducing oxidative stress within lens epithelial cells.(Barden et al. 2008) and significantly prevents and postpones development of cataract formation in rats with hereditary cataracts.(Yamakoshi et al. 2002)



    Robert Ritch, MD.



    Resveratrol (3,5,40-trihydroxystilbene), a powerful polyphenolic antioxidant, is found largely in the skins of red grapes and berries and came to scientific attention as a possible explanation for the low incidence of heart disease among the French, who eat a relatively high-fat diet (the French paradox). Many studies suggest that consuming alcohol (especially red wine) may reduce the incidence of coronary heart disease (CHD). Grape juice, which is not a fermented beverage, is not a significant source of resveratrol. A large number of studies in the past few years suggests its benefit in vitro and in vivo in a variety of human disease models, including cardioprotection, neuroprotection, immune regulation, and cancer chemoprevention. For an extensive review, see (Pervaiz & Holme 2009). Substantial data show that actions of resveratrol include inhibition of lipid peroxidation and platelet aggregation, metal chelating (primarily copper), free radical–scavenging activity, antiinflammatory activity, modulation of lipid metabolism, antifungal properties, and anticancer and estrogen-like activity.(Pervaiz & Holme 2009)


    Resveratrol increases the lifespan of the yeast, Saccharomyces cerevisiae, the nematode, Caenorhabditis elegans, and the fruitfly, Drosophila melanogaster. It was later shown to extend the lifespan of the short-lived fish, Nothobranchius furzeri,(Valenzano & Cellerino 2006) and has now been shown to significantly increase the health and survival of mice on a high-calorie diet, pointing to a new approach to treating diseases of aging.(Baur et al. 2006) Among its multiple functions, resveratrol activates sirtuins (silent information regulator proteins), a family of proteins that play an important role in DNA repair, gene silencing, chromosomal stability and longevity.(Michan & Sinclair 2007)


    The physiologic effects of resveratrol appear to be related to its ability to regulate nutrition and longevity genes.(Pervaiz & Holme 2009) Resveratrol is an effective antioxidant.(Frankel et al. 1993; Chanvitayapongs et al. 1997; Shigematsu et al. 2003) It inhibits lipid peroxidation of low-density lipoprotein (LDL), prevents the cytotoxicity of oxidized LDL, and protects cells against lipid peroxidation.(Chanvitayapongs et al. 1997) Resveratrol protects against the degeneration of neurons after axotomy.(Araki et al. 2004) A single infusion of resveratrol can elicit neuroprotective effects on cerebral ischemia-induced neuron damage through free radical scavenging and cerebral blood elevation due to nitric oxide release.(Lu et al. 2006) Its antiapoptotic activity has led to the suggestion that resveratrol may make a useful dietary supplement for minimizing oxidative injury in immune-perturbed states and human chronic degenerative diseases.(Losa 2003)


    Levels of intracellular heme (iron-protoporphyrin IX), a pro-oxidant, increase after stroke. In neuronal cell cultures, resveratrol induces heme oxygenase 1, suggesting that increased heme oxygenase activity is a unique pathway by which resveratrol can exert its neuroprotective actions.(Zhuang et al. 2003)


    Resveratrol directly inhibits CYP1B1. The versatility of RSV lies in its diverse targeting of membrane and intracellular receptors, signaling molecules, biogenesis enzymes, oxidative systems, DNA-repair mechanisms, and transcription factors, and it can activate or repress a number of signal-transducing pathways found throughout the cell (Pervaiz & Holme 2009)


    There appears to be an association between aging and neurodegenerative diseases, such as Alzheimer’s, and that modulation by both caloric restriction and drugs which mimic caloric restriction, such as resveratrol, can ameliorate these diseases.(Liu et al. 2007) Resveratrol reduces the levels of secreted and intracellular amyloid-ß peptides by proteosomal degradation.(Marambaud et al. 2005)


    In the eye, resveratrol suppresses selenite-induced oxidative stress and cataract formation in rats.(Doganay et al. 2006) The authors suggested that the presence of oxidative stress in selenite cataract development and its prevention by resveratrol support the possibility that high natural consumption of resveratrol in food can help prevent human senile cataract. Resveratrol also induces dilation of retinal arterioles, suggesting a potential benefit for this compound in the treatment of retinal vascular disease.(Nagaoka et al. 2007) Sirtuin-1 activators (such as resveratrol) demonstrate neuroprotective properties in mouse models of optic neuritis and multiple sclerosis.(Shindler et al. 2007)




    Araki T, Y Sasaki & J Milbrandt (2004): Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 305: 954-5.

    Bagchi D, M Bagchi, S Stohs & et al (2002): Cellular protection with proanthocyanidins derived from grape seeds. Ann N Y Acad Sci 957: 260-270.

    Bagchi D, CK Sen, SD Ray & et al (2003): Molecular mechanisms of cardioprotection by a novel grape seed proanthocyanidin extract. Mutat Res 523-524: 87-97.

    Barden CA, HL Chandler, P Lu & et al (2008): Effect of grape polyphenols on oxidative stress in canine lens epithelial cells. Am J Vet Res 69: 94-100.

    Baur JA, KJ Pearson, NL Price & et al (2006): Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444: 337-342.

    Chanvitayapongs S, B Draczynska-Lusiak & AY Sun (1997): Amelioration of oxidative stress by antioxidants and resveratrol in PC12 cells. Neuroreport 8: 1499-1502.

    Doganay S, M Borazan, M Iraz & Y Cigremis (2006): The effect of resveratrol in experimental cataract model formed by sodium selenite. Curr Eye Res 31: 147-53.

    Frankel EN, AL Waterhouse & JE Kinsella (1993): Inhibition of human LDL oxidation by resveratrol. Lancet 341: 1103-1104.

    Kalin R, A Righi, A Del Rosso & et al (2002): Activin, a grape seed-derived proanthocyanidin extract, reduces plasma levels of oxidative stress and adhesion molecules (ICAM-1, VCAM-1 and E-selectin) in systemic sclerosis. Free Radical Res 36: 819-825.

    Liu Q, F Xie, R Rolston & et al (2007): Prevention and treatment of Alzheimer disease and aging: antioxidants. Mini Rev Med Chem 7: 171–180.

    Losa GA (2003): Resveratrol modulates apoptosis and oxidation in human blood mononuclear cells. Eur J Clin Invest 33: 818-823.

    Lu KT, RY Chiou, LG Chen & et al (2006): Neuroprotective effects of resveratrol on cerebral ischemia-induced neuron loss mediated by free radical scavenging and cerebral blood flow elevation. J Agric Food Chem 54: 3126-31.

    Marambaud P, H Zhao & P Davies (2005): Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides. J Biol Chem 280: 37377–82.

    Michan S & D Sinclair (2007): Sirtuins in mammals: Insights into their biological function. Biochem J 404: 1–13.

    Nagaoka T, TW Hein, A Yoshida & et al (2007): Resveratrol, a component of red wine, elicits dilation of isolated porcine retinal arterioles: role of nitric oxide and potassium channels. Invest Ophthalmol Vis Sci 48: 4232-9.

    Nair MP, C Kandaswami, S Mahajan & et al (2002): Grape seed extract proanthocyanidins downregulate HIV-1 entry coreceptors, CCR2b, CCR3 and CCR5 gene expression by normal peripheral blood mononuclear cells. Biol Res 35: 421-431.

    Natella F, F Belelli, V Gentili & et al (2002): Grape seed proanthocyanidins prevent plasma postprandial oxidative stress in humans. J Agric Food Chem 50: 7720-7725.

    Pataki T, I Bak, P Kovacs & et al (2002): Grape seed proanthocyanidins improved cardiac recovery during reperfusion after ischemia in isolated rat hearts. Am J Clin Nutrition 75: 894-899.

    Pervaiz S & AL Holme (2009): Resveratrol: Its Biologic Targets and Functional Activity. Antioxidants Redox Signaling 11: 2851-2897.

    Raina K, RP Singh, R Agarwal & C Agarwal (2007): Oral grape seed extract inhibits prostate tumor growth and progression in TRAMP mice. Cancer Res 67: 5976-82.

    Shao ZH, LB Becker, TL Vanden Hoek & et al (2003): Grape seed proanthocyanidin extract attenuates oxidant injury in cardiomyocytes. Pharmacol Res 47: 463-469.

    Shigematsu S, S Ishida, M Hara & et al (2003): Resveratrol, a red wine constituent polyphenol, prevents superoxide-dependent inflammatory responses induced by ischemia/reperfusion, platelet-activating factor, or oxidants. Free Radic Biol Med 34: 810-817.

    Shindler KS, E Verntura, TS Rex & et al (2007): SIRT1 activation confers neuroprotection in experimental optic neuritis. Invest Ophthalmol Vis Sci 48: 3602-9.

    Valenzano DR & A Cellerino (2006): Resveratrol and the pharmacology of aging: a new vertebrate model to validate an old molecule. Cell Cycle 5: 1027-32.

    Yamakoshi J, M Saito, S Kataoka & S Tokutake (2002): Procyanidin-rich extract from grape seeds prevents cataract formation in hereditary cataractous (ICR/f) rats. J Agric Food Chem 50: 4983-4988.

    Zhuang H, YS Kim, RC Koehler & S Dore (2003): Potential mechanism by which resveratrol, a red wine constituent, protects neurons. Ann N Y Acad Sci 993: 276-286.






    Robert Ritch, MD.



    Pycnogenol, an extract of French maritime pine bark (Pinus pinaster), is primarily composed of procyanidins and phenolic acids and is a potent antioxidant with strong free radical-scavenging activity against reactive oxygen and nitrogen species. Procyanidins are biopolymers of catechin and epicatechin subunits, which are important in human nutrition.(Rohdewald 2002)

    Pycnogenol is effective in patients with venous microangiopathy (Cesarone et al. 2006) (Cesarone et al. 2006) and accelerates healing in leg ulcerations from chronic venous insufficiency(Belcaro et al. 2005) and diabetes.(Belcaro et al. 2006) In chronic venous insufficiency, pycnogenol reduced lower leg circumference and symptoms of pain, cramps, nighttime swelling, feeling of "heaviness", and reddening of the skin.(Koch 2002) Pycnogenol can protect vascular endothelial cells from Aß-induced injury.(Liu et al. 2000) It reversed elevation of serum creatinine, BUN, LDH, IL-1beta, IL-6, and TNF-alpha levels in ischemia reperfusion injury in unilaterally nephrectomized rats.(Ozer Sehirli et al. 2009)

    Pretreatment with pycnogenol reduces smoke-induced platelet aggregation.(Araghi-Niknam et al. 2000) Pycnogenol significantly reduces LDL-cholesterol levels.(Devaraj et al. 2002; Koch 2002) A randomized controlled trial reported it effective for erectile dysfunction.(Stanislavov et al. 2007) It has also been reported to improve symptoms of jet lag.(Belcaro et al. 2008) It inhibits inhibits not only HIV-1 binding to host cells, but also its replication after entry in susceptible cells in vitro.(Feng et al. 2008) It has been reported to increase urinary catecholamines and ameliorate attention deficit hyperactivity disorder in children.(Dvoráková et al. 2007)


    After oral administration of pycnogenol, plasma samples significantly inhibited NFkB activation and MMP-9 release from human monocytes, indicating that it exerts anti-inflammatory effects by inhibiting proinflammatory gene expression.(Grimm et al. 2006) Glutamate inhibits cyclo-oxygenases 1 and 2.(Schafer et al. 2006) This cytotoxicity was inhibited by both GBE and pycnogenol.(Kobayashi et al. 2000) Pycnogenol not only suppresses the generation of reactive oxygen species, but also attenuates caspase-3 activation and DNA fragmentation, suggesting protection against Aß-induced apoptosis.(Peng et al. 2002)


    Pycnogenol has also been reported to inhibit angiotensin-converting enzyme and to enhance the microcirculation by increasing capillary permeability.(Packer et al. 1999) It inhibits progression of preproliferative diabetic retinopathy(Schonlau & Rohdewald 2001) and may reduce the risk of formation of both diabetic retinopathy and cataract.(Kamuren et al. 2006) More recently, in patients with mild to moderate retinal edema, pycnogenol treatment significantly improved both the edema and retinal thickness as measured by high resolution ultrasound.(Steigerwalt et al. 2009) Laser Doppler flow velocity measurements at the central retinal artery showed a statistically significant increase from 34 to 44 cm/s in the Pycnogenol group as compared to marginal effects in the control group.(Steigerwalt et al. 2009)


    Steigerwalt et al(Steigerwalt et al. 2008) evaluated the effects of the food supplement Mirtogenol (Mirtoselect and Pycnogenol on IOP and ocular blood flow in 20 subjects versus 18 controls. After three months of treatment, the IOP was lowered compared to that of untreated controls from a baseline of 25.2 mmHg to 22.0 mmHg (p<0.05). Ocular blood flow (central retinal, ophthalmic, and posterior ciliary arteries) improved both in the systolic and diastolic components as measured by Color Doppler imaging.



    Araghi-Niknam M, S Hosseini, D Larson, P Rohdewald & RR Watson (2000): Pine bark extract reduces platelet aggregation. Integrative Med 2: 73-77.

    Belcaro G, MR Cesarone, BM Errichi & et al (2005): Venous ulcers: microcirculatory improvement and faster healing with local use of Pycnogenol. Angiology 56: 56.

    Belcaro G, MR Cesarone, BM Errichi & et al (2006): Diabetic ulcers: microcirculatory improvement and faster healing with pycnogenol. Clin Appl Thromb Hemost 12: 318-23.

    Belcaro G, MR Cesarone, RJ Steigerwalt & et al (2008): Jet-lag: prevention with Pycnogenol. Preliminary report: evaluation in healthy individuals and in hypertensive patients. Minerva Cardioangiol 56(5 Suppl): 3-9.

    Cesarone MR, G Belcaro, P Rohdewald & et al (2006): Improvement of diabetic microangiopathy with pycnogenol: A prospective, controlled study. Angiology 57: 431-6.

    Cesarone MR, G Belcaro, P Rohdewald & et al (2006): Rapid relief of signs/symptoms in chronic venous microangiopathy with pycnogenol: a prospective, controlled study. Angiology 57: 569-76.

    Devaraj S, S Vega-Lopez, S Kaul N, F., P Rohdewald & I Jialal (2002): Supplementation with a pine bark extract rich in polyphenols increases plasma antioxidant capacity and alters the plasma lipoprotein profile. Lipids 37: 931-934.

    Dvoráková M, D Jezová, P Blazícek & et al (2007): Urinary catecholamines in children with attention deficit hyperactivity disorder (ADHD): modulation by a polyphenolic extract from pine bark (pycnogenol). Nutr Neurosci 10: 151-7.

    Feng WY, R Tanaka, Y Inagaki & et al (2008): Pycnogenol, a procyanidin-rich extract from French maritime pine, inhibits intracellular replication of HIV-1 as well as its binding to host cells. Jpn J Infect Dis 61: 279-85.

    Grimm T, Z Chovanova, J Muchova & et al (2006): Inhibition of NF-kappaB activation and MMP-9 secretion by plasma of human volunteers after ingestion of maritime pine bark extract (Pycnogenol). J Inflamm (Lond) 27: 1.

    Kamuren ZT, CG McPeek, RA Sanders & JB Watkins, 3rd. (2006): Effects of low-carbohydrate diet and Pycnogenol treatment on retinal antioxidant enzymes in normal and diabetic rats. J Ocul Pharmacol Ther 22: 10-18.

    Kobayashi MS, D Han & L Packer (2000): Antioxidants and herbal extracts protect HT-4 neuronal cells against glutamate-induced cytotoxicity. Free Radic Res 32: 115-124.

    Koch R (2002): Comparative study of Venostasin and Pycnogenol in chronic venous insufficiency. Phytother Res 16 Suppl 1: S1-5.

    Liu F, BH Lau, Q Peng & V Shah (2000): Pycnogenol protects vascular endothelial cells from beta-amyloid-induced injury. Biol Pharm Bull 23: 735-737.

    Ozer Sehirli A, G Sener & F Ercan (2009): Protective effects of pycnogenol against ischemia reperfusion-induced oxidative renal injury in rats. Ren Fail 31: 690-7.

    Packer L, G Rimbach & F Virgili (1999): Antioxidant activity and biologic properties of a procyanidin-rich extract from pine (Pinus maritima) bark, pycnogenol. Free Radic Biol Med 27: 704-24.

    Peng QL, AR Buz'Zard & BH Lau (2002): Pycnogenol((R)) protects neurons from amyloid-beta peptide-induced apoptosis. Brain Res Mol Brain Res 104: 55-65.

    Rohdewald P (2002): A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther 40: 158-68.

    Schafer A, Z Chovanova, J Muchova & et a (2006): Inhibition of COX-1 and COX-2 activity by plasma of human volunteers after ingestion of French maritime pine bark extract (Pycnogenol). Biomed Pharmacother 60: 5-9.

    Schonlau F & P Rohdewald (2001): Pycnogenol for diabetic retinopathy. A review. Int Ophthalmol 24: 161-171.

    Stanislavov R, V Nikolova & P Rohdewald (2007): Improvement of erectile function with Prelox: a randomized, double-blind, placebo-controlled, crossover trial. Int J Impot Res Aug 16; [Epub ahead of print].

    Steigerwalt R, G Belcaro, MR Cesarone & et al (2009): Pycnogenol improves microcirculation, retinal edema, and visual acuity in early diabetic retinopathy. J Ocul Pharmacol Ther 25: 537-40.

    Steigerwalt RD, B Gianni, M Paolo & et al (2008): Effects of Mirtogenol on ocular blood flow and intraocular hypertension in asymptomatic subjects. Mol Vis 14: 1288-1292.




    Fish Oil and Omega-3 fatty acids

    Sandra Fernando, MD.



    Omega-3 fatty acids, found most notably in fish oil, include docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). These are long-chain polyunsaturated fatty acids (PUFAs) with an 18-carbon chain precursor that cannot be synthesized by mammals. Therefore, these fatty acids must be obtained through diet or supplementation. Once omega-3 fatty acids are ingested, they undergo elongation and desaturation to form long-chain metabolites that can eventually become incorporated into cell membranes.(Moyad 2005) DHA has many diverse functions at the cellular level including enzyme regulation, membrane fluidity, regulation of ion channels and signal transduction.(Chapkin et al. 2008)


    Fish Oil, Omega-3 Fatty Acids, and Glaucoma

    Aqueous production involves membrane-bound pumps and receptors. Omega-3 deficiency can affect membrane-bound protein activity in rats (Gerbi et al. 2008) and therefore may affect aqueous production. Increasing dietary omega-3 in mice reduces IOP by increasing outflow facility (Nguyen et al. 2007) and diets with increased omega-3 and decreased omega-6 PUFA’s may favor increased synthesis of PG-F2.(Desmettre et al. 2005) In rabbits, intramuscular cod liver oil lowered IOP by 3mmHg at 0.2 ml/day, and 6.5mmHg at 1 ml/day. When treatment with cod liver oil was stopped, IOP rose to baseline levels. (Mancino et al. 1992) However, human studies investigating dietary fat consumption and primary open-angle glaucoma (POAG) showed that a high ratio of dietary omega-3 to omega-6 polyunsaturated fat consumption appears to increase the risk of POAG.(Kang et al. 2004) The trabecular meshwork in glaucoma is also affected by oxidative stress related changes such as cell loss, increased accumulation of extracellular matrix (ECM), and cellular senescence, which are minimized with prostaglandin analogue application in vivo.(Yu et al. 2008)

    DHA and EPA play a role in red cell fluidity, deformability, and aggregability. (Popp-Snijders et al. 1996) POAG patients are hypothesized to have enhanced platelet aggregation, (Bojic et al. 2002; Bojic et al. 1989; Hoyng et al. 1992) and EPA is a precursor to eicosanoids, which have vasodilator and antiaggregatory effects.(Von Schacky et al. 1985; Calder 2003) Reduced plasma EPA and DHA were found in glaucoma patients compared to siblings without glaucoma, and it was postulated that EPA and DHA play a role in modulating impaired systemic microcirculation and ocular blood flow in POAG (Ren et al 2006).

