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Melatonin and Glaucoma
Melatonin is a hormone synthesized in both plants and animals from the amino acid L-tryptophan. In mammals, such as humans, it is secreted by the pineal gland -- and by the retina -- and modulates the body's sleep pattern (and much more). Melatonin production in the body is triggered by darkness and inhibited by light, helping the body manage its natural rhythm. It is available over the counter as a dietary supplement in the United States.
As you will see below, melatonin, by itself, may fulfill all the ideal requirements of a future glaucoma treatment and thus, therapies based on the application of melatonin may have significant potential as a new strategy in glaucoma management.
Melatonin is available in the FitEyes eStore. One recommended product is Melatonin Natural Sleep 60 vcaps by Life Extension
Melatonin and its metabolites are potent protectors against oxidative stress in neurons and have been considered candidate substances for the treatment of neurodegenerative diseases of the central nervous system including glaucoma (see below).
Melatonin has a number of important and diverse functions. As mentioned, it is an antioxidant. It is also a regulatory compound. In the retina it acts as a free radical scavenger (antioxidant) and as a regulator of rod outer segment disc shedding.(White & Fisher 1989; Bandyopadhyay et al. 2000) In other words, it has a protective effect on the photoreceptors' outer membranes and can reverse the effect of ocular hypertension on retinal function.
Melatonin not only protects ocular tissue against free radicals, but also it has a direct effect on intraocular pressure ("IOP"). Several studies have shown circadian changes of the IOP and in particular an effective reduction in the IOP via melatonin. In this context, the circadian (physiological reduction during the night) and seasonal rhythmicity of IOP as well as the influences of nocturnal ocular blood flow and sleep on the IOP could be phenomena associated with the timing of melatonin release.
Melatonin has been shown to directly reduce intraocular pressure and, therefore, may have clinical potential for treating elevated eye pressure.
Melatonin is also a neurohormone that binds to plasma membrane receptors (MT1/MT2).
Melatonin has received attention in various conditions including glaucoma, stroke, Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis. It 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 (programmed cell death) 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)
Partly from an article by Nathan Radcliffe, MD and other sources. See source statement at bottom.
Melatonin and Glaucoma
From article published in Journal of Pineal Research 2010 49(1):1-13
Ruth E. Rosenstein.1,CA Seithikurippu R. Pandi-Perumal,2 Venkataramanujan Srinivasan,3 D. Warren Spence,4 Gregory M. Brown5, Daniel P. Cardinali6
See source statement at bottom.
In most mammals, melatonin is synthesized intraocularly through the same pathway which occurs in the pineal gland (Axelrod, 1974).
Immunocytochemical analysis of ocular tissues obtained from various species, including chickens, rats, and humans, shows that melatonin receptors MT1 and MT2 (formerly Mel1a and Mel1b, respectively) are localized in the cornea, choroid, sclera, retina, and retinal blood vessels (Ascher et al., 1995; Fujieda & Hamadanizadeh, 1999; Scher et al., 2002; Savaskan et al., 2002b; Scher et al., 2003; Wiechmann et al., 2004; Rada & Wiechmann, 2006)
The localization of melatonin receptors in the iris and ciliary processes could indicate that they may be involved in regulating IOP (Osborne et al., 1999). The presence of melatonin receptor Mel1c in the non-pigmented epithelium of the chicken (Wiechmann & Wirsig-Wiechmann, 2001) suggests that melatonin may affect the rate of aqueous humor secretion by the ciliary epithelium and the circadian rhythm of IOP.
Glaucoma, a chronic disease characterized by visual field loss, cupping of the optic nerve head, and irreversible loss of RGCs, is a leading cause of blindness worldwide. It is estimated that half of those affected may not be aware of their condition because symptoms may not occur during the early stages of the disease. When vision loss appears, considerable and permanent damage has already occurred. Medications and surgery can help slow the progression of some forms of the disease, but there is no cure at present. Increased IOP is considered the major risk factor in glaucoma, but visual field loss may continue despite successful lowering IOP. Although the clinical features of glaucoma are well described, the mechanisms resulting in optic nerve damage and RGC death remain to be elucidated.
