Neuroprotection

Neuroprotection Chat Highlights
May 11, 2005

Norma Devine, Editor

http://www.willsglaucoma.org/supportgroup/20050511.htm

 

On Wednesday, May 11, 2005, Dr. Richard Lee, a glaucoma specialist at Bascom Palmer Eye Institute, and the glaucoma chat group discussed "Neuroprotection."

 

 

Moderator:  Welcome, Dr. Lee. We are delighted to have you here tonight.

 

Dr. Richard Lee:  My pleasure to join your chat tonight.

 

Moderator:  Will you please tell us a little about your work?

 

Dr. Richard Lee:  I am a glaucoma specialist at the Bascom Palmer Eye Institute and also run a research lab studying animal and human models of glaucoma.  My research interest is in neuroprotection and pseudoexfoliation glaucoma.

 

Moderator:  I understand that one of your areas of research is neuroprotection.  How do you define neuroprotection?

 

Dr. Richard Lee:  My definition of neuroprotection is therapy that seeks to protect the optic nerve from death and, most importantly, while preserving function.  The nerve can be kept alive by certain drugs, but keeping something alive is no good unless function is also preserved.

 

P:  Is nerve function a matter of all or nothing?

 

Dr. Richard Lee:  That brings up the increasingly important point of what it means for a neuronal cell to be alive and functioning.  A cell needs to be alive to function, but being alive does not mean that it is functioning.  For example, consider the example of a patient in the ICU (intensive care unit), in a coma, hooked up to 10 IVs (intravenous tubes), and a person at home participating in this chat.  Both persons are alive, but only one is truly "functioning."

 

In the same way, we can sometimes find patients with normal cup-to-disc ratios and yet abnormal glaucomatous visual fields.  In other words, structurally, the nerve cells are there but are not functioning.  We have several studies underway to study the difference between structure and function, both in human beings and in a mouse model of glaucoma we are using in the laboratory.  We want to see if we can not only rescue neurons from dying, but also to turn sick, dysfunctional neurons into functioning neurons.

 

P:  Why do glaucoma patients need neuroprotection?

 

Dr. Richard Lee:  Glaucoma patients are already using neuroprotection in terms of their current therapy.  Lowering the IOP (intraocular pressure) is the only clinically proven modality of treatment that works to protect the optic nerve from further damage.  The glaucoma in some patients, however, who have had their pressures lowered as much as is possible -- that is, IOPs in the low teens to high single digits -- continues to progress, with optic nerve head damage and visual field progression.  These are patients in need of an additional modality of treatment that will affect the non-pressure-dependent aspects of glaucomatous optic nerve damage.

 

P:  Besides lowering IOP, what are some other examples of neuroprotection?

 

Dr. Richard Lee:  Neuroprotection can be looked at as using multiple pathways to have an effect on one disease, such as using calcium channel blockers, diuretics, and ACE inhibitors to treat hypertension.  No non-IOP-dependent glaucoma neuroprotectant is currently available.

 

There are many studies (as discussed by Dr. Henderer and others in prior chats) involving drugs that both affect and do not affect IOP, which could possibly be neuroprotectants.  For example, clinical trials are studying glutamate toxicity inhibitors, immune biological response modifiers, alpha agonists, etc.  That is an active area of study, not only in ophthalmology, but also in neurology for degenerative brain disorders.

 

P:  What causes optic nerve cupping?

 

Dr. Richard Lee:  With regard to optic nerve cupping, the basic mechanism is that the retinal ganglion cell (RGC) dies and, in turn, its axon to the brain regresses.  This loss of axons is what is observed when cupping occurs.  Cupping is the progressive disappearance of those retinal ganglion cell axons to the brain.

 

P:  Are retinal ganglion cells the same as optic nerve cells?

 

Dr. Richard Lee:  Yes.  When I talk about retinal ganglion cells, I am referring to the same optic nerve cells.  The optic nerve represents the axons, or phone cables, of the retinal ganglion cells, which are like the receivers of information that is transmitted through those cables to the brain.

 

P:  What have the studies shown so far? Can the sick neurons be turned into healthy ones?

 

Dr. Richard Lee:  These are all experimental studies. Our first step is trying to understand how to quantify and characterize dysfunction.  In human beings, Dr. Porciatti in our department is working on an experimental electro-physiology device that is basically like an EKG (electrocardiogram) of the eye.  The device may be a way to look at the function of the eye, and then to correlate that to the number of retinal ganglion cells present.

 

In animal studies, we are working to understand similar aspects of structure and function so that we can then use these mice, which naturally develop glaucoma, as a treatment model to prevent damage and improve function.  Similar studies have been performed in a monkey model by Harwerth and others in Texas.  These studies characterize a model of glaucoma disease, so we can then test medications for human use.

 

P:  When the retinal ganglion cells are damaged, can they malfunction by sending signals when there is no stimulus?

 

Dr. Richard Lee:  I don't think we know the answer to that question. Our current understanding is that dysfunctional cells are alive, but are too sick to send out signals.  My guess is that they do not send out signals unless there is an appropriate image or light stimulus.

 

P:  What is the potential application of the studies?

 

Dr. Richard Lee:  We hope that these studies will lead to new modalities of treatment for glaucoma.  For example, we have used a large-scale, genome-wide approach to differentially screen the genes associated with glaucoma in these mice.