    In the retina, DHA has been implicated in modifying enzyme activity in photoreceptor cells and providing an environment for conformational changes in rhodopsin. Decreased retinal DHA content affects visual function in monkeys (Lin et al. 1994; Ritch 2007) and a combination of DHA, vitamin E, and vitamin B were reported to improve contrast sensitivity and visual field indices.(Cellini et a. 1998) In addition, DHA protects cells from oxidative stress by modulating levels of pro- and anti-apoptotic proteins of the Bcl-2 family, which protects photoreceptors from oxidative stress. (Rotstein et al. 2002)

    DHA is also enriched in retinal pigment epithelial cells and is a precursor of neuroprotectin D1 (NPD1), which inhibits retinal pigment epithelial cell apoptosis and inhibits oxidative-stress-mediated pro-inflammatory gene induction.(Bazan 2006) DHA also reduces the activation of kainate receptors in retinal reperfusion after ischemia, and is proposed to have a neuroprotective effect in ischemia-induced retinal injury. In rabbits, intraperitoneal DHA was effective in protecting the retina against IOP-induced transient ischemia. (Miyauchi et al. 2001) In addition, oral administration of DHA in rats counteracted kainic acid-induced retinal neurotoxicity (Mizota et al. 2001) and DHA protected against ischemia-reperfusion related retinal cell death in monkeys, partially by inhibiting the formation of hydroxyl radicals.(Murayama et al. 2002) In rodent eyes with laser photocoagulation-induced increased IOP, glial cell activation was significantly lower and protective effects on retinal structures was significantly higher in animals fed with an omega-3 and omega-6 PUFA combination diet compared to controls and those fed a single supplementation (omega-3 or omega-6) diet (Schnebelen et al. 2009) Lastly, DHA combined with lutein and zeaxanthin promotes rat photoreceptor survival after oxidative damage.(Chucair et al. 2007)


    Dosage and Side Effects

    There are many types of nonprescription dietary supplements of omega-3 fatty acids available. However, none are regulated by the same standards as pharmaceutical agents. (Bruntona et al. 2007) In 2004, the FDA approved a formulation of omega-3-acid ethyl esters to reduce high triglyceride levels, which is a combination of omega-3-acid ethyl esters (P-OM3). It contains concentrated forms of EPA (465 mg), DHA (375 mg) and other omega-3 fatty acids (60 mg) for a total of at least 900 mg of omega-3 fatty acids per each one gram capsule.(Bays et al. 2008) In patients with documented coronary heart disease, the American Heart Association recommends one gram of DHA and EPA for cardiovascular protection.(Kris-Etherton et al. 2002) The best dietary sources of EPA and DHA include fatty fish such as salmon, herring, mackerel, halibut and tuna (Mozaffariah et al. 2006) and also some fresh-water fish such as lake herring, lake trout, freshwater salmon and whitefish. (USDA)

    The most common drug-related adverse events associated with omega 3 fatty acid supplementation include dyspepsia and belching.(Reliant Pharmaceuticals 2007) There are no known, clinically significant drug interactions; however, some reports suggest that omega-3 fatty acids may impair platelet aggregation and increase bleeding times.(Vanschoonbeek et al. 2004; Mueller et al 1988) Omega-3 fatty acid supplementation has also been attributed to increased levels of liver transaminases, (Reliant Pharmaceuticals 2007) and a transient increase in glucose levels.(Bays et al. 2008)

    In conclusion, omega-3 fatty acids play an important role in reducing oxidative damage in the retina, improving ocular blood flow and protecting against retinal ischemia induced by increased IOP.



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    docosahexaenoic acid against retinal ischemic injury: an electroretinographic

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    effects of dietary docosahexaenoic acid against kainite induced retinal

    degeneration in rats. Invest Ophthalmol Vis Sci 42:216-21.

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    general health and prevention: part I. Urol Oncol 23:28-35.

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    evaluating the risks and the benefits. JAMA 296:1885–1899.

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    of omega-3 fatty acids. Clin. Pharm 7:795–807.

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    (polyunsaturated fatty acid) prevents ischemic induced injury in the

    mammalian retina. Exp Eye Res 74:671-676.

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    eicosapentaenoic acids. Prostaglandins, Leukotrienes and Essential Fatty Acids 74:157-163.

    Ritch R (2007): Natural compounds: evidence for a protective role in eye disease.

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    docosahexaenoic acid on oxidative stress-induced apoptosis of retina

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    omega-3 and omega-6 polyunsaturated fatty acids is more efficient than

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    Alpha-Lipoic Acid

    Sandra Fernando, MD.


    Background and pharmacology

    Alpha-lipoic acid is a cofactor in the mitochondrial dehydrogenase complex that catalyzes the oxidative decarboxylation of a-keto acids such as pyruvate and á-ketoglutarate.(Osborne 2008; Shay et al. 2009) In this decarboxylation process, á-lipoic acid is reduced to dihydrolipoic acid and the two substances operate as a redox couple. Lipoic acid and dihydrolipoic acid also chelate transition metals and assist in the regeneration of other antioxidants, such as glutathione, α-tocopherol, and ascorbate.(Biewenga et al. 1997) Normally, a-lipoic acid is present in small amounts in mammalian tissue (5-25 nmol/g) and is bound to an enzyme that makes it unavailable as an antioxidant. However, unbound exogenous alpha-lipoic acid has antioxidant effects and can act as a substitute for glutathione.(Packer 1994) Exogenous administration of á-lipoic acid has been shown to reduce ischemic-reperfusion injury in rodent cerebral cortex,(Packer et al. 1997) heart(Freisleben 2000) and peripheral nerve.(Mitsui et al. 1999)


    Alpha-Lipoic Acid and the Eye

    Alpha-lipoic acid exerts potent antioxidant effects in the lens and retina. In the lens, lipoic acid reduces the iron pool from the cytoplasm of lens cells, which increases the cells’ defense against oxidative damage.(Goralska et al. 2003) It also may prevent or slow progression of cataract through mechanisms such as decreasing lens aldose reductase activity and increasing lens glutathione levels.(Maitra et al. 1996; Borenshtein et al. 2001; Kojima et al. 2007)

    In the retina, alpha-lipoic acid decreased the amount of leukostasis in the retinal capillary endothelium in diabetic rats.(Abiko et al. 2003) In experimental diabetes, it corrects decreased retinal ion demand(Berkowitz et al. 2007) and may increase retinal oxygenation.(Roberts et al. 2006) In the diabetic rat retina, abnormal mitochondrial NAD+/NADH ratios and increased 4-hydroxyalkenal levels indicative of hypoxia are ameliorated by treatment with alpha lipoic acid.(Obrosova et al. 2001)

    New hypotheses have emerged about the specific effect of alpha lipoic acid therapy on the pathogenesis of glaucoma. Osborne(Osborne 2008) proposed that decreased blood flow to the optic nerve in glaucoma leads to a compromise in retinal ganglion cell energy requirements, causing the cells to be more susceptible to injury by oxidants (nitric oxide, TNF) released from astrocytes. These effects eventually lead to ganglion cell death because of the inability of mitochondria to maintain normal function. Therefore, agents that specifically enhance ganglion cell mitochondrial energy production and decrease oxidative stress should theoretically be beneficial in a disease such as glaucoma.

    Alpha lipoic acid improved visual function in 45% of glaucoma patients supplemented with lipoic acid(Filina et al. 1995)and two months of alpha lipoic acid supplmentation was found to increase aqueous glutathione levels in POAG patients.(Bunin et al. 1992) In addition, a-lipoic acid supplemenation with vitamin C is believed to increase aqueous humor drainage by reducing the viscosity of trabecular meshwork hyaluronic acid.(Gupta et al. 2008)


    Dosing, Bioavailability, and Side Effects

    Alpha lipoic acid is absorbed by the gastrointestinal tract in a variable manner. After administration of 200 mg a-lipoic acid in humans, only 20-40% is absorbed, which is lowered by its administration in food.(Teichert et al. 1998) After absorption, it rapidly traverses cell membranes in a pH-dependent manner and acts as a substrate for an Na+-dependent multivitamin transporter. Its transport is inhibited by benzoic acid and medium-chain fatty acid(Shay et al. 2009) and it is renally excreted. Alpha-lipoic acid transiently accumulates in the liver, heart, and skeletal muscle, and also crosses the blood-brain barrier.(Harrison & McCormick 1974)

    Dietary sources of a-lipoic acid include muscle meats, heart, kidney, liver, and certain fruits and vegetables.(Akiba et al. 1998) However, it is not likely that a Western diet can achieve levels equivalent to dietary supplements, which range from 50-600 mg.(Shay et al. 2009)

    Alpha-lipoic acid supplementation is not correlated with significant side effects in humans or animals. However, rats were reported to show signs of sedation and apathy after administration of >2 g/kg.(Cremer et al. 2006) In humans, a number of clinical trials used a-lipoic acid supplements up to 2400 mg/day with no reported adverse effects compared to placebo.(Shay et al. 2009)



    Alpha-lipoic acid has powerful antioxidant effects, and can be useful in blocking pathological processes in glaucoma caused by ischemia and oxidation.(Filina et al. 1995; Osborne 2008) However, the lack of clinical trials investigating the benefits of neuroprotective supplements such as a-lipoic acid in glaucoma limits its current use.(Ritch 2007)



    Abiko T, A Abiko, AC Clermont & et al (2003): Characterization of retinal leukostasis and hemodynamics in insulin resistance and diabetes: role of oxidants and protein kinase-C activation. Diabetes 52:829-37.

    Akiba S, S Masugo, L Packer & et al (1998): Assay of protein bound lipoic acid in tissues by a new enzymatic method. Anal Biochem 258:299-304.

    Berkowitz BA, R Roberts, S A. & et al (2007): Impaired apparent ion demand in experimental diabetic retinopathy: correction by lipoic acid. Invest Ophthalmol Vis Sci 48:4753-8.

    Biewenga GP, GR Haenen & A Bast (1997): The pharmacology of the antioxidant lipoic acid. Gen Pharmacol 29:315–331.

    Borenshtein D, R Ofri, M Werman & et al (2001): Cataract development in diabetic sand rats treated with alpha-lipoic acid and its gamma-linolenic acid conjugate. Diabetes Metab Res Rev 17:44-50.

    Bunin AI, AA Filina & VP Erichev (1992): A glutathione deficiency in open-angle glaucoma and the approaches to its correction. Vestn Oftalmol 108:13-5.

    Cremer DR, R Rabeler, A Roberts & et al (2006): Long-term safety of alpha-lipoic acid. Regul Toxicol Pharmacol 46:29-41.

    Filina AA, NG Davydova, SN Endrikhovskii & e al (1995): Lipoic acid as a means of metabolic therapy of open-angle glaucoma. Vestn Oftalmol 11:6-8.

    Freisleben HJ (2000): Lipoic acid reduces ischemia-reperfusion injury in animal models. Toxicology 148:159–171.

    Goralska M, R Dackor, B Holley & MC McGahan (2003): Alpha lipoic acid changes iron uptake and storage in lens epithelial cells. Exp Eye Res 76:241-8.

    Gupta SK, DG Niranjan, SS Agrawal & et al (2008): Recent advances in pharmacotherapy of glaucoma. Indian J Pharmacol 40:197-208.

    Harrison EH & D McCormick (1974): The metabolism of d1-(1,6-14C)lipoic acid in the rat. Arch Biochem Biophys 160:514-522.

    Kojima M, L Sun, I Hata & et al (2007): Efficacy of alpha-lipoic acid against diabetic cataract in rat. Jpn J Ophthalmol 51:10-13.

    Maitra I, E Serbinova, HJ Tritschler & L Packer (1996): Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract formation in newborn rats. Biochem Biophys Res Commun 221:422-9.

    Mitsui Y, JD Schmelzer & PJ Zollman (1999): Alpha-lipoic acid provides neuroprotection from ischemia-reperfusion injury of peripheral nerve. J Neurol Sci. 163:11–16.

    Obrosova IG, MJ Stevens & HJ Lang (2001): Diabetes-induced changes in retinal NAD-redox status: pharmacological modulation and implications for pathogenesis of diabetic retinopathy. Pharmacology 62: 172–180.

    Osborne NN (2008): Pathogenesis of ganglion "cell death" in glaucoma and neuroprotection: focus on ganglion cell axonal mitochondria. Prog Brain Res 173: :339-352.

    Packer L (1994): Antioxidant properties of lipoic acid and its therapeutic effects in

    prevention of diabetes complications and cataracts. A. nn N Y Acad Sci 738: 257-264.

    Packer L, HJ Tritschler & K Wessel (1997): Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med. 22: 359–378.

    Ritch R (2007): Natural compounds – Evidence for a protective role in eye disease. Canad J Ophthalmol 42: 425-438.

    Roberts R, H Luan & BA Berkowitz (2006): Alpha-lipoic acid corrects late-phase supernormal retinal oxygenation response in experimental diabetic retinopathy. Invest Ophthalmol Vis Sci 47: 4077-4082.

    Shay KP, RF Moreau, EJ Smith & et al (2009): Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential. Biochim Biophys Acta 1790: 1149-1160.

    Teichert J, J Kern, H Tritschler & et al (1998): Investigations on the pharmacokinetics of alpha-lipoic acid in healthy volunteers. Int J Clin Pharmachol Ther 36: 625-628.




    Soy sauce

    Aiko Iwase, MD., Ph.D.


    Soy sauce is a widely used fermented seasoning in Asian countries and more recently, world wide. Phytochemicals, as antioxidants and anti-inflammatory agents, may help prevent or delay the progression of age related changes.(Rhone & Basu 2008) Isoflavones are the flavonoids of soy beans, and are reported to significantly reduce serum total cholestrerol and tryacylglycerol and significantly increase HDL cholesterol.(Zhan & Ho 2005) These beneficial attributes of isoflavone have been adopted for the preventive strategies against cardiovascular and arterioscrelotic disease. Studies using nuclear magnetic resonance and electrospray-ionization time-of-flight mass spectrometry analysis suggest that carbohydrate-containing pigments such as melanoidins are the major contributors to the high antioxidant capacity of dark soy sauce.(Wang et al. 2007)

    Various soybean materials obtained in soy processing and products (miso, natto, soy sauce, etc.), include 5 isoflavones - daidzin, glycitin, genistin, daidzein and genistein - but soy sauce contains little of them, while soy sauce oil richly contains daidzein and genistein.(Nishikawa 2008) Deregulated apoptotic mechanisms have been implicated in many pathologic human neurological disorders, including glaucoma. In cerebellar granule cells, genistein and daizein suppressed low potassium-dependent apoptosis at doses of 0.1-20 μM, and survival was about 70% in the presence of 20 μM genistein and about 60% in the presence of 20 μM daizein.(Atlante et al. 2010)

    The manufacturing process and the composition of the starting ingredients differs between countries, and it is likely that differences in the raw materials, fermentation time and heating processes used during the manufacture of soy sauce may affect the composition and antioxidant activity of the final products.(Long et al. 2000) Soy sauce should be considered as a flavoring or seasoning, but not as a functional food, since it contains a relatively high concentration of sodium chloride, but little isoflavone.(Ishii & Koyama 2004; Nishikawa 2008)



    Atlante A, A Bobba, G Paventi, R Pizzuto & S Passarella (2010): Genistein and daidzein prevent low potassium-dependent apoptosis of cerebellar granule cells. Biochemical Pharmacology 79: 758-767.

    Ishii S & T Koyama (2004): Soy sauce - old and new panacea seasoning. J Brewing Society of Japan 99: 218-224.

    Long LH, DC Kwee & B Halliwell (2000): The antioxidant activities of seasonings used in Asian cooking. Powerful antioxidant activity of dark soy sauce revealed using the ABTS assay. Free Radic Res 32: 181–186.

    Nishikawa K (2008): Science of Functional Food. Tokyo. Tech Information S.C. Ltd: 616-617

    Rhone M & A Basu (2008): Phytochemicals and age-related eye disease. Nutrition Reviews 66: 465-472.

    Wang H, AM Jenner, CJ Lee & et al (2007): The identification of antioxidants in dark soy sauce. Free Radical Res 41: 479-488.

    Zhan S & SC Ho (2005): Meta-analysis of the effects of soy protein containing isoflavones on the lipid profile. Am J Clin Nutr 81: 397-408.



    Green Tea

    Aiko Iwase, MD., Ph.D.


    The botanical name of the tea plant is Camellia sinensis. The small-leaf Chinese variety is named Camellia sinensis var. sinensis and the large-leaf black tea discovered in India is named Camellia sinensis var. assamica. In the 8th century, during the Tang Dynasty, Buddhist monks or Japanese envoys are thought to have brought the small-leaf Chinese variety to Japan and thus tea trees cultivated in Japan are Camellia sinensis var. sinensis.(Kakuda 2002) Green tea produced in Japan is mainly produced by steaming and is unfermented, while oolong tea is half-fermented and black tea is full-fermented. Major chemical components (% of dry weight) of green tea are catechins (9.4-16.2%), theanine (0.5-2.4%), caffeine (2.1-4.0%) and vitamin C (0.1-0.4%).(Goto et al. 1996)



    Theanine is a glutamate analogue. A high concentration of theanine (500 μM) reduced glutamate-induced death of cultured rat cortical neurons, suggesting a neuroprotective effect of on glutamate toxicity.(Nozawa et al. 1998) In postischemic neuronal death in field CA1 of the gerbil hippocampus, theanine solution given at a dose of 125 and 500 μM significantly suppressed CA1 neuron damage by 60 and 90%, respectively.(Kakuda 2002) The mechanism of this neuroprotective action may be at least partly attributed to its mild affinity to NMDA and /or AMPA /kainate receptors.(Kakuda et al. 2002)

    Since IC50 values for theanine to these receptors are relatively high, other mechanisms, such as effects on the glutamate transporter, were suggested.(Kakuda 2002) Theanine is absorbed in the intestinal tract, reaching a peak at 0.5-2hours after oral administration.(Yokogoshi et al. 1998; Unno et al. 1999) A recent study showed that oral intake of l-theanine at a dose of 2 and 4 mg/kg attenuated Abeta(1-42)-induced memory impairment in mice, possibly by suppression of ERK/ P38 and NF-kB, as well as the reduction of oxidative damage.(Kim et al. 2009)



    Catechins are the main bioactive constituents of green tea leaves and consist of 8 polyphenolic flavonoid-type compounds; (+)-catechin (C) (-)-epicatechin(EC ), (+)-gallo-catechin(GC), (-)-epigallocatechin(EGC), (+)-gallocatechin(GC), (-)-epigallocatechin(ECG), (+)-gallocatechin gallete(GCG), and (-)-epigallocatechin gallate(EGCG).(Sutherland et al. 2006) EGCG is the most abundant of tea catechins and thought to be responsible for the most of biological activity of green tea.(Kimura et al. 2002) According to Kuroda and Hara, green tea contains C, EC, ECG, EGC and EGCG at concentrations of 21, 98, 90, 411 and 444 mg/L respectively.(Kuroda & Hara 1999)

    Epidemiologial studies have suggested potential relationship between green tea drinking and many types of cancer.(Kohlmeier et al. 1997; Chow et al. 1999; Arab & Il’yasova 2003; Borrelli et al. 2004) Further, green tea drinking was reportedly inversely associated with coronary atherosclerosis(Sasazuki et al. 2000) and cerebrovascular diseases.(Sato et al. 1989) However, it must be noted that there are conflicting reports on whether the most effective source of catechins is tea or fruit.(Arts et al. 2001; Tabak et al. 2001)

    Mechanism of catechin action include free radical scavenging / antioxidant actions (see 2 for review). Among catechins, ECG and EGCG were reported to be the most potent free radical scavengers.(Pannala et al. 1997; Nanjo et al. 1999; Hashimoto et al. 2000; Lotito & Fraga 2000; Zhao et al. 2001) In additoin to direct antioxidant effects, catechins also indirectly increase endogenous antioxidative capacity by increasing levels of such enzymes as superoxide dismutase, catalase, glutathione peroxidase and reductase,(Skrzydlewska et al. 2002) by preventing endogenous antioxidants being depleted by lipid peroxidation,(Lotito & Fraga 2000) or by inhibiting xanthine oxidase.(Aucamp et al. 1997) EGCG was reported to inhibit many points of apoptotic sequence including caspase 3.(Koh et al. 2003; Jeong et al. 2004) and reportedly modulates the expression of proapoptptic genes such as Bax, while inducing antiapoptotic genes such as BCl-2.(Levites et al. 2002)

    Because of the above mentioned free radical scavenging, antioxidant, gene modulating activities, together with the ability to cross the blood-brain barrier,(Mandel et al. 2006) green tea catechins may potentially act as neuroprotectants in vivo. In fact, epidemiological studies suggest that green tea catechins many reduce the risk for Parkinson’s disease.(Checkoway et al. 2002; Tan et al. 2003) Green tea catechins were also reported to protect neuronal death from the Parkinsonian trigger MPTP in animal models.(Levites et al. 2001; Mandel et al. 2005; Bascianetto et al. 2006) EGCG also inhibits catechol-O-methyltransferase and may conserve synaptic dopamine in Parkinson’s disease.(Lu et al. 2003) Green tea catechins, especially EGCG, protect the central nervous system in animal models of stroke.(Lee et al. 2004; Sutherland et al. 2005) In animal models of Alzheimer’s disease, some green tea catechins specifically bind with and help to clear amyloid-beta.(Choi et al. 2001; Bascianetto et al. 2006) In cultured hippocampal cells from rat brain, green tea catechins, especially EGCG, at concentration of 5-10 μM, inhibited formation of amyloid-beta fibrils implicated in neuronal death in Alzheimer’s disease.(Bascianetto et al. 2006)


    Ocular effects of green tea catechins

    Oral intake of EGCG (0.4% in drinking water) was reported to attenuate the light-induced photoreceptor damage in albino rats as measured by the a- and b- wave amplitude and expression of various proteins involved in apoptosis such as caspase-3, caspase-8, Bcl-2 and Bad.(Costa et al. 2008) Beneficial effects of oral intake of EGCG (0.5% in drinking water ) was also demonstrated in a rat ischemia / reperfusion model, which mainly injures the retinal ganglion cell layer. EGCG siginificantly attenuated the change in a- and b-wave amplitudes, activation of caspases and other ischemia/ reperfusion–induced changes in vivo. Further, EGCG inhibited light- induced apoptosis of cultured RGC-5 cells which was caspase-independent almost completely at 10 μM.(Zhang et al. 2008)



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    Arts IC, DR Jacobs, Jr., LJ Harnack, M Gross & A Folsom (2001): Dietary catechins in relation to coronary heart disease death among postmenopausal women. Epidemiology 12: 668-675.