Melatonin concentration in aqueous humor parallels its concentration in plasma, peaking during the dark period (Yu et al., 1990; Liu & Dacus, 1991). Inasmuch as the circadian rhythm of aqueous humor secretion likely contributes to the circadian rhythm of IOP (Smith & Gregory, 1989), it has been suggested that melatonin affects aqueous humor secretion (Wiechmann & Wirsig-Wiechmann, 2001). In nocturnal animals, IOP is low during the light period and high in the dark period (Frampton et al., 1987; Smith & Gregory, 1989; Liu & Dacus, 1991; Benozzi et al., 2002). In contrast, studies in diurnally active humans reveal that IOP levels peak during 11 daytime (Kitazawa & Horie, 1975). Although it has been demonstrated that the administration of melatonin reduces IOP in humans (Samples et al., 1988), to what extent melatonin levels affect circadian IOP rhythm remains to be defined (Osborne, 1994; Pintor et al., 2001). The effect on IOP of topical application of the MT3 (QR2) melatonin binding site agonist 5- methoxycarbonylamino-N- acetyltryptamine (5-MCA-NAT) was evaluated in glaucomatous monkey’s eye (Serle et al., 2004). It was demonstrated that 5-MCA-NAT substantially reduces IOP in glaucomatous monkeys with reductions in IOP ranging from 10 % on day one up to 19 % on day 5, the ocular hypotensive effect lasting for at least 18 hours.
In addition to ocular hypertension, several concomitant factors including elevation of glutamate levels, disorganized NO metabolism, and oxidative damage caused by overproduction of ROS, may significantly contribute to glaucomatous neurodegeneration [for a review, see Hashida et al., 2000). In particular, NO is believed to play a significant role in experimental glaucoma (Neufeld et al., 1997; Neufeld, 2004; Belforte et al., 2007). Although NO is a ubiquitous signaling molecule that participates in a variety of cellular functions, in concert with reactive oxygen species, NO can be transformed into a highly potent and effective cytotoxic entity with pathophysiological significance. NO may also signal through the interaction with reduced cysteines of proteins, changing their function (Martinez-Ruiz & Lamas, 2004), and it modulates the activity of various proteins that contribute to apoptosis (Melino et al., 1997). Furthermore, it has been demonstrated that an extracellular proteolytic pathway in the retina contributes to retinal ganglion cells death via NO-activated metalloproteinase-9 (Manabe et al., 2005).
Several studies, most of them based on Western blotting or immunohistochemical analysis, addressed the issue of NO involvement in human or experimental glaucoma. Increased levels of neuronal NOS (NOS-1) and inducible NOS (NOS-2) were reported in astrocytes of the lamina cribosa and optic nerve head from patients with primary open-angle glaucoma (Liu & Neufeld, 2000). In rats whose extraocular veins were cauterized to produce chronic ocular hypertension and retinal damage, increased expression of NOS-2 but not NOS-1 was found in optic nerve head astrocytes (Wang et al., 2005). Moreover, elevation of hydrostatic pressure in vitro was associated with upregulation of NOS-2 expression in human astrocytes derived from the optic nerve head (Liu & Neufeld, 2000). Most importantly, inhibition of NOS-2 was found to protect against ganglion cell loss in the rat cautery model of glaucoma (Neufeld, 2004). These data support that activation of NOS, especially NOS-2, may play a significant role in glaucomatous optic neuropathy. However, in contrast to these results, Pang et al. (Pang et al., 2005) showed that chronically elevated IOP in the rat induced by episcleral injection of hypertonic saline does not increase NOS-2 immunoreactivity in the optic nerve head, nor in ganglion cell layer.
Moreover, retinal and optic nerve head NOS-2 mRNA levels did not correlate with either IOP level or severity of optic nerve injury, and, additionally, there was no difference between glaucomatous and non-glaucomatous eyes in terms of NOS-2 immunoreactivity in the optic nerve head. Furthermore, aminoguanidine treatment did not affect the development of pressure- induced optic neuropathy in rats (Pang et al., 2005). As already mentioned, these studies did not assess changes in the functional capacity of the retinal nitridergic pathway. More recently, in another experimental model of glaucoma (induced by intracameral injections of hyaluronic acid (HA)) a significant activation of retinal nitridergic pathway was demonstrated (Belforte et al., 2007). In this study, it was shown that retinal NOS activity significantly increases in hypertensive eyes, although no changes in the levels of NOS isoforms were observed in HA- treated eyes. Different mechanisms might modulate NOS activity, including changes in substrate supply, protein phosphorylation, and subcellular localization, among others. The intracellular events triggered by ocular hypertension that could explain the association between ocular hypertension and NOS activity, as well as the isoform(s) of NOS whose activity is augmented by HA-induced ocular hypertension, remain to be defined. However, since glutamate activity at 12 NMDA receptors is one of the most conspicuous promoters of NOS-1 activity, the increase in glutamate synaptic levels previously demonstrated in HA-treated eyes (Moreno et al., 2005) could account for an increase in nNOS activity in this experimental model. Thus, the activation of NOS in hypertensive eyes can be linked to glutamate levels that, in turn, might be elevated to such an extent that they are toxic for ganglion cells. Also in this regard, it has been shown that RGCs in the nNOS-deficient mouse are fairly resistant to NMDA, while damage in the retina of the eNOS-deficient mouse is not distinguishable from that observed in control animals (Vorwerk et al., 1997).