 

We think we have found genes that are specifically affected by glaucoma.  We are busy trying to see, if we correct this dysregulation of gene expression in these laboratory mice, whether we can do the same for human beings and develop molecularly targeted therapy for glaucoma.

 

P:  Do you know much about the work being done by Michal Schwartz at the Weizmann Institute in Israel?  They call it T cell mediated "protective autoimmunity." The only information I found was from 2001, and it was mostly theoretical, and derived from observations made in mice and rats.  But what was interesting was that it was based on a physiological, rather than a pharmaceutical, action.

 

Dr. Richard Lee:  With regard to the work of Michal Schwartz using immune biological response modifiers, that work entered human clinical trials last year in Europe.  The original work was done in rodent nerve transection models and showed significant promise.  The basic premise of this approach is that T cells and immune cells will find a site of optic nerve damage and bring with the T cell the cytokines (signaling molecules that promote survival) and other goodies that will help treat the nerve damage.

 

P:  You mentioned glutamate toxicity inhibitors.  What role does glutamate play in glaucoma?

 

Dr. Richard Lee:  The role of glutamate and "excitotoxicity" in optic nerve damage was a prominent concept in the past, based on some basic science studies suggesting that high levels of glutamate in the vitreous of the eyes of glaucoma patients may be associated with excitotoxic death of retinal ganglion cells.  More recent data, however, suggest this may not be the whole story.  (See data about glaucomatous monkeys reported early this year in the journal, "Investigative Ophthalmology & Visual Science.")

 

In the interim period, drug companies have pursued glutamate antagonists as a possible treatment modality for glaucoma.  One large ongoing clinical trial scheduled to end in four years (2004) has been extended for another year.  Although the company has not yet revealed any results about the data, the concern has been that the study needed to be extended because the results have not been very significant.  We will have to wait and see what the role of glutamate inhibitors may have on treating glaucoma.

 

P:  What are some types of apoptosis?

 

Dr. Richard Lee:  Apoptosis is a naturally occurring form of cell death observed in most multi-cellular forms of life.  Apoptosis is what regulates the regression of the tadpole tail as a frog forms, prevents us from having webbed feet and hands, and causes the death of naturally occurring cancerous cells.

 

Apoptosis involves a very regimented cellular program, where the cell actively participates in its own death by triggering a death program.  The key regulatory molecules in apoptosis are being closely studied by many companies and labs as targets for neuroprotection.

 

P:  How is apoptosis different from necrosis?

 

Dr. Richard Lee:  Apoptosis is an active process on the part of the cell, whereas necrosis is a passive process in which the cell dies without its own participation.  For example, apoptosis requires cellular energy on the part of the cell designated to die, whereas in necrosis the cell's cell membrane and nucleus fall apart passively in response to an outside signal to die.

 

P:  In neuroprotection, is there a difference between protecting the optic nerve "cables" (the RGC axons) and the RGC bodies?

 

Dr. Richard Lee:  The axons cannot survive without the retinal ganglion cells, because they are an extension of the retinal ganglion cell.

 

P:  What are ACE inhibitors, which you mentioned near the beginning of the chat?

 

Dr. Richard Lee:  ACE (angiotension converting enzyme) inhibitors are used to treat hypertension, and affect the renin-angiotensin pathway that is involved in maintaining blood pressure.  ACE is a protease that is involved in cutting up and activating molecules, which can raise the blood pressure. (Systemic blood pressure is not the same as intraocular pressure.)

 

P:  There seems to be some controversy over the putative neuroprotective effects of oral ginkgo biloba supplements.  What's your view of their utility in this regard?  To whatever extent are they beneficial, and what's the minimum, clinically therapeutic, daily dosage?

 

Dr. Richard Lee:  I will have to answer that question with a personal anecdote. My mother cooks with ginkgo nuts in her stir fry.  Now I don't really care for the taste of it, but she firmly believes it is good for me, so I eat her gingko stir fry and she is happy and I am happy.  However, am I any healthier for this?

 

Many people have extolled the virtues of herbal remedies.  After all, many of our drugs originated from herbs.  The Chinese have used foxglove for hundreds of years for heart problems, before we knew it had digitalis in it.  On the other hand, ginkgo, when broken down into its chemical constituents (over 60 bioactive compounds have been isolated so far) has multiple effects, from affecting platelet aggregation factor and affecting blood flow to affecting muscle contractility, etc.  Basically, in its entirety, no net effect has been proven with regard to glaucoma treatment and neuroprotection.  That having been said, it does not appear to be harmful.

 

So back to my anecdote:  If it doesn't harm me and makes my mother happy, I'll take it.  Otherwise, I would be just as complacent without taking it.  However, bear in the mind that the only true beneficiary is the herbal company that sold the pills.

 

P:  Dr. Lee, maybe the ginkgo nuts increased your IQ.

 

Dr. Richard Lee:  With regard to IQ, several good studies have shown that ginkgo, which was originally touted as a great drug to improve memory, has been shown not to have any effect on improving memory (Journal of American Medical Association, 2000).  I am less certain about any studies with ginkgo and IQ.

 

Moderator:  Thank you, Dr. Lee, for an informative chat.

 

Dr. Richard Lee:  You are all welcome.  It was a pleasure.

 

 

 

 

On May 18, Dr. Wilson discussed "Flucuating IOP's" in the Chat room. Click here for highlights of that meeting.