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    Hashimoto R, M Yaita, K Tanaka, Y Hara & S Kojo (2000): Inhibition of radical reaction of apolipoprotein B-100 and alpha-tocopherol in human plasma by green tea catechins. J Agric Food Chem 48: 6380-6383.

    Jeong JH, HJ Kim, TJ Lee & et al (2004): Epigallocatechin 3-gallate attenuates neuronal damage induced by 3-hydroxykynurenine. Toxicology 195: 53– 60.

    Kakuda T (2002): Neuroprotective effects of the green tea components theanine and catechins. Biol Pharm Bull 25: 1513-1518.

    Kakuda T, A Nozawa, A Sugimoto & H Niino (2002): Inhibition by theanine of binding of AMPA, kainate, and MDL 105519 to glutamate receptors. Biosci Biotechnol Biochem 66: 2683–2686.

    Kim TI, YK Lee, SG Park & et al (2009): L-Theanine, an amino acid in green tea, attenuates beta-amyloid-induced cognitive dysfunction and neurotoxicity: reduction in oxidative damage and inactivation of ERK/p38 kinase and NF-KappaB pathways. Free Radic Biol Med. 47: 1601-1610.

    Kimura M, K Umegaki, Y Kasuya, A Sugisawa & M Higuchi (2002): The relation between single/double or repeated tea catechin ingestions and plasma antioxidant activity in humans. Eur J Clin Nutr 56: 1186-1193.

    Koh SH, SH Kim, H Kwon & et al (2003): Epigallocatechin gallate protects nerve growth factor differentiated PC12 cells from oxidative-radical-stress-induced apoptosis through its effect on phosphoinositide 3-kinase/Akt and glycogen synthase kinase-3. Brain Res Mol Brain Res 118: 72–81.

    Kohlmeier L, KG Weterings, S Steck & F Kok (1997): Tea and cancer prevention: an evaluation of the epidemiologic literature. Nutr Cancer 27: 1–13.

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    Lee H, JH Bae & S Lee (2004): Protective effect of green tea polyphenol EGCG against neuronal damage and brain edema after unilateral cerebral ischemia in gerbils. J Neurosci Res 77: 892-900.

    Levites Y, T Amit, MB Youdim & S Mandel (2002): Involvement of protein kinase C activation and cell survival/cell cycle genes in green tea polyphenol (-)-epigallocatechin 3-gallate neuroprotective action. J Biol Chem 277: 30574–80.

    Levites Y, O Weinreb, G Maor & et al (2001): Green tea polyphenol(-)-epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration. J Neurochem 78: 1073-1082.

    Lotito SB & C Fraga (2000): Catechins delay lipid oxidation and alphatocopherol and beta-carotene depletion following ascorbate depletion in human plasma. Proc Soc Exp Biol Med 225: 32-38.

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    Sasazuki S, H Kodama, K Yoshimasu & et al (2000): Relation between green tea consumption and the severity of coronary atherosclerosis among Japanese men and women. Ann Epidemiol 10: 401–408.

    Sato Y, H Nakatsuka, T Watanabe & et al (1989): Possible contribution of green tea drinking habits to the prevention of stroke. Tohoku J Exp Med 157: 337– 43.

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    Sutherland BA, RM Rahman & I Appleton (2006): Mechanism of action of green tea catechins, with a focus on ischemia-induced neurodegeneration. J Nutr Biochem 17: 291-306.

    Sutherland BA, OM Shaw, AN Clarkson & et al (2005): Neuroprotective effects of (-)-epigallocatechin gallate after hypoxia-ischemia-induced brain damage: novel mechanism of action. FASEB J 19: 258-260.

    Tabak C, A I.C., S H.A., H D. & K D. (2001): Chronic obstructive pulmonary disease and intake of catechins, flavonols, and flavones: the MORGEN Study. Am J Respir Crit Care Med 164: 61–64.

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    Coffee, Chocolate, and Cocoa

    Michael S Kook, M.D.


    Glial activation and oxidative stress have been increasingly implicated in glaucoma. For instance, unstable ocular blood flow and/or perfusion pressure causing repeated ischemia and reperfusion appears highly relevant in inducing oxidative stress.(Claridge & Smith 1994; Harris et al. 1997; Evans et al. 1999; Osusky et al. 2000; Gherghel et al. 2001; Harris et al. 2002; Polska et al. 2002; Sehi et al. 2005; Choi et al. 2006; Clifford et al. 2006; Galambos & et al 2006; Choi et al. 2007) This in turn may lead to damage to a variety of macromolecules, such as proteins, lipids, sugar residues, or DNA, and thereby to cell death, such as that of retinal ganglion cells. Natural anti-oxidants may thus be important therapeutic modalities.

    Coffee beans contain about 8% phenolic compounds, with anti-oxidative effects due to their free radical scavenging and metal-chelating activities.(Kim et al. 2002; Daglia et al. 2004; Wen et al. 2004; Takenaka et al. 2005; Mozaffarieh et al. 2008) The compound 3-methyl-1,2-cyclopentanedione (MCP), isolated from the coffee extract, is a selective scavenger of peroxynitrite.(Nardini et al. 1997) MCP donates a proton to peroxynitrite to neutralize it through the chemical conversion of one of its carbonyl groups, which becomes reduced to a hydroxyl group. Polyphenols in coffee inhibit lipid peroxidation and protect against mutagenicity.(Stadler et al. 1994). Despite much debate on the effects of coffee on glaucoma, its antioxidant potential deserves further research.

    Chocolate is derived from cocoa beans from the seed of Theobroma cacao.(Heiss et al. 2003; Miller et al. 2006) It contains a class of flavonoids, flavan-3-ols and their oligomers (procyanidins), Dark chocolate generally contains at least twice as much cacao, and thus twice the polyphenols as milk chocolate. In addition, the milk in milk chocolate may reduce absorption of cacao. The anti-oxidative capacity of cacao is higher than that of wine or green tea because of much higher levels of phenolic phytochemicals.(Lee et al. 2003) Several in vivo studies have provided support that the consumption of cacao-rich food, such as dark chocolate, is associated with a reduced risk of vascular disease.(Engler et al. 2004; Heiss et al. 2006) The mechanism is due to the action of flavan-3-ols, which augment endothelial NOS, and thereby nitric oxide, to improve endothelium-dependent vasorelaxation.(Karim et al. 2000; Grassi et al. 2005) Ingestion of cacao also decreases both systolic and diastolic blood pressure, improves insulin sensitivity, reduces LDL oxidation susceptibility (thereby increasing the serum total antioxidant capacity and HDL-cholesterol concentrations),(Taubert et al. 2003) and reduces platelet adhesiveness and clotting.(Innes et al. 2003; Hermann et al. 2006) Because of these multiple beneficial effects, chocolate also deserves further research and may prove of value in the treatment of glaucoma.

    Cocoa pods from the cocoa tree (Theobroma cacao) are harvested and the beans removed and fermented. Dried and roasted beans contain about 300 chemicals, including caffeine, theobromine, and phenethylamine. Chocolate liquor is prepared by finely grinding the nib of the cocoa bean and is the basis for all chocolate products.

    Cocoa powder is made by removing part of the cocoa butter from the liquor. Bittersweet chocolate, or dark chocolate, contains at least 15% chocolate liquor but may contain as much as 60%, with the remainder being cocoa butter, sugar, and other additives. Milk chocolate is the predominant form of chocolate consumed in the U.S. and typically contains 10-12% chocolate liquor. Therefore, cocoa like dark chocolate contains both a high quantity and quality of phenol antioxidants.(Wan et al. 2001) The consumption of polyphenolic flavonoids from cocoa decreased the risk of heart disease in a cross-cultural epidemiological study.(Wan et al. 2001) This antioxidant activity may exert beneficial effects and may prove valuable in the non-pharmaceutical treatment of glaucoma.(Grässel 1992; Innes et al. 2003; Taubert et al. 2003)



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    Heiss C, H Schroeter, J Balzer & et al (2006): Endothelial function, nitric oxide, and cocoa flavonols. J Cardiovasc Pharmacol 47(Suppl 2): S128-35.

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    Innes AJ, G Kennedy, M McLaren & et al (2003): Dark chocolate inhibits platelet aggregation in healthy volunteers. Platelets 14: 325-7.

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    Lee KW, YJ Kim, HJ Lee & et al (2003): Cocoa has more phenolic phytochemicals and a higher antioxidant capacity than teas and red wine. J Agric Food Chem 51: 7292-5.

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    Nardini M, N F., G V. & et al (1997): Effect of caffeic acid dietary supplementation on the antioxidant defense system in rat: an in vivo study. Arch Biochem Biophys 342: 157-160.

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    Polska E, A Doelemeyer, A Luksch & et al (2002): Partial antagonism of endothelin 1-induced vasoconstriction in the human choroid by topical unoprostone isopropyl. Arch Ophthalmol 120: 348-52.

    Sehi M, JG Flanagan, L Zeng & et al (2005): Anterior optic nerve capillary blood flow response to diurnal variation of mean ocular perfusion pressure in early untreated primary open-angle glaucoma. Invest Ophthalmol Vis Sci 46: 4581-4587.

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    Taubert D, R Berkels, R Roesen & et al (2003): Chocolate and blood pressure in elderly individuals with isolated systolic hypertension. JAMA 290: 1029-30.

    Wan Y, JA Vinson, TD Etherton & et al (2001): Effects of cocoa powder and dark chocolate on LDL oxidative susceptibility and prostaglandin concentrations in humans. Am J Clin Nutr 74: 596-602.

    Wen X, M Takenaka, M Murata & et al (2004): Antioxidative activity of a zinc-chelating substance in coffee. Biosci Biotechnol Biochem 68: 2313-2318.




    N-acetyl cysteine

    Robert Nussenblatt, MD


    N-acetylcysteine (NAC) is an acetylated variant of L-cysteine and has several medical indications. Its use is based on its proposed mechanism of influencing both anti-oxidant and nitric oxide systems, which can be very active during infections and stress. Glutathione is one of the body’s major anti-oxidants(Dekhuijzen 2004) and helps to detoxify substances that harmful during inflammatory and infectious processes. Glutathione is composed of glutamate, glycine and cysteine. Cysteine is present in cells in the lowest concentration of the three.(Dickinson et al. 2003) Since glutathione production is dependent on the presence of these three substrates, a low concentration of cysteine may inhibit rapid production of gluthathione when needed. Therefore exogenously administered NAC could help in meeting this anti-oxidant need. A second mechanism of action is as a vasodilator by its effect on nitric oxide. (Ardissino et al. 1997)

    Perhaps its best known indication is as an antidote for acetaminophen overdose. NAPQI is the toxic metabolite of acetaminophen. NAC replenishes glutathione, which then binds directly to the toxic metabolite. This enhances a nontoxic sulfate conjugation in the liver cell. (Smilkstein et al. 1988) NAC has also been evaluated in another clinical adverse event, contrast induced nephropathy, which occurs in about 2% of cases with normal serum creatinines. However, patients with serum creatinine levels above 2.0 mg/dL or with diabetes are at high risk to develop this complication.(Rihal et al. 2002) An initial prophylactic trial using NAC showed a positive result.(Tepel et al. 2000) A large number of controlled studies ensued with varied findings, the majority either showing an effect or the result being inconclusive.(Millea 2009) NAC is not used standardly as prophylaxis.

    Several studies have evaluated NAC in treating chronic obstructive pulmonary disease (COPD). In an open label study of almost 1400 patients, NAC resulted in clear clinical improvement.(Tattersall et al. 1983) There was a decrease in the viscosity of phlegm and decreased coughing shortness of breath. Another trial showed a decrease in the deterioration of the FEV1 in older patients treated with NAC. (Lundback et al. 1992) In addition, there have been several randomized trials with the majority showing a clinical benefit to NAC therapy. (Millea 2009)

    In another pulmonary disorder, pulmonary fibrosis, a study randomizing patients to either NAC (600mg TID) and placebo also showed that the deterioration of lung function was slowed in those patients receiving the active therapy.(Demedts et al. 2005) In one randomized controlled trial, NAC was useful in attenuating and preventing the signs and symptoms of influenza in a frail population. (De Flora et al. 1997)

    Side effects at doses 1200 mg BID or lower have been minimal with mostly gastrointestinal problems along with skin rashes. At the higher doses used to treat acetaminophen toxicity, there can more severe adverse events including tinnitus, headache, rash, chills, fever, and an allergic reaction.

    The potential use of NAC in ocular disorders has been suggested in several studies, both of the retina and the trabecular meshwork. One study emphasized the importance of neuroprotection in glutamate induced cytotoxicity.(Aoun et al. 2003) In this study using rat RGC-5 cells, glutamate treatment resulted in RGC-5 cell death. Pretreatment of these cells with NAC resulted in a reversal of the cytotoxic effects. A second model evaluated the glaucoma associated mutant optineurin in the induced death of RGC.(Chalasani et al. 2007) Plasmids expressing either the wild type or various optineurin mutants were inserted into a variety of cells lines. The E50K mutation of optineurin-induced RGC death. Reactive oxygen species were produced with the expression of E50K. The addtion of NAC inhibited the cell death. Finally, a recent study evaluated the potential role of antioxidants in defects potentially leading to POAG. He et al suggested that a mitochondrial complex 1 defect is associated with trabecular cell degeneration.(He et al. 2008) Cultured trabecular cells from POAG patients had significantly higher reactive oxygen species levels compared to controls. Anti-oxidants, including NAC, protected against cell death by inhibiting ROS generation and cytochrome C release.



    Aoun P, JW Simpkins & N Agarwal (2003): Role of PPAR-gamma ligands in neuroprotection against glutamate-induced cytotoxicity in retinal ganglion cells. Invest Ophthalmol Vis Sci 44: 2999-3004.

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    Chalasani ML, V Radha, V Gupta, N Agarwal, D Balasubramanian & G Swarup (2007): A glaucoma-associated mutant of optineurin selectively induces death of retinal ganglion cells which is inhibited by antioxidants. Invest Ophthalmol Vis Sci 48: 1607-14.

    De Flora S, C Grassi & L Carati (1997): Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J 10: 1535-41.

    Dekhuijzen PN (2004): Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease. Eur Respir J 23: 629-36.

    Demedts M, J Behr, R Buhl, U Costabel, R Dekhuijzen, HM Jansen, W MacNee, M Thomeer, B Wallaert, F Laurent, AG Nicholson, EK Verbeken, J Verschakelen, CD Flower, F Capron, S Petruzzelli, P De Vuyst, JM van den Bosch, E Rodriguez-Becerra, G Corvasce, I Lankhorst, M Sardina & M Montanari (2005): High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 353: 2229-42.

    Dickinson DA, DR Moellering, KE Iles, RP Patel, AL Levonen, A Wigley, VM Darley-Usmar & HJ Forman (2003): Cytoprotection against oxidative stress and the regulation of glutathione synthesis. Biol Chem 384: 527-37.

    He Y, KW Leung, YH Zhang, S Duan, XF Zhong, RZ Jiang, Z Peng, J Tombran-Tink & J Ge (2008): Mitochondrial complex I defect induces ROS release and degeneration in trabecular meshwork cells of POAG patients: protection by antioxidants. Invest Ophthalmol Vis Sci 49: 1447-58.

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    Robert Nussenblatt, MD


    Taurine (2-aminoethanesulfonic acid) is the decarboxylation product of cysteine, and is mainly obtained from diet. It is a free sulfur ß-amino acid found in animal tissue and is one of the most abundant low molecular weight compounds, present in the micromolar range per gram wet weight. While the body can make taurine from sulfur precursers, it is produced endogenously in the liver from methionine and cysteine. Enzymes that are needed for taurine production include cysteine sulfinic acid decarboxylase, which is the rate limiting step in the cascade leading to taurine.(Militante & Lombardini 2004) However, the amount produced is insufficient and dietary sources are needed. Taurine is found freely in the cytosol and is found particularly in the heart, retina, brain and blood.

    Taurine has been associated with many different physiologic activities, including calcium transport, antioxidation, neurotransmission, and regulation of protein phosphorylation.(Huxtable & Sebring 1986) It should be added that the dominant role of taurine still needs to be determined. Significant changes in plasma and tissue levels occur in aging rats.(Wallace & Dawson 1990) These decreases are noted in the eye as well(Eppler & Dawson 2001) and may be due to a decrease in liver biosynthetic enzymes. Of interest is that withdrawing taurine from the diet of animals does not enhance the decrease; yet augmenting the exogenous amount of taurine helps to resolve the deficit. However these observations are in the rat. In the human, the data is less robust. What has been shown is that taurine concentrations increase in the cerebrospinal fluid of aging humans (Tohgi et al. 1993), and by upwards of 30%.

    As with other tissues, taurine is found in high concentrations in phagocytic cells. It is believed to provide protection against inflammatory cytotoxicity, anti-oxidant activity, and membrane stabilization. Taurine appears to mediate these effects by eliminating highly toxic HOCL and generating non-toxic TauCl. TauCl appears to suppress the production of many inflammatory mediators, including NO, TNF-alpha, IL-1, Il-2, and IL-6. It appears to suppress production of IL-10 as well, which is a downregulatory cytokine.(Schuller-Levis & Park 2004; Kim & Cha 2009) It would appear that taurine in phagocytes prevents chronic inflammatory processes. The underlying mechanisms in macrophages appears to be the inhibition of NO by the suppression of the activation of several factors, including Ras, ERK1/2, and NF-kB. In neutrophils, taurine appears to exert an inhibitory effect by inhibiting p47phox and the assembly of the NADPH-oxidase complex. (Kim & Cha 2009)

    Taurine appears to play an important in ocular development. It appears structurally similar to the neurotransmitters GABA and glycine. Taurine plays a role aslo in the formation and maintenance of neural tissue. Kittens given taurine-deficient diets exhibited retinal degeneration and CNS defects.(Sturman 1986) Interestingly, taurine increased the numbers of rod photoreceptors in retinal culture.(Altshuler et al. 1993) It appears to act in retinal progenitors via the GlyRa2 subunit containing glycine receptors.(Young & Cepko 2004) As noted above, levels in animals decrease with aging, and specific ERG changes in rats can be associated with these decreased tissue levels, reflecting the fact that the retina has a decreased ability to deal with oxidative stress.(Militante & Lombardini 2004) Exogenous taurine administration may be helpful in preventing age related changes in the retina.(Militante & Lombardini 2004) Taurine concentrations seem to be markedly decreased in injured photoreceptors of dogs with glaucoma.(Madl et al. 2005) Taurine transformed rat retinal ganglia are protected from hypoxia-induced apoptosis, probably through the prevention of mitochondrial dysfunction.(Chen et al. 2009) One report in a small number of rabbits suggested that when topically applied 0.5% timolol was mixed with several amino acids, including taurine, the IOP decrease in the rabbit eye was greater than with timolol alone. (Olah & Veselovsky 2007)



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    Sturman JA (1986): Nutritional taurine and central nervous system development. Ann N Y Acad Sci 477: 196-213.

    Tohgi H, S Takahashi & T Abe (1993): The effect of age on concentrations of monoamines, amino acids, and their related substances in the cerebrospinal fluid. J Neural Transm Park Dis Dement Sect 5: 215-26.

    Wallace DR & R Dawson, Jr. (1990): Decreased plasma taurine in aged rats. Gerontology 36: 19-27.

    Young TL & CL Cepko (2004): A role for ligand-gated ion channels in rod photoreceptor development. Neuron 41: 867-79.





    Vincenzo Parisi


    The natural history of glaucoma involves the early impairment of the innermost retinal layers, which may precede the onset of visual field defects,(Parisi et al. 2006) subsequently followed by damage due to transynaptic degeneration in post-retinal visual pathways and, in particular, at the level of the lateral geniculate nucleus.(Yücel et al. 2003) Glaucoma must not be considered exclusively as a disease involving ocular structures, but a pathology in which regions of the brain involved in vision are also compromised.