In addition to NOS activity, another limiting step in the regulation of NO biosynthesis is the availability of the precursor L-arginine. L-arginine influx and mRNA levels of cationic amino acid transporter type 1 and 2 (CAT-1 and CAT-2) are significantly increased in the retinas from hypertensive eyes (Belforte et al., 2007). Purified NOS from different sources has been reported to have a low half-saturating L-arginine concentration (EC50 ~ 10 μM). Since high levels of intracellular L-arginine ranging from 0.1 - 1 mM have been measured in many systems (Block et al., 1995), it is expectable that endogenous L-arginine would support maximal activation of NOS. However, several in vivo and in vitro studies indicate that NO production under physiological conditions can be enhanced by extracellular L-arginine, despite saturating intracellular L-arginine concentrations. This has been termed “the arginine paradox” (Kurz & Harrison, 1997). One possible explanation could be that intracellular L-arginine is sequestered in one or more pools that are poorly, if at all, accessible to NOS, whereas extracellular L-arginine transported into the cells is preferentially delivered to NO biosynthesis (Kurz & Harrison, 1997).
Therefore, it seems likely that to induce the activation of NOS, an influx of L-arginine is essential. The coordination between NOS activity and L-arginine uptake has been demonstrated in several systems such as diabetic rat retina (do Carmo et al., 1998). A similar coordination between NO biosynthesis and intracellular L-arginine availability seems to occur in the retina from hypertensive eyes. Recently, it was demonstrated that activation of NMDA receptors in cultured retinal cells promoted an increase in the intracellular L-arginine pool available for NO synthesis (Cossenza et al., 2006). In this process, the increase in both NOS activity and L- arginine influx could be triggered by higher levels of synaptic glutamate levels in retinas from eyes injected with HA (Moreno et al., 2005). Notably, it was demonstrated that both diurnal and nocturnal retinal melatonin levels decreased in hypertensive eyes (Moreno et al., 2004). In addition, a significant decrease in the retinal antioxidant defense system activity was observed in the retinas from eyes injected with HA. Taking into account the conclusive evidence from numerous studies showing that melatonin has significant antioxidant and antinitridergic activity, together with the correlative evidence that retinal melatonin levels are reduced in tandem with the decrease in the antioxidant defense system activity and the increase in the retinal nitridergic pathway, it is tempting to postulate that a causal relationship exists between these phenomena.
Defected mitochondrial respiratory chain, in addition to causing a severe ATP deficiency, often augments ROS generation in mitochondria, which enhances pathological conditions and diseases. In fact, mitochondrial dysfunction-associated oxidative stress has also been implicated as a risk factor in glaucoma patients (Abu-Amero et al., 2006). In this sense, it was shown that melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production (López et al, 2009). Moreover, it was demonstrated that melatonin inhibits mitochondrial NOS isoform (Escames et al., 2007). In the glaucoma model induced by HA injections, the retinal nitridergic pathway activation and the decrease in the antioxidant defense system preceded both functional and histological alterations provoked by ocular hypertension. Therefore, it is possible that oxidative stress and an overactivation of the retinal nitridergic system could contribute to the hypertension-induced retinal damage. In the glaucoma model induced by chronic injections of HA, it has been recently 13 shown that a subcutaneous pellet of melatonin significantly prevents the electroretinographic dysfunction and diminishes the vulnerability of retinal ganglion cells to the deleterious effects of ocular hypertension (Rosenstein et al., 2009).
Besides the effect of melatonin as a retinal antioxidant which could protect retinal ganglion cells from ocular hypertensive damage, the pathogenic role of oxidative stress in increasing IOP by reducing aqueous outflow facility is supported by various experimental studies performed in vitro and in vivo. In vitro treatment of human trabecular meshwork cells with hydrogen peroxide alters cellular adhesion and integrity (Zhou et al, 1999). In an animal study, perfusion of trabecular meshwork cells with peroxide has shown to reduce aqueous humor drainage from the anterior chamber of the calf’s eye (Kahn et al., 1983). Moreover, human trabecular meshwork endothelium has been reported to be an enriched site of NO synthesis. NO can interact with oxygen or metals, such as copper or iron, to modulate outflow resistance of the trabecular meshwork (Haefliger et al., 1999). In this way, being an effective antioxidant and an antinitridergic melatonin can be beneficial not only at retinal level, but also in the eye anterior chamber, contributing to restore the aqueous humor drainage.