    The possibility of inducing an improvement of glaucomatous visual function pharmacologically with cytidine-5’-diphosphocholine (citicoline) was suggested in 1989.(Pecori Giraldi et al. 1989) A similar treatment was used in different brain disorders ascribed to vascular, traumatic or degenerative processes.(Zappia et al. 1985; Cacabelos et al. 1996)

    Citicoline (exogenous CDP-choline) is a nontoxic and well-tolerated substance that acts as an intermediary in the synthesis of phosphatidylcholine, a major phospholipid in the neuronal membrane, through = activation of the biosynthesis of structural membrane phospholipids. It increases the metabolism of cerebral structures and inhibits phospholipid degradation. Enhancement of phosphatidylcholine synthesis may counteract neuronal apoptosis and provide neuroprotection.(Grieb & Rejdak 2002) Citicoline has been reported to have a neuroprotective effect on kainic acid-induced neurotoxicity in the retina.(Han et al. 2005)

    Citicoline may therefore have potential neuroprotective and neuromodulator roles, as demonstrated in conditions of cerebral hypoxia and ischemia.(Secades & Frontera 1995; Weiss 1995) In addition, it induces an increase in the levels of different neurotransmitters and neuromodulators, including noradrenaline, in the central nervous system. Several studies suggest that citicoline successfully increases the level of consciousness in different brain disorders ascribed to vascular, traumatic or degenerative processes.(Zappia et al. 1985; Cacabelos et al. 1996) When administered, citicoline is rapidly transformed to cytidine and choline, which are believed to provide neuroprotection by enhancing phosphatidylcholine synthesis; a similar effect may occur in glaucomatous retinal ganglion cells.(Grieb & Rejdak 2002)

    The first studies reported that treatment with citicoline could induce an improvement of glaucomatous visual field defects.(Pecori Giraldi et al. 1989) Subsequent studies questioned whether this improvement was related to a real enhancement of ganglion cell function and neural conduction along the visual pathways, or whether it was due to the associated effects of citicoline on the level of consciousness and attention.(Cacabelos et al. 1996)

    To explore these hypotheses, further studies evaluated the effects of oral (1600 mg/die) or intramuscular (1000 mg/die) citicoline treatment, administered for 60 days, on retinal function and neural conduction in the visual pathways of glaucoma patients with moderate visual defects; these studies used an electrophysiological approach, pattern electroretinograpy, to evaluate ganglion cell function and visual evoked potentials to evaluate neural conduction along visual pathways.(Parisi et al. 1999; Parisi et al. 2008) Oral or intramuscular treatment with citicoline induced an improvement of both PERG and VEP responses, with an increase in amplitudes and a shortening in times-to-peaks.

    Nevertheless, the beneficial effects of citicoline were treatment-dependent. In particular, 300 days after the end of treatment, no differences were detected with respect to pre-treatment conditions. When a second period of citicoline administration was performed, it was observed that even after a long period of wash-out (120 days), the improvement in visual function was once again evident, suggesting that repeated treatments may inhibit the development of the visual impairment.(Parisi et al. 1999; Parisi et al. 2008)

    The effects of citicoline on the neural visual system were revealed by improvement in visual acuity,(Porciatti et al. 1998) in VEP responses, and in contrast sensitivity in amblyopic subjects after treatment. Since similar results were obtained in amblyopic subjects with levodopa,(Leguire et al. 1993) and in studies of patients with Parkinson’s disease, citicoline was recommended as a complement to levodopa therapy.(Birbamer et al. 1990) The addition of CDP-choline to patching therapy was no more effective than patching alone after 30-days, but that adding CDP-choline to patching stabilised the effects obtained during treatment of amblyopia.(Fresina et al. 2008) A dopaminergic-like activity could be suggested to explain PERG and VEP results after treatment with citicoline.

    These results raise an interesting question: can oral or intramuscular citicoline effects be considered as “neuroprotective”, preventing the development of glaucoma? Considering that after the first period of wash-out there were no differences with respect to pre-treatment conditions, one cycle of treatment with citicoline is not sufficient to induce changes in the natural history of glaucoma. On the other hand, we observed that the second treatment period with oral citicoline induced an improvement which persisted after 120 days of wash-out.

    The results obtained in the first study(D'Andrea et al. 1989) were further explored in a restricted cohort of selected patients (12 OAG patients only), in which a series of 60 day-periods of treatment each followed by 120 days of wash-out, were carried out during a total period of 8 years.(Parisi 2005) This study showed that after 8 years, glaucomatous patients subjected to citicoline treatment displayed a stable or improved electrophysiological and visual field condition compared to pre-treatment (8 years before), while in similar glaucoma patients without citicoline treatment, there was worsening of the electrophysiological and visual field impairment with respect to pre-treatment conditions (8 years before).

    Indeed, the data observed in glaucoma patients treated with beta-blockers plus several periods of treatment with intramuscular citicoline with respect to results in glaucoma patients treated with beta-blockers only may suggest the potential use of citicoline in order to obtain the stabilisation or improvement of visual function in glaucoma.

    In agreement with similar studies,(Secades & Frontera 1995; Weiss 1995; Porciatti et al. 1998; Parisi et al. 1999; Parisi 2005) an important aspect is the lack of adverse pharmacological side effects in all participating subjects, even after long-term administration of the drug.

    All this indicates the potential use of citicoline in the medical treatment of glaucoma, as a complement to hypotensive therapy, with a possible direct neuroprotective effect.



    Birbamer G, E Gesterbrand, J Rainer & R Eberhardt (1990): CDP-choline in the treatment of Parkinson’s disease. New Trends Clin Pharmacol 4:1-6.

    Cacabelos R, J Caamano, MJ Gomez et al (1996): Therapeutic effects of CDP-choline in Alzheimer's disease. Cognition, brain mapping, cerebrovascular hemodynamics, and immune factors. Ann NY Acad Sci 777:399-403.

    D'Andrea D, MP Cichetti & S Di Staso (1989): Unusual retinal involvement in a case of unilateral pseudoexfoliation glaucoma. Clin Ocul Patol Ocul 10:460-464.

    Fresina M, A Dickmann, A Salerni, F De Gregorio & EC Campos (2008): Effect of oral CDP-choline on visual function in young amblyopic patients. Graefes Arch Clin Exp Ophthalmol 246:143-150.

    Grieb P & R Rejdak (2002): Pharmacodynamics of citicoline relevant to the treatment of glaucoma. J Neurosci Res 67:143-148.

    Han YS, IY Chung, JM Park & JM Yu (2005): Neuroprotective effect of citicoline on retinal cell damage induced by kainic acid in rats. Korean J Ophthalmol 19:219-26.

    Leguire LE, GL Rogers, B D.L., PD Walson & ML McGregor (1993): Levodopa/carbidopa for childhood amblyopia. Invest Ophthalmol Vis Sci 34:3090-3095.

    Parisi V (2005): Electrophysiological assessment of glaucomatous visual dysfunction during treatment with cytidine-5'-diphosphocholine (citicoline): a study of 8 years of follow-up. Doc Ophthalmol 110:91-102.

    Parisi V, G Coppola, M Centofanti & et al (2008): Evidence of the neuroprotective role of citicoline in glaucoma patients. Prog Brain Res 173:541-554.

    Parisi V, G Manni, G Colacino & MG Bucci (1999): Cytidine-5'-diphosphocholine (citicoline) improves retinal and cortical responses in patients with glaucoma. Ophthalmology 106:1126-34.

    Parisi V, S Miglior, G Manni, M Centofanti & M Bucci (2006): Clinical ability of pattern electroretinograms and visual evoked potentials in detecting visual dysfunction in ocular hypertension and glaucoma. Ophthalmology 113:216-228.

    Pecori Giraldi J, M Virno, G Covelli, G Grechi & F De Gregorio (1989): Therapeutic value of citicoline in the treatment of glaucoma (computerized and automated perimetric investigation). Int Ophthalmol 13:109-112.

    Porciatti V, C Schiavi, P Benedetti, A Baldi & EC Campos (1998): Cytidine-5'-diphosphocholine improves visual acuity, contrast sensitivity and visually-evoked potentials of amblyopic subjects. Curr Eye Res 17:141-148.

    Secades JJ & G Frontera (1995): CDP-choline: pharmacological and clinical review. Methods Find Exp Clin Pharmacol 17 Suppl B:1-54.

    Weiss GB (1995): Metabolism and actions of CDP-choline as an endogenous compound and administered exogenously as citicoline. Life Sci 56:637-660.

    Yücel YH, Q Zhang, RN Weinreb & et al (2003): Effects of retinal ganglion cell loss on magno-, parvo-, koniocellular pathways in the lateral geniculate nucleus and visual cortex in glaucoma. Prog Retin Eye Res 22:465-481.

    Zappia V, P Kennedy, BI Nilsson & P Galletti (1985): Novel biochemical, pharmacological and clinical aspects of cytidine-diphosphocholine. Elsevier





    Vincenzo Parisi and Robert Ritch



    Carnosine (beta-alanyl-L-histidine) has been suggested as supplementary therapy in several ocular disorders. In particular, cataract patients treated with carnosine showed improved visual function.(Babizhayev 2009; Babizhayev et al. 2009) it should be noted that Dr Babizhayev is CEO of Innovative Vision Products (IVP), the holder of patents for the use of N-Acetylcarnosine.

    The rationale for the potential use of carnosine in glaucoma is once again based on the analogies between glaucoma and Alzheimer’s disease. In fact, advanced glycation end products (AGEs) may contribute to the Alzheimer pathology and carnosine, a natural antioxidant and transition-metal ion sequestering agent, may inhibit the formation of AGEs.(Reddy et al. 2005) In addition, carnosine seems to have a neuroprotective effect in animal models in which cerebral ischemia was induced.(Rajanikant et al. 2007)

    In rats with ischemic acute renal failure, 2 weeks of prior feeding of a diet containing L-carnosine- attenuated the ischemia/reperfusion-induced renal dysfunction, while histologic renal damage, such as tubular necrosis, was significantly reduced.(Fujii et al. 2005) Slowing of the rate of cataract formation has been reported in rats.(Liu et al. 2009)

    Since there is lack of information in the literature regarding the use of carnosine in glaucoma, experimental studies in glaucomatous animal models treated with carnosine and subsequent controlled clinical trials performed in glaucomatous patients could shed light on its possible therapeutic role.




    Babizhayev MA (2009): Current ocular drug delivery challenges for N-acetylcarnosine: novel patented routes and modes of delivery, design for enhancement of therapeutic activity and drug delivery relationships. Recent Pat Drug Deliv Formul 3: 229-265.

    Babizhayev MA, L Burke, P Micans & SP Richer (2009): N-Acetylcarnosine sustained drug delivery eye drops to control the signs of ageless vision: glare sensitivity, cataract amelioration and quality of vision currently available treatment for the challenging 50,000-patient population. Clin Interv Aging 4: 31-50.

    Fujii T, M Takaoka, N Tsuruoka & et al (2005): Dietary supplementation of L-carnosine prevents ischemia/reperfusion-induced renal injury in rats. Biol Pharm Bull 28: 361-363.

    Liu YF, HW Liu & SL Peng (2009): [Effects of L-canosine in preventing and treating rat cataract induced by sodium selenite]. Zhonghua Yan Ke Za Zhi 45: 533-536.

    Rajanikant GK, D Zemke, MC Senut & et al (2007): Carnosine is neuroprotective against permanent focal cerebral ischemia in mice. Stroke 38: 3023-3031.

    Reddy VP, MR Garrett, G Perry & MA Smith (2005): Carnosine: a versatile antioxidant and antiglycating agent. Sci Aging Knowledge Environ.




    Vincenzo Parisi and Robert Ritch


    Carnitine, an amino acid derivative found in high energy demanding tissues (skeletal muscles, myocardium, liver), is essential for the intermediary metabolism of fatty acids. It plays an important role in such ocular tissues as the ciliary body, where muscle cells are present and may be an important energy reserve.(Pessotto et al. 1994) After carnitine treatment, patients with Alzheimer’s disease improved on psychometric testing,(Thal et al. 2000; Hudson & Tabet 2003; Montgomery et al. 2003) and patients with chemotherapy-induced peripheral neuropathy showed amelioration of sensory amplitude and conduction velocity.(De Grandis 2007)

    In animal models, carnitine protects against selenite-induced cataract(Geraldine et al. 2006) and ischemia-reperfusion retinal injury.(Kocer et al. 2003) It protects RPE cells against hydrogen peroxide-induced oxidative damage.(Shamsi et al. 2007) Patients with early age-related macular degeneration showed improved visual function and fundus alterations after carnitine treatment.(Feher et al. 2005)

    Carnitine prevents glutamate neurotoxicity in primary cultures of cerebellar neurons.(Llansola et al. 2002) and, by increasing the level of ATP, may improve mitochondrial function.(Evangeliou & Vlassopoulos 2003; Kumaran et al. 2005) Considerable evidence suggests that mitochondrial dysfunction and oxidative damage may play a role in the pathogenesis of Parkinson's disease and that acetyl- L-carnitine is beneficial in animal models of the disease.(Beal 2003) Mitochondrial dysfunction has been observed in patients with glaucoma.(Kong et al. 2009) Thus, one could hypothesize that improved ganglion cell function and neural conduction along the optic nerve could occur after carnitine treatment in glaucoma patients.

    At present there is lack of information regarding controlled clinical trials performed in glaucomatous patients treated with carnitine.




    Beal MF (2003): Bioenergetic approaches for neuroprotection in Parkinson's disease. Ann Neurol 53 Suppl 3: S39-47.

    De Grandis D (2007): Acetyl-L-carnitine for the treatment of chemotherapy-induced peripheral neuropathy: a short review. CNS Drugs 21 Suppl 1: 39-43.

    Evangeliou A & D Vlassopoulos (2003): Carnitine Metabolism and Deficit - When Supplementation is Necessary? Curr Pharm Biotechnol 4: 211-219.

    Feher J, B Kovacs, I Kovacs & et al (2005): Improvement of Visual Functions and Fundus Alterations in Early Age-Related Macular Degeneration Treated with a Combination of Acetyl-L-Carnitine, n-3 Fatty Acids, and Coenzyme Q10. Ophthalmologica 219: 154-166.

    Geraldine P, B Sneha, R Elanchezhian & et al (2006): Prevention of selenite-induced cataracttogenesis by acetyl-L-carnitine: an experimental study. Exp Eye Res 83: 1340-1349.

    Hudson S & N Tabet (2003): Acetyl-L-carnitine for dementia. Cochrane Database Syst Rev CD003158.

    Kocer I, D Kulacoglu, I Altuntas & et al (2003): Protection of the retina from ischemia-reperfusion injury by L-carnitine in guinea pigs. Eur J Ophthalmol 13: 80-85.

    Kong GY, NJ Van Bergen, IA Trounce & JG Crowston (2009): Mitochondrial dysfunction and glaucoma. J Glaucoma 18: 93-100.

    Kumaran S, KS Panneerselvam, S Shila, K Sivarajan & C Panneerselvam (2005): Age-associated deficit of mitochondrial oxidative phosphorylation in skeletal muscle: Role of carnitine and lipoic acid. Vasc Med 280: 83-89.

    Llansola M, S Erceg, M Hernandez-Viadel & V Felipo (2002): Prevention of ammonia and glutamate neurotoxicity by carnitine: molecular mechanisms. Metab Brain Dis 17: 389-397.

    Montgomery SA, LJ Thal & R Amrein (2003): Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol 18: 61–71.

    Pessotto P, P Valeri & E Arrigoni-Martelli (1994): The presence of L-carnitine in ocular tissues of the rabbit. J Ocul Pharmacol 10: 643-51.

    Shamsi FA, IA Chaudhry, ME Bouton & AA Al-Rajhi (2007): L-carnitine protects human retinal pigment epithelial cells from oxidative damage. Curr Eye Res 32: 575-84.

    Thal LJ, M Calvani, A Amato & et al (2000): A 1-year controlled trial of acetyl-l-carnitine in early-onset Alzheimer disease. Neurology 55: 805– 810.




    Coenzyme Q10

    Nathan Radcliffe, MD.


    Coenzyme Q10 (CoQ10), also known as ubiquinone, is a membrane bound mitochondrial antioxidant cofactor that participates in the electron transport chain. CoQ10 has been shown to improve mitochondrial function and is currently being evaluated in clinical trials for Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.(Littarru & Tiano 2007; Chaturvedi & Beal 2008) In humans with Parkinson’s disease, there is evidence that CoQ10 can slow the rate of functional decline compared to placebo.(Shults et al. 2002)

    CoQ10 Has received interest in glaucoma because it is a free radical scavenger and inhibits apoptosis by blocking Bax.(Papucci et al. 2003; Littarru & Tiano 2007) Mitochondrial dysfunction and oxidative stress have been implicated in the development of glaucomatous optic neuropathy.(Tezel 2006) In a rat model of pressure-induced retinal ischemia/reperfusion injury, CoQ10 administration inhibited glutamate increases and prevented retinal ganglion cell (RGC) apoptosis.(Nucci et al. 2007) Guo and Cordeiro have shown that CoQ10 inhibits staurosporine induced RGC apoptosis as visualized with the detection of apoptosing retinal cells technique.(Guo & Cordeiro 2008) As a result of these and other studies, CoQ10 has received recent attention for a potential role for neuroprotection in glaucoma.(Russo et al. 2008) However, there are no randomized clinical trials showing that CoQ10 is effective for glaucoma neuroprotection in humans, nor are there any experimental ocular hypertension/glaucoma animal studies demonstrating a neuroprotective effect of CoQ10.




    Chaturvedi RK & M Beal (2008): Mitochondrial approaches for neuroprotection. Ann N Y Acad Sci 1147: 395-412.

    Guo L & MF Cordeiro (2008): Assessment of neuroprotection in the retina with DARC. Prog Brain Res 173: 437-450.

    Littarru GP & L Tiano (2007): Bioenergetic and antioxidant properties of coenzyme Q10: recent developments. Mol. Biotechnol 37: 31–37.

    Nucci C, R Tartaglione, A Cerulli & et al (2007): Retinal damage caused by high intraocular pressure-induced transient ischemia is prevented by coenzyme Q10 in rat. Int Rev Neurobiol 82: 397-406.

    Papucci L, N Schiavone, E Witort & et al (2003): Coenzyme Q10 prevents apoptosis by inhibiting mitochondrial depolarization independently of its free radical-scavenging property. J Biol Chem.

    Russo R, F Cavaliere, L Rombolà & et al (2008): Rational basis for the development of coenzyme Q10 as a neurotherapeutic agent for retinal protection. Prog Brain Res 173: 575-82.

    Shults CW, D Oakes, K Kieburtz & et al (2002): Effects of coenzyme Q(10) in early Parkinson disease- Evidence of slowing of the functional decline. Arch Neurol 59: 1541-1552.

    Tezel G (2006): Oxidative stress in glaucomatous neurodegeneration: mechanisms and consequences. Prog Brain Res 25: 490-513.



    Folic acid

    Nathan Radcliffe, MD.


    Folic acid is an essential vitamin that is involved (in its active form tetrahydrofolate) in nucleotide biosynthesis and homocysteine (HCY) remethylation. Folate is found in green, leafy vegetables and in many breads and cereals fortified with folate. Folic acid deficiency (as well as certain medications and enzymatic deficiencies) can result in elevated levels of HCY. Hyperhomocysteinemia (HHCY) is a strong risk factor for atherosclerotic and thromboembolic disease. Elevated HCY levels are associated with several neurodegenerative diseases, including Alzheimer’s disease.(Seshadri et al. 2002; Ravaglia et al. 2005) Supplemental folic acid, combined with other B-vitamins (B-6 and B-12) can lower HCY levels by at least 30%.(Lobo et al. 1999) A number of large, randomized trials investigating the effects of lowering HCY with folate and B vitamins on cardiovascular and cerebrovascular endpoints have been performed without any strong evidence of benefit to HCY lowering.(Herrmann et al. 2007) Additionally, a recent large scale randomized trial showed that high-dose B vitamin supplements did not slow cognitive decline in individuals with mild to moderate AD.(Aisen et al. 2008)

    Homocysteine is toxic to retinal ganglion cells (RGCs) through stimulation of N-methyl-D-aspartate (NMDA) receptors and this excitotoxic damage is possibly potentiated by simultaneous elevation of HCY and glutamate.(Moore et al. 2001) An in vitro study of the effects of toxic concentrations of HCY on rat retinal tissues found HCY to be damaging to RGCs as well as to the outer and inner nuclear layers.(Viktorov et al. 2006) These findings raise the question of whether HHCY could be involved in the pathophysiology of glaucomatous optic neuropathy.

    While the findings about HCY levels in POAG are somewhat conflicting, they have not been consistently found to be higher than controls.(Vessani et al. 2003; Wang et al. 2004; Roedl et al. 2007) Levels of HCY are elevated in exfoliation glaucoma while folate, vitamin B12 and B6 levels are reduced in this condition.(Vessani et al. 2003; Cumurcu et al. 2006; Saricaoglu et al. 2006; Roedl et al. 2007) In summary, while there are intriguing connections between glaucoma and folate deficiency/elevated HCY, there is currently no evidence from experimental animal studies or human clinical trials to substantiate folate supplementation for glaucoma, we do advocate treating those patients, particularly those with exfoliation syndrome, in whom HCY levels are elevated. Furthermore, the lack of an observed benefit to HCY lowering with folate and B-vitamin supplementation in large cardiovascular trials raises the possibility that HCY may be a marker, rather than a cause, of these pathologies.



    Aisen PS, LS Schneider, M Sano & et al (2008): Alzheimer Disease Cooperative Study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA 300: 1774-83.

    Cumurcu T, S Sahin & E Aydin (2006): Serum homocysteine, vitamin B 12 and folic acid levels in different types of glaucoma. BMC Ophthalmol 6: 6.

    Herrmann W, M Herrmann & R Obeid (2007): Hyperhomocysteinaemia: a critical review of old and new aspects. Curr Drug Metab 8: 17-31.

    Lobo A, A Naso, K Arheart & et al (1999): Reduction of homocysteine levels in coronary artery disease by low-dose folic acid combined with vitamins B6 and B12. Am J Cardiol 83: 821-825.

    Moore P, A El-sherbeny, P Roon & et al (2001): Apoptotic cell death in the mouse retinal ganglion cell layer is induced in vivo by the excitatory amino acid homocysteine. Exp Eye Res 73: 45-57.

    Ravaglia G, P Forti, F Maioli & et al (2005): Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 82: 636-43.

    Roedl JB, S Bleich, U Reulbach & et al (2007): Homocysteine in tear fluid of patients with pseudoexfoliation glaucoma. J Glaucoma 16: 234-239.

    Roedl JB, S Bleich, U Reulbach & et al (2007): Vitamin deficiency and hyperhomocysteinemia in pseudoexfoliation glaucoma. . J Neural Transm 114: 571-575.

    Saricaoglu MS, A Karakurt, A Sengun & H Hasiripi (2006): Plasma homocysteine levels and vitamin B status in patients with pseudoexfoliation syndrome. Saudi Med J 27: 833-7.

    Seshadri S, A Beiser, J Selhub & et al (2002): Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346: 476-83.

    Vessani RM, JM Liebmann, M Jofe & R Ritch (2003): Plasma homocysteine is elevated in patients with exfoliation syndrome. Am J Ophthalmol 136: 41-46.

    Viktorov IV, OP Aleksandrova & NY Alekseeva (2006): Homocysteine toxicity in organotypic cultures of rat retina. Bull Exp Biol Med 141: 471-4.

    Wang G, FA Medeiros, BA Barshop & RN Weinreb (2004): Total plasma homocysteine and primary open-angle glaucoma. Am J Ophthalmol 137: 401-406.




    Nathan Radcliffe, MD.


    Glutathione is an antioxidant tripeptide of glutamate and a major intracellular antioxidant which neutralizes free radicals and reactive oxygen species. While glutathione depletion was initially thought to be a by-product of oxidative stress during apoptosis, current evidence suggests that glutathione may be involved in the regulation of apoptosis.(Gionfriddo et al. 2009)

    In monkeys with experimental glaucoma, Müller cells have increased extracellular glutamate, likely due to increased transport and metabolism of glutamate.(Carter-Dawson et al. 2004) In DBA/2J mice which develop glaucoma, glutathione depletion occurred, but this depletion was blocked by administration of the antioxidant alpha-luminol, suggesting that oxidative stress, including glutathione depletion, may play a role in glaucomatous neuronal damage.(Gionfriddo et al. 2009) In mice with deficiencies of the glutamate transporters GLAST or EAAC1, spontaneous retinal nerve fiber and optic nerve degeneration occurred in the absence of elevated IOP, and the administration of a glutamate receptor blocker prevented RGC loss.(Harada et al. 2007) However, in a glaucoma model of mice with these glutamate transporter deficiencies, there was no accumulation of glutathione in Müller cells, as has been previously observed in experimental glaucoma. The investigators proposed that these mice represent the first animal model of normal pressure glaucoma.

    Glutathione deficiency and oxidative stress have been hypothesized to play a role in both anterior segment glaucoma pathophysiology (trabecular meshwork function) as well as in optic nerve apoptosis.(Saccà et al. 2007; Ferreira et al. 2009) In particular the trabecular meshwork may be more sensitive to oxidative damage than the cornea or iris.(Izzotti et al. 2009) Patients with POAG have been shown to have low levels of circulating serum glutathione.(Gherghel et al. 2005) Furthermore, Turkish patients with POAG are more likely to poses the null genotype in the glutathione S-transferase M1 gene, though this finding was not replicated in a subsequent study.(Yildirim et al. 2005; Unal et al. 2007) Several additional Glutathione S-transferase deficiencies were more prevalent in Arab patients with glaucoma, suggesting that the role of glutathione transfer in glaucoma deserves further attention.(Abu-Amero et al. 2008) In summary, there is animal model evidence that glutathione may play a role in glaucoma. This pathway represents a potential target that will require further study before a therapeutic approach in humans can be explored.




    Abu-Amero KK, J Morales, GH Mohamed, MN Osman & TM Bosley (2008): Glutathione S-transferase M1 and T1 polymorphisms in Arab glaucoma patients. Mol Vis 14: 425-30.

    Carter-Dawson L, FF Shen, RS Harwerth & et al (2004): Glutathione content is altered in Müller cells of monkey eyes with experimental glaucoma. Neurosci Lett 24;364: 7-10.

    Ferreira SM, SF Lerner, R Brunzini & et al (2009): Antioxidant status in the aqueous humour of patients with glaucoma associated with exfoliation syndrome. Eye 23: 1691-1697.

    Gherghel D, HR Griffiths, EJ Hilton, IA Cunliffe & SL Hosking (2005): Systemic reduction in glutathione levels occurs in patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci 46: 877-83.

    Gionfriddo JR, KS Freeman, A Groth & et al (2009): alpha-Luminol prevents decreases in glutamate, glutathione, and glutamine synthetase in the retinas of glaucomatous DBA/2J mice. Vet Ophthalmol 12: 325-32.

    Harada T, C Harada, K Nakamura & et al (2007): The potential role of glutamate transporters in the pathogenesis of normal tension glaucoma. J Clin Invest. 117: 1763-70.

    Izzotti A, SC Sacca, M Longobardi & C Cartiglia (2009): Sensitivity of ocular anterior-chamber tissues to oxidative damage and its relevance to glaucoma pathogenesis. Invest Ophthalmol Vis Sci Epub June 10.

    Saccà SC, A Izzotti, P Rossi & C Traverso (2007): Glaucomatous outflow pathway and oxidative stress. Exp Eye Res 84: 389-99.

    Unal M, M Guven, K Devranoglu & et al (2007): Glutathione S transferase M1 and T1 genetic polymorphisms are related to the risk of primary open-angle glaucoma: a study in a Turkish population. Br J Ophthalmol 91: 527-30.

    Yildirim O, NA Ateş, L Tamer & et al (2005): May glutathione S-transferase M1 positive genotype afford protection against primary open-angle glaucoma? Graefes Arch Clin Exp Ophthalmol 243: 327-33.




    Nathan Radcliffe, MD.


    Melatonin is an antioxidant regulatory compound produced by the pineal gland and by the retina, where it acts as a free radical scavenger and as a regulator of rod outer segment disc shedding.(White & Fisher 1989; Bandyopadhyay et al. 2000) Melatonin is also a neurohormone that binds to plasma membrane receptors (MT1/MT2) and is available over the counter as a dietary supplement in the United States. Melatonin has received attention in stroke, Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis and has been suggested to be potentially neuroprotective through its inhibition of the hamster retinal nitridergic pathway.(Sáenz et al. 2002; Mozaffarieh et al. 2008; Radogna et al. 2009) Furthermore, melatonin suppresses nitric oxide mediated retinal damage, including apoptosis in the rat retina.(Siu et al. 2004) Melatonin may also reduce apoptosis in astrocytoma cells through inhibition of phospholipase C.(Radogna et al. 2009) Melatonin is protective against retinal ischemia/reperfusion injury in guinea pigs and specifically in RGCs of rats.(Celebi et al. 2002; Tang et al. 2006) There is no experimental evidence for a protective role of Melatonin in glaucoma in either humans or animal models. Further study is required to determine the potential value of this antioxidant compound in glaucoma.



    Bandyopadhyay D, K Biswas, U Bandyopadhyay, RJ Reiter & R Banerjee (2000): Melatonin protects against stress-induced gastric lesions by scavenging the hydroxyl radical. J Pineal Res 29: 143-51.

    Celebi S, N Dilsiz, T Yilmaz & AS Kükner (2002): Effects of melatonin, vitamin E and octreotide on lipid peroxidation during ischemia-reperfusion in the guinea pig retina. Eur J Ophthalmol 12: 77-83.

    Mozaffarieh M, MC Grieshaber, S Orgül & J Flammer (2008): The potential value of natural antioxidative treatment in glaucoma. Surv Ophthalmol 53: 479-505.

    Radogna F, S Nuccitelli, F Mengoni & L Ghibelli (2009): Neuroprotection by melatonin on astrocytoma cell death. Ann N Y Acad Sci 1171: 509-13.

    Sáenz DA, AG Turjanski, GB Sacca & et al (2002): Physiological concentrations of melatonin inhibit the nitridergic pathway in the Syrian hamster retina. J Pineal Res 33: 31-36.

    Siu AW, GG Ortiz, G Benitez-King, CH To & RJ Reiter (2004): Effects of melatonin on the nitric oxide treated retina. Br J Ophthalmol 88: 1078-81.

    Tang Q, Y Hu & Y Cao (2006): Neuroprotective effect of melatonin on retinal ganglion cells in rats. J Huazhong Univ Sci Technolog Med Sci 26: 235-237.

    White MP & LJ Fisher (1989): Effects of exogenous melatonin on circadian disc shedding in the albino rat retina. Vision Res 29.



    Salvia miltiorrhiza

    Douglas Rhee, MD



    Salvia miltiorrhiza (Red Sage, Chinese Sage, dan shen) is a perennial flowering plant approximately 30-60 cm high that is native to China and Japan. In traditional Chinese medicine, red sage is believed to improve circulation and is used to treat hypertension and cardiovascular disease, especially acute myocardial infarction and strokes.

    In patients with glaucoma, one report claimed to stabilize the visual field in patient with moderate to advanced glaucoma. (Wu ZZ et al. 1983). The mechanism was presumed to be independent of IOP.


    Possible Beneficial Mechanisms of Action

    There has been little direct study with red sage and glaucoma. In an experimental model of elevated IOP in rabbits, intravenous red sage resulted in near complete preservation of RGC compared to controls.(Zhu and Cai 1993) The same group also found less reduction of axoplasmic flow in this rabbit model in red sage treated group (intravenous); this beneficial effect was potentiated by concurrent use of topical timolol.(Zhu and Cai 1991)

    Although there has been little direct study of glaucoma, there has been extensive study of red sage in other areas, with over 1,000 studies listed in pubmed (; search term “salvia miltiorrhiza”) in March 2010. Many of these studies have focused on the anti-oxidant and anti-inflammatory properties attributed to red sage or Tanshionone IIA (Tan IIA), its principle active ingredient, in cardiovascular, tumor, and acute hepatic injury research. In these studies, several proteins and pathways that have been associated with glaucoma have been affected, albeit in different cell types. A brief review is presented.

    Anti-oxidant and Redox Scavenger

    The predominant activity that is believed to be confered by red sage is as an anti-oxidant. In atherosclerotic lesions, smooth muscle cells grow in response to oxidative stress, such as homocysteine. In a rat model of atherosclerosis, an extract of red sage inhibited the growth of vascular smooth muscle cells and decreased the intracellular reactive oxygen species concentration.(Hung et al. 2010) By surveying several different signaling pathways, the investigators determined that the red sage was acting through the protein kinase C/ mitogen-activated kinase (PKC/MAPK). Although the receptor is unknown, they used two-dimentional immunoblotting and mass spectrometry to compare the protein extracts from cells treated with homocysteine compared to those receiving homocysteine and red sage to show significant change in cytoskeleton and chaperone proteins. Red sage exerted its protective effect through scavenging of reactive oxygen species and modulation of protein carbonylation to inhibit cell proliferation.(Hung et al. 2010)

    In a separate study, red sage directly lowered total plasma homocysteine by increase the activity of trans-sulphuration enzymes that metabolize homocysteine.(Cao et al 2009)

    Tan IIA alleviated oxidative damage induced by glutathione-induced hyperstimulation of the NMDA receptor (i.e. excitotoxicity) in human neuroblastoma SH-SY5Y cells.(Sun ZY et al 2010) There is some evidence indicating a direct effect mitigating NMDA receptor excitoxicity.(Sun X et al. 2003)

    Red sage has been reported to have some protective effective effect on hepatic damage, apparently through an antioxidant mechanism.(Park et al 2009) Red sage was protective against reperfusion injury in liver through inhibiting oxidation and also antagonizing TNF-a.(Liang R et al 2009)

    Anti-inflammatory Effects

    In an experimental model of myocardial infarction, Tan IIA blocked nuclear factor-kappaB2 (NF-kappaB2) and transforming growth factor beta-1 (TGFb1) secretion in rat cardiac cells.(Ren et al. 2010) In liver injury models, Tan IIA reduced levels of interleukins -2, -4, (tumor necrosis factor alpha (TNFa), and interferon-gamma.(Liu et al. 2010) In a prospective randomized controlled trial of an extract containing red sage, along with panax notoginseng and dryobalanops camphor, in 106 patients who had an ischemic stroke or TIA were managed with conventional therapy with or without this extract, the experimental group had a lower rate of recurrent stroke/TIA.(Xu et al 2009)

    Effect on Blood Viscosity

    In beagles, intravenously administered salvianolic acid B (another active compound found in red sage), decreased blood viscosity, while oral administration had no effect.(Gao et al 2009) In humans, red sage can potentiate the effects of warfarin, leading to bleeding complications.(Chan 2001)

    Vasodilatory effects

    In rat cardiac arterioles, red sage induced vasodilation by increasing production of nitric oxide from the endothelial cells either directly, or from a locally produced cytochrome P450 metabolite, via calcium-activated potassium channels.(Wu GB et al 2009)

    In rats, whole red sage extract given intravenously can lower blood pressure.(Leung et al 2009) Further studies with Tan IIA showed it lower systemic blood pressure in rats with spontaneous elevated blood pressure via ATP-sensitive potassium channels to lower intracellular calcium.(Xiping et al 2009)

    Effect on Extracellular Matrix Modulation

    Tan IIA inhibits proliferation and induces apoptosis of tumor cells in breast and colon cancer cells, in vitro.(Lu et al 2009 and Shan 2009) Although seemingly unrelated to the pathogenesis of glaucoma, Tan IIA suppressed NF-kappaB signaling and reduced urokinase plasminogen activator and matrix metalloproteinases (MMPs) -2, -9, and increased tissue inhibitors of metalloproteinases (TIMPs) -1 and -2.(Hung YC 2010) In an experimental model of acute myocardial infarction, salvianolic acid regulated MMP-9 enzyme levels in cardiac cells.(Jiang 2009) In vitro testing of pure extracts of MMPs, red sage blocked rat MMPs-1, -2, and -9 activity.(Liang et al 2009)

    In hepatoma HepG2 cells, red sage extract inhibited cell invasion by modulating smad2/3 signaling of TGFb1.(Liu et al 2010) In a rat model of diabetic nephropathy, Tan IIA decreased TGFb1 and collagen IV deposition.(Kim et al 2009) In rate mesangial cells, red sage decreased production of plasminogen activator inhibitor-1 (PAI-1) by antagonizing angiotensin II.(Yuan et al 2008)


    Red Sage and the Eye


    Red sage has been reported to be beneficial for the preservation of visual field in a single report via an IOP-independent mechanism. Using a rabbit model of ocular hypertension, Zhu and Cai implicate the anti-inflammatory and vasodilatory effects of red sage. Using modern molecular techniques in non-ocular tissues and animal models, red sage affects several pathways that may be involved in the pathogenesis of glaucoma.

    Despite the failure of memantine to demonstrate a clear therapeutic advantage, NMDA-receptor mediated excitotoxicity still has significant experimental evidence implicating it as a contributor to secondary RGC death.(Seki and Lipton 2008) Oxidative stress has been implicated in the pathogenesis of open angle glaucoma, particularly exfoliative glaucoma.(Schlötzer-Scherhardt 2010 and Zhou L et al 1999) Furthermore, TGFß1 levels are increased in aqueous humor and deposits of exfoliation material in patients with exfoliative glaucoma.(Koliakos et al 2001 and Schlötzer-Schrehardt et al 2001) The relationship between TGFß1 and exfoliation syndrome is more complicated than a simple mutational one.(Krumbiegel 2009) TGFß1 likely contributes to the formation of deposits seen in the trabecular meshwork. Red sage has been shown to antagonize TGFb1. Downregulating NF-kappaB in RGC confirms protection against apoptosis.(Sappington and Calkins 2008 and Ando et al 2005) Capillary vasodilation and decreasing blood viscosity may confer increased blood flow to the optic nerve. However, caution should be applied as red sage can induce bleeding complications in patients on anti-coagulant therapy.

    The effect on MMP and TIMP balance could be deleterious to IOP as the shifting of this balance toward greater MMP activity correlates to IOP lowering.(Ooi et al 2009) Red sage has a tendency to shift the MMP/TIMP balance towards decreased MMP activity.




    Ando A, Yamazaki Y, Kaneko S, et al (2005). Cytoprotection by nipradilol, an anti-glaucomatous agent, via down-regulation of apoptosis regulated gene expression and activation of NF-kappaB. Exp Eye Res 80:501-507

    Cao Y, Chai JG, Chen YC, et al (2009). Beneficial effects of danshensu, an active component of Salvia miltiorrhiza, on homocysteine metabolism via the trans-sulphuration pathway in rats. Br J Pharmacol. 157(3):482-90. Epub 2009 Apr 30.

    Chan, T.Y. 2001. "Interaction between warfarin and danshen (Salvia miltiorrhiza)" The Annals of Pharmacotherapy, Vol. 35, No. 4, pp. 501-504.

    Gao DY, Han LM, Zhang LH, et al (2009). Bioavailability of salvianolic acid B and effect on blood vsicosities after oral administration of salvianolic acids in beagle dogs. Arch Pharm Res 32:773-779

    Hung YC, Wang PW, Pan TL. (2010) Functional proteomics reveal the effect of Salvia miltiorrhiza aqueous extract against vascular atherosclerotic lesions. Biochim Biophys Acta. Feb 17 [Epub ahead of print]

    Jiang B, Wu W, Li M, et al. (2009) Cardioprotection and matrix metalloproteinase-9 regulation of salvianolic acids on myocardial infarction in rats. Planta Med. 75:1286-92.

    Kim SK, Jung KH, Lee BC.(2009) Protective effect of Tanshinone IIA on the early stage of experimental diabetic nephropathy. Biol Pharm Bull. 32:220-4.

    Koliakos GG, Scholotzer-Schrehardt U, Konstas AG, et al (2001). Transforming and insulin-like growth factors in the aqueous humor of patients with exfoliation syndrome. Graefes Arch Clin Exp Ophthalmol. 239:482-487

    Krumbiegel M, Pasutto F, Mardin CY, et al (2009). Exploring functional candidate genes for genetic association in german atients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma. Invest Ophthalmol Vis Sci. 50:2796-2801

    Leung SW, Zhu DY, Man RY. (2009) Effects of the aqueous extract of Salvia Miltiorrhiza (danshen) and its magnesium tanshinoate B-enriched form on blood pressure. Phytother Res. Nov 26. [Epub ahead of print]

    Liang R, Bruns H, Kincius M, et al (2009). Danshen protects liver grafts from ischemia/reperfusion injury in experimental liver transplantation in rats. Transpl Int. 22:1100-1109.

    Liang YH, Li P, Huang QF, et al (2009). Salvianolic acid B in vitro inhibited matrix metalloproteinases-1, -2, and -9 activities. Zhong Xi Yi Jie He Xue Bao. 7:145-150.

    Liu X, Yang Y, Zhang X, et al.(2010) Compound Astragalus and Salvia miltiorrhiza extract inhibits cell invasion by modulating transforming growth factor-beta/Smad in HepG2 cell. J Gastroenterol Hepatol. 25:420-406.

    Lu Q, Zhang P, Zhang X, et al. (2009) Experimental study of the anti-cancer mechanism of tanshionone IIA against human breast cancer. Int J Mol Med 24:773-780

    Ooi YH, Oh DJ, Rhee DJ. (2009) Effect of bimatoprost, latanoprost, and unoprostone on matrix metalloproteinases and their inhibitors in human ciliary body smooth muscle cells. Invest Ophthalmol Vis Sci 50:5259-5265 Epub May 14

    Park EJ, Zhao YZ, Kim YC, et al. (2009) Preventive effects of a purified extract isolated from Salvia miltiorrhiza enriched with tanshinone I, tanshinone IIA and cryptotanshinone on hepatocyte injury in vitro and in vivo. Food Chem Toxicol. 47:2742-2748.