Besides the mechanisms already described, there are other beneficial mechanisms of melatonin for glaucoma treatment (Figure 2). Several lines of evidence support that the obstruction of retrograde transport at the optic nerve head results in the deprivation of neurotrophic support to RGCs, leading to apoptotic cell death in glaucoma (Quigley et al., 2000; Johnson et al., 2009). An important corollary to this concept is the implication that appropriate enhancement of neurotrophic support will prolong the survival of injured RGC. Of particular importance is the fact that brain-derived neurotrophic factor (BDNF) not only promotes ganglion cell survival following damage to the optic nerve, but also helps to preserve the structural integrity of the surviving neurons, which in turn results in enhanced visual function (Weber et al., 2008). As for the link between melatonin and neurotrophins, it has been suggested that melatonin may participate in neurodevelopment and in the regulation of neurotrophic factors (Jimenez et al., 2007; Niles et al., 2004). In vitro, melatonin promotes the viability and neuronal differentiation of neural stem cells and increases their production of BDNF (Kong et al., 2008). Moreover, ramelteon (a melatonin receptor agonist) is capable of increasing BDNF protein in primary cultures of cerebellar granule cells (Imbesi et al., 2008).
In addition to ocular hypertension, the majority of glaucoma patients show signs of reduced ocular blood flow as well as ischemic signs in the eye, supporting that hemodynamic factors are involved as well in glaucomatous neuropathy. In this sense, it was shown that melatonin could increase the survival rate and rescue and restore injured RGCs in an experimental model of ischemia/reperfusion in rats (Tang et al., 2006), and it counteracts ischemia-induced apoptosis in human retinal pigment epithelial cells (Osborne et al., 1998). Finally, while the cellular mechanisms involved in the loss of ganglion cells observed in glaucomatous neuropathy are based on a phenomenon of apoptosis, melatonin was shown to have antiapoptotic properties acting through several mechanisms, such as reduction of caspases, cytochrome c release, and modulation of Bcl-2 and Bax genes, among others. Figure 2 summarizes some of the ethiopathogenic mechanisms involved in glaucomatous neuropathy and the effect of melatonin on these mechanisms.
Neuroprotective drugs in the treatment of glaucoma
According to Osborne et al. (Osborne et al., 1999), neuroprotective agents will be more beneficial to patients in which neurons die slowly, as seen in glaucoma, than in a disease in which the death of a set of neurons is more rapid. Many compounds such as betaxolol, 14 brimonidine, calcium channel blockers, antioxidants such as vitamin E and coenzyme Q, and Ginkgo biloba extracts have been tried in animals and have been shown to protect the retina against free radical damage and lipid peroxidation (Ritch, 2000). Calcium channel blockers have been shown to neutralize NMDA-induced intracellular Ca2+ influx. Netland and coworkers (Netland et al., 1993) demonstrated a decrease in glaucoma progression in patients treated with Ca2+ channel blockers. On the other hand, the NMDA antagonist memantine effectively blocked the excitotoxic response of RGCs both in culture and in vivo conditions (Vorwerk et al., 1996). However, a recent study showed that the progression of glaucoma was significantly lower in patients receiving a higher dose of memantine than in patients receiving a low dose of memantine, but there was no clear benefit compared to patients receiving placebo. Melatonin has been demonstrated to be an effective neuroprotective agent in various experimental models and also is being used in the treatment of neurodegenerative diseases such as Alzheimer disease and Parkinsonism, where it has been shown to improve the clinical condition of the patients (Reiter et al., 1999; Srinivasan et al., 2005, 2006; Furio et al., 2007; Dowling et al., 2008). As discussed above, melatonin acts as an efficient retinal antioxidant (Siu et al., 1999). In addition, melatonin has been shown to act as a potent inhibitor of the retinal nitridergic pathway since it directly reacts with NO (Turjanski et al., 2000), decreases NOS activity, the uptake of NOS substrate (L-arginine), as well as the increase in cGMP content induced by L-arginine (Sáenz et al., 2002). Moreover, melatonin is a potent inhibitor of NOS-1 and NOS-2 gene expression (Poliandri et al., 2006) and it also reduces NO-induced retinal oxidative damage both in vitro (Siu et al., 1999) and in vivo (Siu et al., 2004). In view of this evidence, melatonin could be a promising agent for the management of glaucoma, inasmuch as it exhibits antioxidant and antinitridergic properties, as well as reducing retinal glutamate synaptic levels, among other mechanism (Figure 2).
As already mentioned, the current management of glaucoma is mainly directed at the control of IOP. However, it would be clearly preferable for a therapy to have as its main goal the prevention of the death of ganglion cells rather than a symptomatic treatment. The results presented above support the conclusion that a decrease in the retinal nitridergic pathway activity as well as an antioxidant treatment may prevent glaucomatous cell death. Melatonin, by itself, may fulfill all these requirements and thus, therapies based on the application of melatonin may have significant potential as a new strategy in glaucoma management.
Source: http://www.fiteyes.com/Non-pharmaceutical-medications-approaches-glaucom... from Melatonin article by Nathan Radcliffe, MD