    Ren ZH, Tong YH, Xu W, et al. (2010) Tanshionen IIA attenuates inflammatory responses of rats with myocardial infarction by reducing MCP-1 expression. Phytomedicine. 17:212-218

    Sappington RM, Calkins DJ. (2008) Contribution of TRPV1 to microglia-derived IL-6 and NFkappaB translocation with elevated hydrostatic pressure. Invest Ophthalmol Vis Sci. 49:3004-3017

    Schloetzer-Schrehardt U, Zenkel M, Kuchle M, et al.(2001) Role of transforming growth factor-beta1 and its latent form binding protein in pseudoexfoliation syndrome. Exp Eye Res. 73:765-780

    Schlotzer-Scherhardt U. (2010) [Oxidative stress and pseudoexfoliation glaucoma] Klin Monbl Augenheilkd. 227:108-113

    Seki M, Lipton SA. (2008) Targeting excitotoxic/free radical signaling pathways for therapeutic intervention in glaucoma. Prog Brain Res. 173:495-510.

    Shan YF, Shen X, Xie YK, et al. (2009) Inhibitory effects of tanshionene II-A on invasion and metastasis of human colon carcinoma cells. Acta Pharmacol Sin. 30:1537-1542

    Sun X, Chan LN, Gong X, et al.(2003) N-methyl-D-aspartate receptor antagonist activity in traditional Chinese stroke medicines. Neurosignals 12:31-38

    Sun ZW, Zhang L, Zhu SJ, et al. (2010) Excitotoxicity effects of glutamate on human neuroblastoma SH-SY5Y cells via oxidative damage. Neurosci Bull. 26:8-16

    Xiping Z, Jun F, Chengjun W, et al. (2009) Effect of salvia miltiorrhizae on pulmonary apoptosis of rats with severe acute pancreatitis or obstructive jaundice. Inflammation. 32:287-95.

    Xu G, Zhao W, Zhou Z, et al. (2009) Danshen extracts decrease blood C reactive protein and prevent ischemic stroke recurrence: a controlled pilot study. Phytother Res. 23:1721-1725.

    Wu GB, Zhou EX, Qing DX. (2009) Tanshinone II(A) elicited vasodilation in rat coronary arteriole: roles of nitric oxide and potassium channels. Eur J Pharmacol. 617:102-107.

    Wu ZZ, Jiang YQ, Yi SM, et al. (1983) Radix Salviae Miltiorrhizae in middle and late stage glaucoma. Chin Med J 96:445-447

    Yuan J, Wang X, Chen T, et al. (2008) Salvia miltiorrhiza depresses plasminogen activator inhibitor-1 production through inhibition of angiotensin II. Am J Chin Med. 36:1005-1015.

    Zhou L, Lik Y, Yue BY. (2009)Oxidative stress affects cytoskeletal structure and cell-matrix interactions in cells from an ocular tissue: the trabecular meshwork. J Cell Physiol 180:182-189

    Zhu MD, Cai FY. (1991) [The effect of inj. Salviae Miltiorrhizae Co. on the retrograde axoplasmic transport in the optic nerve of rabbits with chronic IOP elevation] Zhonghua Yan Ke Za Zhi 27:174-178

    Zhu MD, Cai FY. (1991) Evidence of compromised circulation in the pathogenesis of optic nerve damage in chronic glaucomatous rabbit. Chin Med J (Engl). 106:922-927



    Trifolium pratense (Common name: red clover)

    Douglas Rhee, MD



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    Trifolium pretense is a species of clover, native to Europe, western Asia and Africa, but present in many other regions. It is a perennial, growing to approximately 20-80 cm tall. There are seven varieties of T. pretense and it is both the state flower of Vermont and the national flower of Denmark.

    Traditionally, red clover has been for irregular menses, menopause, and fertility. For ocular use, folklore and supplementation advertisements extol its use for “sore eyes” and conjunctivitis. The chemically active compounds in red clover are primarily isoflavones, but there is also a weak amount of coumarin and cyanogenic glycosides. There is significant evidence that these isoflavones act as “phytoestrogens,” hence their effect on menopausal symptoms etc. (Adaikan et al 2009 and Chedraui et al 2008) One of the components from red clover, puerarin, was reported to have an IOP lowering effect.


    Potential Beneficial Mechanisms of Action

    There are numerous different individual compounds that are considered isoflavones. In particular, puerarin, which has beta-blocker activity, was reported to lower IOP at 1% topical preparation. (Kang 1993) Because of its possible effect on IOP, several groups have looked into systemic delivery, contact lens delivery, and topical permeability of puerarin. (Deng et al 2006, Qi et al 2007, Wu et al 2006, and Xu et al 2010)

    Puerarin also has vascular effects. It is anti-vasoconstrictive in rat aorta via endothelial nitric oxide production.(Yan et al 2009). Puerarin analogues increase chroidal blood flow.(Xuan B, et al 1999) Puerarin also inhibits vascular endothelial growth factor and hypoxia inducible factor 1 alpha in an experimental rat model of diabetic retinopathy.(Teng Y et al 2009) In patients with diabetic retinopathy, puerarin reportedly caused a lower blood viscosity and improvement in several aspects of retinal circulation.(Ren P et al 2000)

    In summary, Red clover contains several different bioactive isoflavones. Puerarin has the most bioactivity related to eye disease. Its principal mechanism of action is IOP lowering, likely through a beta-blocker effect. There is also evidence that puerarin improves ocular blood flow.



    Adaikan PG, Srilatha B, Wheat AJ. (2009) Efficacy of red clover isoflavones in the menopausal rabbit model. Fertil Steril. 92:2008-2013

    Chedraui P, San Miguel G, Hidalgo L, et al. (2008) Effect of Trifolium pretense-derived isoflavones on the lipid profile of postmenopausal women with increased body mass index. Gynocol Endocrinol. 24:620-624.

    Deng X, Zhang Q, Hu S, et al. (2006) [Pharmacokinetics of puerarin in the aqueous humor and vitrious of rabbit eye following systemic administration] Yan Ke Xue Bao 22:275-279

    Kang RX. (1993) [The intraocular pressure depressive effect of puerarin] Zhonghua Yan Ke Za Zhi 29:336-339

    Teng Y, Cui H, Yang M, et al (2009) Protecitive effect of puerarin on diabetic retinopathy in rats. Mol Biol Rep 36:1129-1133

    Qi H, Chen W, Huang C, et al. (2007) Development of the poloxamer analogs/carbopol-based in situ gelling and mucoadhesive ophthalmic delivery system for puerarin. In J Pharm 7;337:178-187

    Ren P, Hu H, Zhang R. (2000) [Observation on efficacy of peurarin in treating diabetic retinopathy] Zhongguo Zhong Xi Yi Jie He Za Zhi. 20:574-576

    Wu CJ, Huang QW, Qi HY, et al (2006) Promoting effect of bornol on the permeability of puerarin eye drops and timolol maleate eye drops through the cornea in vitro. Pharmazie 61:783-788.

    Xu J, Li X, Sun F. (2010) Preparation and evaluation of a contact lens vehicle for puerarin delivery. J Biomater Sci Polym Ed. 21:271-288

    Xuan B, Zhou YH, Yang RL, et al. (1999) Improvement of ocular blood flow and retinal functions with puerarin analogs. J Ocul Pharmacol Ther 15:207-216

    Yan LP, Zhuang YL, Chan SW, et al. (2009) Analysis of the mechanisms underlying the endothelium-dependent antivascoconstriction of puerarin in rat aorta. Naunyn Schmiedebergs Arch Pharmacol 379:587-597



    Bear Bile

    Douglas Rhee, MD



    Bear bile is produced in the liver, stored in the gall bladder, and extracted from Asian black bears, otherwise known as “moon bears” because of a characteristic white-colored crescent-shaped fur on their chests. The harvest of bear bile is extremely controversial. The active ingredients of bile are ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA), which can be collected from slaughterhouses and purified.

    Bear bile has been prescribed in traditional Chinese medicine for thousands of years for improving vision and other purported benefits.(Cidian 2004; Ventura 2009) As of March 2010, there are no references in pubmed (; search terms “glaucoma,” “tauroursodeoxycholic acid,” “ and ursodeoxycholic acid). “Bear bile” reveals approximately 100 articles. One study has examined the potential therapeutic benefit of TUDCA in a mouse model of retinal degeneration.(Boatright et al. 2006)


    Possible Beneficial Mechanisms of Action


    A recent study by Boatright et al using TUDCA was given subcutaneously (2 doses separated by 16 hours) was given to two mouse models of retinal degeneration, the Pde6brd10 (rd10) and light-induced retinal degeneration (LIRD) mice. Both strains have mutations in the beta subunit of rod photoreceptor cGMP phosphodiesterase causing a loss of photoreceptors through apoptosis. In the TUDCA treated rd10 and LIRD mice, there was a significant decrease in apoptotic markers, using TUNEL and anti-active casepase-3 immunostaining. The preservation of photoreceptors resulted in preserved functioning on electroretinograms. It is noteworthy that RGC are not affected in the rd10 and LIRD mice, nor did treatment affect RGC.(Boatright et al. 2006) Thus, generalizing these findings to glaucoma without further study would not be warranted. In non-ocular tissue, TUDCA has also been shown to decrease the rate of rat cardiac cells undergoing apoptosis following an experimental model of acute myocardial infarction.(Rivard et al. 2007)



    TUDCA has some demonstrated anti-apoptotic effects. It remains unclear if TUDCA acts only through caspase dependent pathways and at what step the cascade is blocked. As the pathogenesis of glaucoma likely involves apoptotic RGC death, TUDCA merits further study in relevant glaucoma models and cell types.



    Boatright JH, AG Moring, C McElroy & et al (2006): Tool from ancient pharmacopoeia prevents vision loss. Mol Vis 12: 1706-1714.

    Cidian ZYD (2004): Dictionary of Traditional Chinese Medicine. Shanghai. Shanghai Science and Technology Press: Pages.

    Rivard AL, CJ Steer, BT Kren & et al (2007): Administration of tauroursodeoxycholic acid (TUDCA) reduces apoptosis following myocardial infarction in rat. Am J Chin Med 35: 279-295.

    Ventura L (2009): Introduction: complimentary medicine in ophthalmology. J Ocul biol Dis Infor 2: 95-97.




    Kwok-Fai SO and Raymond Chuen-Chung CHANG


    This discussion will focus on the Series Panax ginsengs including Panax ginseng and Panax quinquefolius. Ginsenosides are considered the active components of ginseng. The roots of American ginseng (P. quinquefolius) and Asian ginseng (P. ginseng) are taken orally. According to the Chinese medicine literature, ginseng powerfully augments genuine Qi, fortifies the spleen and lung, calms the mind and enhances mental function. The medical concept of Qi is related to it being the basic substance that makes up the human body.

    The root of North American ginseng (Panax quinquefolium) exerts immunostimulatory effects on the CNS.(Kim et al. 1998) The saponin fraction of ginseng, ginsenosides, protects ischemic hippocampal neurons(Lim et al. 1997) and cortical neurons(Kim et al. 1998; Kim et al. 2000) from glutamate-induced neurotoxicity. In addition, saponins of Panax quinquefolius L. delay neuronal death during ischemia(Wen et al. 1996; Attele et al. 1999) and glutamate-induced excitotoxicity.(Kim et al. 1998)

    Using a mixture of American ginseng (P. quinquefolius L) extract, Ginkgo biloba extra and St John’s Wort (Hypericum perforatum) extract, in combination or alone, we have investigated the survival and regeneration of axotomized RGC in an optic nerve transaction model in adult hamsters.(Cheung et al. 2002) Effects of herbal extracts on axonal regeneration was studied by attaching a peripheral nerve graft onto the transected ocular stump to induce regeneration. Operated animals received daily oral administration of vehicle or herbal extracts, alone or in combination, for 7 and 21 days, respectively, in the survival and regeneration experiments. Surviving and regenerating RGC were retrogradely labeled with Fluoro-Gold. The eyes were enucleated and the retinas were flat-mounted for the counting of the labeled RGCs. Treatment with ginseng, Ginkgo biloba and St. John’s Wort alone failed to offer neuroprotection to injured RGC. However, treatment using the mixture with the 3 extracts significantly augmented RGC survival 7 days post-axotomy. Treatment with the same mixture also induced a significant (87%) increase in the number of regenerating RGC 21 days after optic nerve transaction. It also suggests that the therapeutic value of herbal remedies can be maximized by the use of mixtures of appropriate herbs. In an argon laser-induced glaucoma model in rats, there is a 16% RGC loss in the experimental eye with high IOP(Chan et al. 2007) 14 days after the laser-induced injury. Using the same mixture of the 3 extracts, we have shown that almost all RGC survived after the injury (unpublished observation).


    The mechanism on how the herbal extract work is still not clear. However, it may be related to enhancement of the immune system. The immune response triggered by traumatic injury plays a crucial role in neuronal degeneration in the CNS. Autoimmune T cells against myelin basic protein in the CNS significantly promote the recovery and reduce the spread of damaged area in optic nerve and spinal cord crush models.(Moalem et al. 1999; Hauben et al. 2000) The neuroprotective effect of autoimmune T cells may be related to the natural autoimmune T cells found in healthy individuals.(Eitan et al. 1992) Enhancing the neuroprotective effect by increasing the T cell response or modifying the T cells to an appropriate phenotype against a particular insult may provide a novel therapy for neurodegenerative diseases.(Schwartz et al. 1999) Panax ginseng has mitogenic activity to T-lymphocytes.(Mizuno et al. 1994) Polysaccharides from ginseng induce the production of interferon-gamma and of TNF-alpha in vitro.(Gao et al. 1996) Augmentation of cell-mediated immune functions, including chemotaxis, phagocytosis, lymphocytes and natural killer cell activities, have been demonstrated in human after treatment with Panax ginseng.(Scaglione et al. 1990) We hypothesize that herbal extracts exert their neuroprotective function on damaged RGC by enhancing the immune response after experimental glaucoma and optic nerve injury.




    Attele AS, JA Wu & CS Yuan (1999): Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 58: 1685-1693.

    Chan HC, RCC Chang , AKC Ip & et al (2007): Neuroprotective effects of Lycium barbarum Lynn, a traditional Chinese herbal medicine in protecting retinal ganglion cells in an ocular hypertension model of glaucoma. Exp Neurol 203: 269-273.

    Cheung ZH, K-F So, Q Lu & et al (2002): Enhanced survival and regeneration of axotomized retinal ganglion cells by a mixture of herbal extracts. J Neurotrauma 19: 369-378.

    Eitan S, R Zisling, A Cohen & et al (1992): Identification of an interleukin 2-like substance as a factor cytotoxic to oligodendrocytes and associated with central nervous system regeneration. Proc Natl Acad Sci USA 89: 5442-5446.

    Gao H, F Wang, EJ Lien & MD Trousdale (1996): Immunostimulating polysaccharides from Panax notoginseng. Pharm Res 13: 1196-1200.

    Hauben E, U Nevo, E Yoles & et al (2000): Autoimmune T cells as potential neuroprotective therapy for spinal cord injury. Lancet 355: 286-287.

    Kim HS, YT Hong, KW Oh & et al (1998): Inhibition by ginsenosides Rb1 and Rg1 of methamphetamine-induced hyperactivity, conditioned place preference and postsynaptic dopamine receptor supersensitivity in mice. Gen Pharmacol 30: 783-789.

    Kim SR, SH Sung, SW Kwon & et al (2000): Dammarane derivatives protect cultured rat cortical cells from glutamate-induced neurotoxicity. J Pharm Pharmacol 52: 1505-1511.

    Kim YC, SR Kim, GJ Markelonis & TH Oh (1998): Ginsenosides Rb1 and Rg3 protect cultured rat cortical cells from glutamate-induced neurodegeneration. J Neurosci Res 53: 426-432.

    Lim JH, TC Wen, M S. & et al (1997): Protection of ischemic hippocampal neurons by ginsenoside Rb1, a main ingredient of ginseng root. Neurosci Res: 191-200.

    Mizuno M, J Yamada, H Terai & et al (1994): Differences in immunomodulating effects between wild and cultured Panax ginseng. Biochem Biophys Res Commun 200: 1627-1678.

    Moalem G, R Leibowitz-Amit, E Yoles & et al (1999): Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat Med 5: 49-55.

    Scaglione F, F Ferrara, S Dugnani & et al (1990): Immunomodulatory effects of two extracts of Panax ginseng C.A. Meyer. Drugs Exp Clin Res 16: 537-542.

    Schwartz M, I Cohen, O Lazarov-Spiegler & et al (1999): The remedy may lie in ourselves: prospects for immune cell therapy in central nervous system protection and repair. J Mol Med 77: 713-717.

    Wen TC, H Yoshimura, S Matsuda & et al (1996): Ginseng root prevents learning disability and neuronal loss in gerbils with 5-minute forebrain ischemia. Acta Neuropathol (Berl) 91: 15-22.




    Kwok-Fai SO and Raymond Chuen-Chung CHANG



    RGC death underlies visual loss in glaucoma. (Flammer et al., 2002; Harwerth et al., 2002). Although elevated IOP is the most important known risk factor for glaucomatous damage, the pathophysiological mechanisms may be mediated via some combination of IOP-dependent compressive effects of the cribriform plates in the lamina cribosa on the RGC axons, pressure-induced tissue ischemia, and local neuroimmune responses. To protect RGC, non-pharmaceutical medicine may play an important role either directly or by modulating glial responses. For example, involvement of microglia in glaucoma has been reported both in human and animal models. In human glaucomatous eyes, microglia in the optic nerve head and parapapillary region become activated and redistributed.(Neufeld 1999) In animal models, the presence of microglia in retinas exposed to chronic ocular hypertension appears as early as three days and lasts for about two months.(Wang et al. 2000; Naskar et al. 2002) Activation of microglia may provide neuroprotective factors. However, over-activation of these CNS macrophages can be detrimental, because they produce free-radicals and pro-inflammatory cytokines. Having multiple effects on both RGC and the neighboring glial cells, Wolfberry is an ideal candidate in this therapeutic and preventive pursuit.


    Wolfberry (Lycium barbarum L. belonging to the Solanaceae family, also named Fructus Lycii) has been regarded as an “upper class” Chinese medicine, indicating that its fruit can be an ingredient in Chinese cuisine or formulated Chinese medicine. According to tradition, Wolfberry can nourish the liver and kidney, helping the re-balance of ‘Yin’ and ‘Yang’ in the body. The biological effects of Wolfberry have received increasing attention. Its value in Chinese and herbal medicine are high and significant as long as we can provide scientific evidence with modern technology.


    The attractive red color of Wolfberry has led us to believe that it must play a role in strengthening eyesight and protecting our eyes. According to Chinese medicine theory, nourishing the liver in turn nourishes the eyes. Chemical analysis of Wolfberry shows that it contains high levels of carotene and zeaxanthin, which can provide nutrients and anti-oxidants directly to the eyes.(Xie et al. 2001; Carpentier et al. 2009; Li et al. 2009; Nakajima et al. 2009) However, our routine diet does not rely on Wolfberry to provide carotene. Therefore, protective effects of Wolfberry to the eyes should not be limited to high carotene and zeaxanthine content. There are other protective mechanisms, both direct and indirect.


    In fact, increasing lines of experimental studies have revealed that Wolfberry has a wide array of functions which may be due to its high polysaccharide content instead of zeaxanthin and carotene. The polysaccharides in Wolfberry can exhibit anti-aging, anti-tumor, cytoprotective, neuromodulation and immune modulation effects. To elicit anti-aging effects, polysaccharides from Wolfberry modulate other organs or systems. We name this type of modulation ‘indirect effects’. Alternatively, polysaccharides can directly act on cells antagonizing toxins.


    Evidence for the Neuroprotective Effects of Wolfberry

    arly reports from our laboratory demonstrated the neuroprotective effects of Wolfberry in a laser-induced photocoagulation of ocular hypertension model.(Chan et al. 2007) Survival of RGC was nearly 100% back to normal. Indeed, Wolfberry has long been known to improve eyesight.(Li 1885; Sing 1991; Lam & But 1999; Sommerburg et al. 1999; Leung et al. 2001) Recently, it has also been shown that Wolfberry can restore visual function in experimental light-induced phototoxicity and macular degeneration.(Lam & But 1999; Sommerburg et al. 1999; Leung et al. 2001) Wolfberry also protects RGCs from glutamate- and nitric oxide (NO)-induced neuronal apoptosis in the retina.(Lam & But 1999; Sommerburg et al. 1999) Indeed, by using primary neuronal cell cultures as an experimental model, we have recently shown that Wolfberry can antagonize glutamate excitotoxicity.(Ho et al. 2009)

    While attenuation of glutamate and NO neurotoxicity by a natural herb is not surprising, the re-adjustment of body immunity in aging by this natural herb is novel. Polysaccharide isolated from natural herbs serving as biological response modifiers can effectively modulate immunity. For example, the polysaccharide extract of Wolfberry enhances phagocytic activity in macrophages, stimulates proliferation of splenocytes and lymphocytes, activates nuclear factor κB (NF-κB) in B-lymphocytes, up-regulates mRNA expression for interleukin-2 (IL-2) and TNFα in human peripheral blood mononuclear cells, stimulates cytotoxic T lymphocyte (CTL) toxicity, and enhances the production of antibody in experimental rats and even in aged patients.(Du & Qian 1995; Peng et al. 2001; Gan et al. 2003; Gan et al. 2004) As Wolfberry elicits mild but not potent stimulation of immunity, all the above immune stimulatory findings prompt us to hypothesize that polysaccharide extracts can be used to manifest neuroprotection by immunocompetent cells such as microglia/macrophages and lymphocytes. In fact, our results demonstrated that Wolfberry modulates the activation processes of retinal microglia.(Chiu et al. 2009) Further research is needed to examine the role of Wolfberry in manipulating neuroimmune responses of both microglia and astrocytes to protect RGC against glaucoma.

    Wolfberry can also stimulate the expression of neuroprotective and neurotrophic proteins. We have recently shown that Wolfberry can induce the expression of B2-crystallin.(Chiu et al. 2010) Since B2-crystallin is a chaperone to stabilize misfolded proteins and facilitates axon elongation in neuroregeneration,(Liedtke et al. 2007) expression of this kind of chaperone will help RGC survive under stress. In addition to treatment, Wolfberry can reduce the risk factors leading to neurodegenerative diseases. For example, it attenuates the neurotoxicity of hyperhomocysteinemia,(Ho et al. 2010) a risk factor leading to vascular problems and possibly glaucoma.(Clement et al. 2009)

    Taken together, ours and other results have shown that Wolfberry may prevent glaucoma, serve as herbal medicine to treat glaucoma by attenuating pathological factors, exerting direct neuroprotection on RGC and modulate glial responses. Wolfberry has great potential to be developed into a disease-modifying drug for the treatment of glaucoma.



    Astragalus root and Angelica sinensis vs glaucoma

    He wei

    Shenyang He eye hospital

    • Background

    At present ,it is still not reported that Astragalus root and Angelica sinensis directly applied for the treatment of glaucoma . Accroding to the basis of its pharmacological effects and a number of animal model test study ,we found that it may protect the optic nerve of glaucoma.


    • Astragalus root pharmacological effects

    Astragalus is one of the legume , the dry root of Astragalus membrana and Astragalus membranaceus. Now it is used on the Heart disease, strengthen immunity, blood system diseases, etc.But it can reduce the damage of Ischemia and hypoxia..

    It has been reported that astragalus root can reduce the production of ischemia-reperfusion free radicals . And it can eliminate the free radicals and reduce the accumulation of metabolites in the hypoxia organization. In addition, astragalus root can improve microcirculation and increase the resistance of capillaries to prevent the physical and chemical factors that caused an increase in capillary fragility and permeability. [1]


    • Angelica sinensis pharmacological effects

    Chinese angelica is one of Umbelliferae plant , the root of Angelica sinensis is good to human liver, heart, spleen, properties Gan, Xin Wen, blood circulation, regulate menstruation pain, Runzao Hua Chang and other effects, it is one of the most frequently used traditional Chinese medicine. [2]

    The current study found that: Angelica has significant pharmacological effects on the body's cardiovascular system, blood system, immune system and it has anti-tumor, regulate uterine smooth muscle, anti-inflammatory, anti-injury and other role in a wide range of clinical applications.

    The study also found that water extract of angelica can inhibit the chemical iluminescence system, and can scavenge oxygen free radicals.Angelica can removed oxygen free radicals producted by Hypoxanthine -Xanthine oxidase system and hydroxyl free radicals in Fenton reaction. It can inhibit lipid peroxidation in mice liver homogenate supernatant induced by oxygen free radical generation system. [3]

    Ferulic acid is One of the elements of Angelica sinensis. Ferulic acid can reduce the superoxide radical and hydrogen peroxide-induced membrane lipid peroxidation, reduce the formation of malondialdehyde , can significantly reduce the hydroxyl free radical and MDA hemolysis. [4]


    • The study on Angelica inhibit glaucoma apoptosis of retinal ganglion cells

    The retinal ganglion cell damage mechanism is mainly a mechanical theory, flow theory, glutamate toxicity and free radical damage, etc. [5]

    Modern research shows that optic neuropathy caused by glaucoma is based on the retinal ganglion cells (retinal ganglion cells, RGCs) apoptosis. So the possible mechanism of apoptosis in glaucoma RGCs mainly optic hemodynamic abnormalities [6 - 7], glutamate excitotoxicity, free radicals and other metabolic disorders [8 - 10]. Angelica has the effect of passing through the blood circulation ,thus reducing blood viscosity and promoting blood circulation and anti-oxidation. In addition, glutamate excitotoxicity is the most important factor, which triggered Cascade of damage of glaucoma and / or retinal ganglion cell . Glutamate excitotoxicity need a large number of calcium influx,NMDA receptor antagonists and calcium influx inhibition agents can prevent Glutamate excitotoxicity. [11- 12] Angelica has a calcium antagonistic effect and to reduce free radical damage [13]. So Angelica nourishing may lower blood viscosity and improve blood circulation , reduce glutamate toxicity and free radical damage , antioxidant effects, thus inhibiting apoptosis of RGCs to protect RGCs cells.


    • Here are a animal experiments confirmed that Angelica can inhibit the ganglion cell apoptosis.

    The 50 rat model of chronic ocular hypertension was producted by .cauterizing the sclera intravenous. 50 SD rats were divided into normal group, Timolol group (T), Timolol and traditional Chinese medicine group (TC) and high intraocular pressure untreated group (EP). It was observed 4,6,8 weeks,and then put to death to fininsh pathology experiment, counting the number of apoptotic retinal ganglion cells.

    Results: TC apoptotic RGCs number 1.01 ± 0.55 (a / beds), significantly lower than T group 5.1 ± 0.74 and the EP group 7.28 ± 0.44 ( P <0.01). The number of the apoptosis of RGCs is no significant difference between the normal group and treatment group , but obviously lower than the EP group (P <0.01).

    So Angelica has a certain role. in the protection of glaucoma damage .


    • Conclusion

    The study about the effects of Astragalus root and Angelica sinensis in glaucoma optic nerve damage is so little But there is some Theory and their pharmacological effects support our Hypothesis. They may protect the retinal ganglion cells by improve blood circulation ,antioxidant, reduce ischemia-reperfusion damage and so on .However, the lack of clinical trials investigating the benefits of neuroprotective supplements such as Astragalus root and Angelica sinensis in glaucoma limits its current use. So it need more animal and clinical trials to confirm..


    • References





    5.Sucher NJ,Lipton SA,Dreyer EB.Molecular basis ofglutamatetoxicity in retinal ganglion cells. Vision Res,1997,37:3483- 3493

    6. 刘杏, 周文炳, 葛坚, 等.中药川芎嗪治疗原发性开角型青光眼视功能损害的疗效[J].中国实用眼科杂志, 1999,17(l):14- 17

    7.HayReh S S, Zimmer man MB , Jonas J B . NoctUrnal arterial hypotension and its role in OPtic nerve head and ocular ischemic disorders [J]. Amj ophthalmol ,1994, 117, 603- 624

    8. Lam TT, SiewE , Chu R et all. AmeliorativeeffectofMK- 80lon retinal ischemia [ Jl . J 0cul Pharmacol Ther,1997.13:129- 137

    9. Ko ML, Hu DN , RitchR , et all . The Combined effect of Brain- derived neurotrophic factor and a free radical scavenger in experimenial glaucoma . [ J ] . Invest ophihal mol Vis Sci , 2000,41(10):71

    10. Sucher NJ, Lei52, LIPton SA , et all . Calcium channel antagonist sattenuateNMDA recePtor mediated neurotoxity of cells in culture IJI . BrainRes,1991, 551:297

    11.Levy Dl, SucherNJ , LiptonSA , et all·Kedox modulatlo not NMUA receptor meQateQtoxlcl tylnmamm mammalian ceniral neurons. [J].NeurosciLett,1990,110:291- 296

    12. Takahashi K, Lam TT, EdwardD P, et a. Protective effects off luner Izineon ischemic injury in the rat retina [Jl.Arch Ophthalmol ,1992,110:862- 870

    13.顾娟红.黄茂对缺血大鼠心肌钙及脂质过氧化物的影响.[J].上海医科大学学报, 1997,24(4) :270- 272




    Acupuncture and Glaucoma

    Simon Law



    Acupuncture, a branch of Chinese traditional medicine, has been used for over 2000 years in the treatment of various illnesses. In the past two decades, it has grown in popularity in Western countries. In Chinese traditional medicine, the body is seen as a delicate balance of two opposing and inseparable forces: yin and yang. Yin represents the cold, slow, or passive principle, while yang represents the hot, excited, or active principle. An imbalance of these two forces is associated with blockage in the flow of Qi (vital force or energy) and leads to various illnesses. Qi flows along pathways known as meridians with acupuncture points on the human body that connect with them (NCCAM 2009). The underlying philosophy of acupuncture is that disorders related to the flow of Qi can be prevented or treated by stimulating the relevant acupuncture points on the body surface. The points are stimulated typically by inserting needles; however, related techniques such as manual (acupressure), electrical or laser stimulation of acupuncture points are also often included under this term.(Rhee et al. 2001)

    Mechanisms of action

    The exact mechanism or physiologic process of the effects of acupuncture is far from clearly delineated. Research efforts have focused on explaining how it works within the framework of Western medicine. Different mechanisms of action have been proposed.(Cho et al. 2006)(Moffet 2009) The most commonly cited mechanism is that it stimulates the release of neurochemicals (usually endogenous opioids or serotonin). "Gate theory" or segmental effects is another proposed mechanism specifically for analgesia. In the "gate theory", sensory input from acupuncture is thought to block or interfere with nociceptive pain signals at the spinal level. A number of studies also report a possibility of altered physiologic functions that are regulated by the autonomic nervous system, such as heart rate, blood pressure, post-menopausal vasomotor symptoms, and respiration. By incorporating the results from studies on different systems, a model termed the broad sense hypothalamus-pituitary-adrenal (BS-HPA) axis has been proposed.(Cho et al. 2006) The model hypothesizes that the central nervous system is essential for processing the effect of acupuncture by modulating the autonomic nervous system, neuroimmune system and hormonal regulation.(Kim et al. 2007)(Sakai et al. 2007) It seems likely that different mechanisms proposed are part of an elaborate interaction of different body systems. Acupuncture may simply stimulate self-regulatory processes and this would account for reported benefits in many pathologic conditions.(Moffet 2009)


    Potential effects on glaucoma

    Ocular effects associated with acupuncture have been studied in animal models and small samples of subjects. Some studies report potentially beneficial effects of IOP reduction, improvement of central visual acuity, alteration of visual field, increase of ocular blood flow, preservation of normal waveform characteristics of multifocal electroretinogram (mfERG), alteration of visual function tested by visual evoked potential (VEP), and increase of retinal nerve growth factor.

    Intraocular pressure and central vision


    Most clinical studies of the effect of acupuncture on IOP and vision are case series and results are conflicting. Dabov et al(Dabov et al. 1985) reported that treatment resulted in IOP reduction measured by Maklakoff tonometry in 3 of 8 patients with glaucoma. In this study, 50 patients of a variety of eye diseases were enrolled, and all reported a subjective improvement of vision. Uhrig et al(Uhrig et al. 2003) reported a significant IOP decrease 15 minutes and 24 hours after acupuncture treatment in 3 patients with glaucoma and 15 patients with ocular hypertension. Liu et al(Liu et al. 1994) measured IOP before and 5 minutes after single point acupuncture in 79 eyes of 40 normal subjects. IOP was lowered in 49 eyes, increased in 8, and there was no change in 22. Mean IOP was significantly lowered by 1.61 mmHg. Wu et al(Wu et al. 1988) measured IOP after acupuncture (24.9±0.9 mmHg) in 120 patients with primary open angle glaucoma and found it significantly lower than baseline (33.7±1.1 mmHg). Kurusu et al,(Kurusu et al. 2005) in 22 eyes of 11 patients with glaucoma, found IOP significantly reduced and visual acuity significantly improved 15 minutes after acupuncture. However, the effect weakened with time following each treatment, with subjects returning nearly to baseline levels by 3-4 days following a treatment. In 21 patients with POAG and 13 with OHT, Ewert and Schwanitz(Ewert & Schwanitz 2008) found acupuncture to lower IOP significantly. Patients also reported subjective improvement of quality of life and better compliance with medications. Wong et al(Wong & Ching 1980) observed increased visual acuity but no significant change of IOP in glaucoma patients. Sold-Darseff and Leydhecker(Sold-Darseff & Leydhecker 1978) treated 18 patients with glaucoma and found no significant alterations of IOP.

    Most, if not all, of the studies included no control group nor compared acupuncture with application of sham needles. In addition, different types of glaucoma were usually enrolled and patients were frequently on medical therapy with multiple topical drops or systemic carbonic anhydrase inhibitors.

    Research conducted on animals to investigate the effects of acupuncture on IOP has been more consistent. In a rabbit model of glaucoma evaluating the effects of electroacupuncture using two acupuncture needles placed in close proximity to the sciatic nerve, Chu et al(Chu & Potter 2002) noted a reduction of IOP up to 9 hours after the stimulation. A simultaneous reduction of blood pressure, aqueous flow rate, and aqueous catecholamine levels (norepinephrine and dopamine) were recorded during the early time period of electroacupuncture induced hypotension, but sustained IOP reduction seems to be associated with increased aqueous humor endorphin levels. In addition, the opioid receptor antagonist, naloxone, inhibited the IOP reduction associated with electroacupuncture. The electroacupuncture-induced ocular hypotension was reduced markedly in sympathetically denervated eyes.(Chu & Potter 2002) IOP in dogs receiving treatment at 3 acupuncture points was approximately 10% lower than in control dogs receiving no acupuncture.(Kim et al. 2005) Ralston et al(Ralston 1977) observed a decrease in IOP following acupuncture in experimentally induced glaucoma in dogs.


    Visual field


    In a study to ascertain the effects of contralateral acupuncture on brain function using blind-spot mapping, 40 healthy volunteers in whom the right-side blind spot was larger than that on the left were randomly assigned a single point electroacupuncture treatment applied to a point on either the right or the left side of the body. Electroacupuncture to the contralateral side decreased the blind-spot size on perimetry, whereas that to the ipsilateral side increased the blind-spot size. The authors suggested that contralateral side electroacupuncture treatment has a better effect on brain function.(Woo et al. 2006)


    Blood flow


    Chorioretinal blood flow measured with the Heidelberg Retinal Flowmeter showed a significant increase during single point acupuncture between the thumb and forefinger in healthy young volunteers.(Naruse et al. 2000) Experienced subjects showed greater changes than unexperienced ones. Stimulation of specific acupuncture points produced specific effects on blood flow in arteries to the brain and eye. Blood flow velocity in the supertrochlear artery in patients with eye diseases was increased by acupuncture treatment to eye-specific acupuncture points, while no significant increase of blood flow velocity was measured in the middle cerebral artery. On the other hand, stimulation of acupuncture points believed to increase cranial circulation increased blood flow velocity in the middle cerebral artery significantly, but left the supratrochlear artery unaffected.(Litscher et al. 1999) In another study, blood flow velocity of the ophthalmic artery in healthy volunteers increased during acupuncture.(Litscher 2002) Increase of blood flow volume of the central retinal artery (CRA) was associated with treatment with only one of the 3 acupuncture points studied along the GB meridian as measured by Color Doppler imaging and acupuncture treatment of a non-meridian acupuncture point was not associated with change of retinal blood flow.(Mizukami et al. 2006)


    Multifocal ERG (mfERG)


    In a rat glaucoma model, Chan et al(Chan et al. 2005) found that 2-Hz but not 100-Hz electroacupuncture treatment preserved mfERG waveform characteristics in terms of the N/P ratio. The same group had previously shown that 2-Hz electroacupuncture treatment inhibit the expression of nitric oxide synthase-2 (NOS-2), which may have a role in glaucoma damage.(Leung et al. 2000)


    Visual evoked potential (VEP)


    Sagara et al(Sagara et al. 2006) analyzed 19 healthy subjects (38 eyes) and found that in those with delayed P100 latencies of ≥101.7 msec (total average of the group), acupuncture stimulation contributed to a pattern reversal of the VEP by shortening the P100 latency to closer to the average.


    Retinal growth factor


    Applying low-frequency electroacupuncture treatment to Royal College of Surgeons (RCS) rats (an inherited retinitis pigmentosa rat model) during a critical developmental stage of retinal cell degeneration was associated with an increase of retinal nerve growth factor (NGF) protein and brain derived nerve factor (BDNF) protein and NGF high-affinity receptor (TrkA) expression, when compared with controls.(Pagani et al. 2006) The treatment was also associated with an increase of outer nuclear layer (ONL) thickness and enhanced vascularization.


    Retinal ganglion cells (RGCs)


    In rabbits subjected to high-pressure perfusion of the anterior chamber by increasing IOP to 30 mmHg and 50 mmHg, those receiving electroacupuncture treatments had more relatively intact RGC remaining compared to those without treatment.(Zhou et al. 2008)


    Limitations of study


    The term acupuncture embraces a variety of stimulation techniques, including different types of acupuncture needles used, electric or laser stimulation with or without needle acupuncture, application of moxibustion with acupuncture, and acupressure without needling. In addition, different acupuncture points or groups of points, different intensity, duration, and frequency or repetition rate of stimulation were studied under the same category of acupuncture.

    The acupuncture points chosen for studying the effect on glaucoma were usually based on clinical experience and traditional theory of Chinese medicine. It is important to remember that Chinese traditional medicine views diseases as an imbalance of two opposing forces, yin and yang. Therefore, the selection of points was based on the traditional way of using points for symptoms and applied to a new disease.(Blackwell & Macpherson 1992) Clinically, the number of main points or supplemental points to be used for treating a particular disease or symptom is not fixed and may vary during the course of acupuncture treatment based on the patient’s response. For instance, it is customary to use the traditional eye specific main points initially and judging from the response, resort to supplemental points when necessary. This clinical heterogeneity makes comparisons or analyses on studies on acupuncture difficult. For instance, the number of acupuncture points studied may vary from 1 to more than 20 among different studies.

    Most of the studies of the effects of acupuncture on glaucoma are case series with no comparison group or control group included. A comparison group on another treatment may provide a valid differentiation of the exposure to acupuncture treatment, but possible placebo effects associated with acupuncture treatment cannot be controlled for. Some acupuncture studies on other illnesses include a control group using sham acupuncture. However, sham acupuncture may not be considered as a non-inert placebo and may elicit a physiological response. One may argue that the effects of acupuncture may not depend on specific points, location or techniques.(Moffet 2006)



    Complications and safety


    Relatively few complications from the use of acupuncture have been reported to the Food and Drug Administration (NCCAM 2009).




    Because of ethical considerations, randomized clinical trials comparing acupuncture alone with standard glaucoma treatment or placebo are unlikely to be justified in the near future in countries where standards of care have already been established. However, trials in which acupuncture in combination with another glaucoma treatment is compared with the other glaucoma treatment alone will be of interest. It would be valuable for experienced researchers and clinicians to agree on certain basic standards in administration of acupuncture in clinical trials. Adequate data on IOP, central visual acuity, contrast sensitivity, visual field changes, optic nerve and retinal nerve fiber layer analysis, ocular blood flow, pattern electroretinography (PERG), multifocal ERG, visual evoked potential (VEP), multifocal visual evoked potential (mfVEP), potential harms, visual-related quality of life and economic outcomes will help in evaluating effectiveness and safety of acupuncture appropriately.(Law & Li 2007)





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    Chan HH, MC Leung & KF So (2005): Electroacupuncture provides a new approach to neuroprotection in rats with induced glaucoma. J Altern Complementary Med 11: 315-322.

    Cho ZH, SC Hwang, EK Wong & et al (2006): Neural substrates, experimental evidences and functional hypothesis of acupuncture mechanisms. Acta Neurol Scand 113: 370-377.

    Chu TC & DE Potter (2002): Ocular hypotension induced by electroacupuncture. J Ocul Pharmacol Therap 18: 293-305.

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    Ewert H & R Schwanitz (2008): [Influence of acupuncture on intraocular pressure and compliance of patients with ocular hypertension or primary wide-angle glaucoma. First results of a controlled prospective follow-up study]. Deutsche Zeitsch Akupunktur 51: 13-20.

    Kim HW, SY Kang, SY Yoon & et al (2007): Low-frequency electroacupuncture suppresses zymosan-induced peripheral inflammation via activation of sympathetic post-ganglionic neurons. Brain Res 1148: 69-75.

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    Litscher G, L Wang, NH Yang & G Schwarz (1999): Computer-controlled acupuncture. Quantification and separation of specific effects. Neurol Res 21: 530-534.

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    Clement C.Y. Tham



    Glaucoma is a disease of the optic nerve, with progressive and irreversible loss of optic nerve fibers. Risk factors for glaucoma include intraocular pressure (IOP), age, race, family history, refractive error, and vascular factors. Exercise has both short- and long-term effects on IOP and vascular factors, such as ocular blood flow (OBF). Exercise may, therefore, influence the pathogenesis and / or progression of glaucoma.


    Potentially beneficial effects of exercise in glaucoma patients

    Intraocular pressure-lowering effects

    Isometric exercise is defined as work performed by a muscle with no change in the length of that muscle. In general, acute isometric exercise results in acute but transient IOP reduction,(Harris et al., 1992,Marcus et al., 1974) which correlates with hyperventilation and hypocapnia.(Poole et al., 1988,Imms and Mehta, 1989,Marcus et al., 1974,Wiley and Lind, 1971)

    Dynamic (isokinetic) exercise is defined as work performed by a muscle with change in length of that muscle. Walking and swimming are examples of dynamic exercise. Acute dynamic exercise results in acute but transient IOP lowering in the post-exercise period.(Leighton and Phillips, 1970,Leighton, 1972,Myers, 1974,Qureshi, 1996,Qureshi, 1995a,Qureshi, 1995b) The magnitude of IOP lowering can be up to 12.86 mmHg in glaucoma patients. IOP lowering induced by dynamic exercise appears to correlate with the intensity of the exertion,(Qureshi, 1995b,Harris et al., 1994,Qureshi et al., 1996b,Kiuchi et al., 1994) and is more pronounced in glaucoma patients than in normals.(Qureshi, 1995b) It has no significant correlation with blood pressure,(Qureshi et al., 1996b,Karabatakis et al., 2004) heart rate,(Krejci et al., 1981) or hypocapnia.(Martin et al., 1999) The IOP-lowering effect appears to be addictive to the effect of glaucoma drugs.(Natsis et al., 2009) There is no significant difference in IOP lowering between aerobic and anaerobic exercises.(Kielar et al., 1975) Dynamic exercise results in greater IOP reduction than isometric exercise, but of shorter duration.(Avunduk et al., 1999,Avunduk et al., 1999)

    The mechanisms underlying exercise-induced IOP reduction are not well delineated. Three mechanisms have been proposed: osmotic dehydration of the globe, reduced aqueous production due to reduced ultrafiltration, and a hypothalamic reflex.(Feitl and Krupin, 1996,Podos et al., 1971,Krupin and Civan, 1996)

    The above exercise-induced IOP lowerings were all short-lived, and their relevance in the long-term management of chronic glaucoma is uncertain. Long-term regular exercise is associated with overall improvement in physical fitness. Physical fitness appears to be associated with lower baseline IOP (Qureshi et al., 1996a,Passo et al., 1992,Passo et al., 1991,Passo et al., 1987) but diminished acute IOP-lowering response to exercise.(Qureshi, 1996,Passo et al., 1987,Qureshi et al., 1996a) On termination of the exercise regimen, values return to pre-training levels within 3 weeks.(Passo et al., 1991) Such sustained reduction of IOP associated with regular exercise and improved physical fitness may be more relevant to the halting of glaucoma progression, but controlled studies are needed to confirm such potential therapeutic benefits.


    Effect of exercise on ocular blood flow

    Reduced ocular blood flow (OBF) is a potential risk factor for glaucoma.(Moore et al., 2008) In healthy subjects, OBF is unchanged during exercise due to vascular autoregulation.(Kiss et al., 2001,Riva et al., 1997) This autoregulation fails at ocular perfusion pressures greater than 67% above baseline.(Kiss et al., 2001,Riva et al., 1997) The relevance of these findings to the pathogenesis and progression of glaucoma is uncertain. The effect of exercise on OBF in glaucoma patients has not been studied.


    Potential deleterious effects of exercise in glaucoma patients

    Certain isometric exercises, such as weightlifting and exercise at maximal exertion, may paradoxically increase IOP,(Brody et al., 1999,Dane et al., 2006a,Dane et al., 2006b,Dickerman et al., 1999,Vieira et al., 2006,Wimpissinger et al., 2003) and the increase may be even more significant when the subjects are holding their breath.(Vieira et al., 2006) Raised intracranial pressure may contribute to the IOP increase.(Dickerman et al., 1999)

    Exercise may also provoke increased IOP in patients with pigmentary glaucoma.(Gallenga et al., 1997) In these patients, the potentially harmful effect of exercise on IOP should be carefully weighed against the beneficial effects of exercise on general health.

    Young adults with advanced glaucoma may sometimes experience a temporary loss of vision during vigorous exercise. This was attributed to a ‘vascular steal’ phenomenon.(Shah et al., 2001) The relevance of this phenomenon to glaucoma progression is uncertain.



    In general, acute exercise results in an acute but transient IOP reduction in the post-exercise period. Physical fitness secondary to a long-term regular exercise regimen is associated with lower long-term baseline IOP. Certain types of exercise, e.g. weight lifting, may increase IOP. Certain subtypes of glaucoma, e.g. pigmentary glaucoma, may have IOP increase after exercise. However, it remains uncertain whether such exercise-induced IOP changes correlate with glaucoma pathogenesis and / or progression. Taking also into consideration the beneficial effects of exercise on general health and well being, the author believes glaucoma patients should be encouraged to perform regular aerobic exercise.





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    Stress in glaucoma

    Lori Ventura



    The effects of psychological stress on ocular illness in general and on glaucoma in particular are given little to no consideration in the pathogenesis or treatment of disease. It is clear from a plethora of articles in all fields of medicine that no organ system is protected from the effects of negative emotional states.[1] As a part of the central nervous system, and privy to the alarmed cross-talk of local hormones and neurotransmitters, one would surmise that the eye and its projections would be particularly vulnerable to the effects of psychological stress.


    The stress response

    Sympathetic activation

    The complexities of stressor-induced activation of SAM (sympathetic adrenomedullary) and the HPA (hypothalamic pituitary axis) and has been comprehensively reviewed in other publications.[2-4] An abbreviated summary of the neural pathways provoked by stressors is provided here. Stressful stimuli may first be perceived visually or auditorily, or may be triggered by emotional signaling or imagery at the right pre-frontal cortex. Whatever the origin of the stressor, there is signaling to the hippocampus for an interpretation of the event based on memory. From the hippocampus, stimuli which evoke a fear response will synapse with neurons in the amygdala sending efferent projections to the paraventricular nucleus (PVN) of the hypothalamus which secretes corticotropin releasing hormone (CRH) and arginine vasopressin (AVP).[5] In addition to an antidiuretic effect, AVP increases peripheral vascular resistance to increase arterial blood pressure. Corticotropin releasing hormone (CRH) travels in the hypothalamo-hypophyseal portal circulation to the pituitary (perhaps within 10 seconds) to stimulate the release of ACTH, enkephalins and endorphins.[5, 6] In addition to regulation of ACTH release (and later cortisol production), CRH flows diffusely throughout the brain, and serves as a neurotransmitter that mediates acute as well as chronic sympathetic arousal, providing an important link between the autonomic and adrenocortical branches of the stress response.[6] Noradrenergic centers in the brainstem (locus coeruleus) and spinal cord activate the sympathetic adrenomedullary (SAM) release of epinephrine from the adrenal medulla and norepinephrine from the peripheral autonomic nervous system. CRH and noradrenergic neurons in the CNS innervate and stimulate each other.[5]


    Activation of the hypothalamic pituitary axis (HPA)

    Acutely stressful stimuli activate SAM within seconds as well as neurons of the hypothalamus to produce cortisol release hormone (CRH). CRH-containing neurons stimulate the pituitary to release ACTH, endorphins and enkephalins into the bloodstream.[5] ACTH then stimulates the release of cortisol from the adrenal cortex. The hypothalamic pituitary axis (HPA) response to stress is not as immediate as SAM, but occurs within minutes.[6] Under normal non-stressed conditions, cortisol levels peak in the early morning hours, fall over the course of the day, in a fairly steep slope, to reach a low around 4PM and remain low throughout the night only to peak again in the morning, and this is known as the diurnal fluctuation. Under conditions of chronic stress, the feedback inhibition of cortisol at the hypothalamus is dysregulated to result in a flattening of the normally steep slope whereby serum cortisol levels should significantly fall over the course of the day. With chronic stress and a flattened cortisol slope the levels of serum cortisol remain elevated throughout the afternoon and night, never falling to the lowest levels of the normal diurnal curve. How this dysregulation occurs is complex. It is due, in part, to CNS noradrenergic stimulation of CRH which overrides feedback inhibition at the hypothalamus.[6] Cortisol receptors at the hypothalamus may become less sensitive under chronically stressful conditions.




    Chronic Psychological Stress

    Conditions that produce the chronic elevation of cortisol, are life altering events which are associated with sleeplessness. The conditions which are most likely to induce chronic debilitating stress are the emotional adjustments of retirement, reduction in income, chronic illness, loss of mobility or function, isolation from or loss of loved ones, marital discord, divorce, chronic strain such as caregiver’s stress, problems with children, re-location, problems with school performance, work dissatisfaction, and many others.




    The first mechanism by which stress may cause injury to the eye is through diminished microvascular perfusion through sympathetic nervous system overdrive. Acutely, the immediate response to psychological stress is activation of sympathetic adrenomedullary axis or SAM, with vasoconstriction of blood vessels which may be narrowed to varying degrees from years of arteriolosclerosis. Stress-induced vasospasm may compromise perfusion of the microvascular beds of the circulatory system of the optic nerve, thereby inducing hypoxia, which may acutely exacerbate glaucoma. Initial ischemic insult with a sudden vaso-occlusive event, or subsequent reperfusion injury may induce damage. Chronic psychological stress, with ongoing activation of SAM, results in vasoconstriction which may be prolonged, and may lead to hypertension and accelerated progression of arteriolosclerosis. Ocular conditions which may theoretically be exacerbated by acute or chronic psychological stress would be any of the microangiopathic diseases such as hypertensive retinopathy and/or diabetic retinopathy, etc.



    Endogenous cortisol elevation

    The second potential mechanism of how stress may exacerbate ocular disease is through the overdrive of the hypothalamic pituitary axis (HPA). As mentioned, chronic psychological stress has been shown to elevate cortisol levels to induce a flattening of the daytime cortisol slope. [7] Such chronic cortisol elevation, and flattening of the slope, is associated with worsening outcomes in breast cancer [7], and may have deleterious effects on ocular diseases. There is an implied association between chronic stress and central serous chorioretinopathy(CSR), since CSR is known to occur in Cushing’s Disease with endogenous cortisol excess.[8] Ocular hypertension and glaucoma also occur in endogenous Cushing’s Disease.[9]





    Psychological stress and vasospasm in glaucoma

    Retinal ganglion cells (RGCs) as one of the most metabolically active cells of the body have high numbers of mitochondria. Mitochondria play an important role in energy (ATP) production through the oxidative phosphorylation pathway and the regulation of cell death by apoptosis.[10] Mitochondria are particularly abundant along the unmyelinated intraretinal axons of the RGCs to supply energy in high demand for electrical conduction and axonal transport.[11] A steady supply of oxygen is necessary for oxidative phosphorylation to generate ATP. The microvascular supply of oxygen to RGC axons may deteriorate with aging as progressive arteriolosclerosis may result in vascular compromise of the inner retinal circulation. There is a natural loss of RGCs with aging in the normal population.[12] Several risk factors for glaucoma have been identified, some of which are strong including high intraocular pressure, increasing age, family history of glaucoma, Black race, and other possible risk factors including high myopia, hypertension, diabetes, migraine headache and vasospasm. These latter four implicate further vascular insult to an already compromised microvascular supply of oxygen secondary to the arteriolosclerotic changes of aging. Psychological stress-induced vasospasm of the supply to the optic nerve may further reduce perfusion in these diseased conditions, and theoretically worsen axonal function which may lead to premature apoptosis. Whether the ischemia itself and/or reperfusion injury damages these structures is under investigation.[10]


    Stress and endogenous cortisol elevation in glaucoma

    Endogenous elevation of cortisol levels secondary to chronic psychological stress may be damaging to the trabecular outflow apparatus depending on the concentration and duration of this elevation. Human trabecular meshwork cells contain glucocorticoid receptors[13, 14], and would therefore be expected to respond to glucocorticoid administration. The exogenous administration of glucocorticoids in man can generate a progressively elevated intraocular pressure (IOP) which is dependent on glucocorticoid potency, pharmacokinetics, duration of treatment, route of administration, as well as differences in individual responsiveness.[15] Glucocorticoid-induced ocular hypertension is due to increased aqueous humor outflow resistance.[15, 16] Morphological examination of the trabecular meshwork of patients with glucocorticoid-induced glaucoma has shown an increased deposition of extracellular material in the trabecular beams and in the juxtacanalicular tissue, and a decrease in intratrabecular spaces.[15, 17] With topical, periocular, intravitreal or oral administration of steroids for ocular inflammatory conditions, patients may suffer from a steroid-induced intraocular pressure elevation which may be severe and prolonged enough to require filtering surgery of the eye to lower the IOP. Jaffe et al[18] studied the effects of intravitreal fluocinolone acetonide implants (Retisert) for treatment of uveitis. By week 34 following implantation, 51.1% of implanted eyes required ocular antihypertensive drops, and 5.8% underwent glaucoma filtering surgery. During this same period, the IOP of the fellow eyes did not rise significantly. In August of 2008, safety labeling changes were approved by FDA’s Center for Drug Evaluation and Research (CDER). Based on clinical trials with Retisert, CDER warned that approximately 77% of patients will require IOP lowering medications to control intraocular pressure and 37% of patients will require filtering procedures to control intraocular pressure within 3-years post implantation. Endogenous cortisol elevation of Cushing’s Disease is known to be associated with ocular hypertension.[9] At the Bascom Palmer Eye Institute, an anecdotal case of an intraocular pressure spike in a previously controlled glaucoma patient stricken by a severe chronic psychological stressor has been observed. Pressure elevation lasted for several weeks, and then returned to baseline levels as the patient coped with and adjusted to the stressor. The relationship between endogenous cortisol elevation and intraocular pressure responses requires further study.


    Immune balance in glaucoma

    Inflammatory mechanisms of glaucoma are being studied by different investigators. Michal Schwartz has pioneered the concept of harnessing the immune system to combat neurodegenerative diseases including glaucoma.[19] Her group has shown that immune deficiency or suppression impair the recovery process after optic nerve crush, whereas boosting a self-specific immune response, by both passive and active immunization, promotes recovery. Those same T cells that can lead to the development of autoimmune disease can protect neurons under neurodegenerative conditions, and it is a sub-population of regulatory T cells which regulates the autoimmune response to promote protection over injury. Dr. Schwartz’ team introduced the concept of a therapeutic T-cell mediated vaccination to boost the immune response to facilitate neuroprotection in glaucoma.[19] This immune defense involves lymphocytes, resident and infiltrating innate immune cells, the microglia, and macrophages. The antigens of choice are synthetic antigens, such as glatiramer acetate, that weakly cross-react with self-antigens in the retina and optic nerves. The vaccine induces a beneficial immune response that recruits immune effector cells to counteract or neutralize many of the compounds and factors that contribute to ongoing destruction, and in addition supports cell renewal and repair.[20]


    Immune balance and psychological stress in glaucoma

    Working with Cohen et al[21], Dr. Schwartz has also published that maladaptation to mental stress in mice was mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4+CD25+ cells. This begs the question of how maladaptation to psychological stress may affect immune balance in patients with glaucoma. Furthermore, a different team lead by Wax and Tezel has proposed that the inflammatory cytokine TNF-may be harmful to retinal ganglion cells thereby having an etiologic role in glaucoma.[22, 23] While ischemic insults are implicated as the trigger for TNF-mediated damage to the RGC, it is not known what effect psychological stress may have as an inciting factor in RGC damage in glaucoma. It is known that psychosocial stress may alter TNF- production in other diseases such as cancer, Chron’s disease, and other autoimmune conditions.



    When IOP is markedly elevated, clinicians often inquire about the recent use of oral, topical or injected steroids, but fail to ask about emotional stressors. There is an implication that since exogenous steroid use may lead to increased intraocular pressure and glaucoma, a prolonged stress-induced increase in endogenous cortisol and catacholamines, with subsequent alterations of the immune response, may also be at play. Clinicians may consider inquiry regarding potential psychosocial or environmental stressors in the context of a previously well-controlled glaucoma patient who develops a dramatic IOP increase or sudden deterioration of function. Finally, the effects of meditation [24] and acupuncture[25] which are thought to act on enhanced parasympathetic tone and the release of endorphins[26], may be helpful in mitigating the stress response in glaucoma.



    1. Vedhara, K.a.I., M, Human Psychoneuroimmunology. 2005, Oxford: Oxford University Press.

    2. Chrousos, G.P., Stressors, stress, and neuroendocrine integration of the adaptive response. The 1997 Hans Selye Memorial Lecture. Ann N Y Acad Sci, 1998. 851: p. 311-35.

    3. Charmandari, E., C. Tsigos, and G. Chrousos, Endocrinology of the stress response. Annu Rev Physiol, 2005. 67: p. 259-84.

    4. McEwen, B.S., Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann N Y Acad Sci, 2004. 1032: p. 1-7.

    5. Tausk, F., I. Elenkov, and J. Moynihan, Psychoneuroimmunology. Dermatol Ther, 2008. 21(1): p. 22-31.

    6. Sapolsky, R.M., L.M. Romero, and A.U. Munck, How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev, 2000. 21(1): p. 55-89.

    7. Sephton, S.E., et al., Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst, 2000. 92(12): p. 994-1000.

    8. Garg, S.P., et al., Endogenous cortisol profile in patients with central serous chorioretinopathy. Br J Ophthalmol, 1997. 81(11): p. 962-4.

    9. Huschle, O.K., et al., [Glaucoma in central hypothalamic-hypophyseal Cushing syndrome]. Fortschr Ophthalmol, 1990. 87(5): p. 453-6.

    10. Kong, G.Y., et al., Mitochondrial dysfunction and glaucoma. J Glaucoma, 2009. 18(2): p. 93-100.

    11. Wang, L., et al., Varicosities of intraretinal ganglion cell axons in human and nonhuman primates. Invest Ophthalmol Vis Sci, 2003. 44(1): p. 2-9.

    12. Porciatti, V. and L.M. Ventura, Normative data for a user-friendly paradigm for pattern electroretinogram recording. Ophthalmology, 2004. 111(1): p. 161-8.

    13. Weinreb, R.N., et al., Detection of glucocorticoid receptors in cultured human trabecular cells. Invest Ophthalmol Vis Sci, 1981. 21(3): p. 403-7.

    14. Hernandez, M.R., et al., Glucocorticoid target cells in human outflow pathway: autopsy and surgical specimens. Invest Ophthalmol Vis Sci, 1983. 24(12): p. 1612-6.

    15. Wordinger, R.J. and A.F. Clark, Effects of glucocorticoids on the trabecular meshwork: towards a better understanding of glaucoma. Prog Retin Eye Res, 1999. 18(5): p. 629-67.

    16. Bernstein, H.N. and B. Schwartz, Effects of long-term systemic steroids on ocular pressure and tonographic values. Arch Ophthalmol, 1962. 68: p. 742-53.

    17. Rohen, J.W., E. Linner, and R. Witmer, Electron microscopic studies on the trabecular meshwork in two cases of corticosteroid-glaucoma. Exp Eye Res, 1973. 17(1): p. 19-31.

    18. Jaffe, G.J., et al., Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study. Ophthalmology, 2006. 113(6): p. 1020-7.

    19. Bakalash, S., et al., T-cell-based vaccination for morphological and functional neuroprotection in a rat model of chronically elevated intraocular pressure. J Mol Med, 2005. 83(11): p. 904-16.

    20. Schwartz, M., Modulating the immune system: a vaccine for glaucoma? Can J Ophthalmol, 2007. 42(3): p. 439-41.

    21. Cohen, H., et al., Maladaptation to mental stress mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4+CD25+ cells. J Neurobiol, 2006. 66(6): p. 552-63.

    22. Yan, X., et al., Matrix metalloproteinases and tumor necrosis factor alpha in glaucomatous optic nerve head. Arch Ophthalmol, 2000. 118(5): p. 666-73.

    23. Tezel, G. and M.B. Wax, Increased production of tumor necrosis factor-alpha by glial cells exposed to simulated ischemia or elevated hydrostatic pressure induces apoptosis in cocultured retinal ganglion cells. J Neurosci, 2000. 20(23): p. 8693-700.

    24. Tang, Y.Y., et al., Central and autonomic nervous system interaction is altered by short-term meditation. Proc Natl Acad Sci U S A, 2009. 106(22): p. 8865-70.

    25. Mori, H., et al., Pupillary response induced by acupuncture stimulation--an experimental study. Acupunct Med, 2008. 26(2): p. 79-86.

    26. Sapolsky, R.M., Why Zebras Don't Get Ulcers. 2nd ed. 1998, New York: W. H. Freeman.





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