Neuroprotection
Chat Highlights
June 19, 2002

Norma Devine, Editor

On Wednesday, June 19, 2002, Dr. Jeff Henderer, a glaucoma specialist at Wills, and the glaucoma chat group discussed "Neuroprotection."

P:  Dr. Henderer, what does neuroprotection mean?

Dr. Jeff Henderer:  Generally, it means to protect the nerve, the optic nerve in this case, from dying.  Specifically, it usually refers to the process of protecting the nerve independent of lowering IOP (intraocular pressure).  I must say that lowering IOP is neuroprotective, too.

P:  When it comes to interventions, it seems that lowering IOP would be easier to study than actual neuroprotection.  How long would the shortest possible trial be to confirm the effectiveness of a neuroprotective agent that was independent of IOP?

Dr. Jeff Henderer:  Yes, you'd think it would be easier to study the effectiveness of lowering IOP, but the normal-tension and advanced glaucoma intervention trials took seven years!  Any neuroprotection study might take just as long, unless a marker for progression can be found that changes faster than visual fields.

P:  I am a bit confused by the use of a lot of technical terms.  Is neuroprotection a surgical procedure?

Dr. Jeff Henderer:  Neuroprotection is simply a term used to describe the treatment strategy to prevent nerve death.  It can be surgery, if that is the tool used, to lower the IOP that then prevents more glaucomatous damage.

P:  Does neuroprotection only work from "outside" the nerve by reducing pressure, or from the "inside" by increasing blood flow?  

Dr. Jeff Henderer:  Well, blood flow issues are postulated to be important in glaucoma, perhaps in some forms more than others.  Improving blood flow is probably a good idea, provided it doesn't come at the expense of something else that is important.  In other words, you don't want to steal blood from somewhere that also may be important.  

P:  How is the optic nerve protected?

Dr. Jeff Henderer:  The nerve is thought to be protected by preventing cell death.  It seems that glaucoma cell death is due primarily to apoptosis, and the hope is that apoptosis can be prevented in some way.  

P:  Would you explain apoptosis, please?  

Dr. Jeff Henderer:  Apoptosis is one of two forms of cell death. The other is necrosis. Apoptosis is the "natural" form of cell death. It is essentially programmed suicide.  This is a very important process in our bodies that occurs naturally every day.  If it didn't, we might all have cancers. In any case, preventing this form of cell death specifically in the optic nerve is what most investigators are after.

P:  If you had high pressure without optic nerve damage, how long would the nerve be protected?  

Dr. Jeff Henderer:  According to the results of the Ocular Hypertension Treatment Study (OHTS) just published in the past few days, about 10% of the eyes developed glaucoma after about seven years or so.  

P:  Why not say 90% of the eyes did not develop glaucoma after about seven years?

Dr. Jeff Henderer:  You have found one of the principle findings of the study, which is going to be overlooked by most.  I salute your insight!

P:  Is blood flow the key to neuroprotection?

Dr. Jeff Henderer:  Certainly ischemia (lack of blood flow and oxygen) can play a role.  Whether it is the primary cause, no one knows.  People who have strokes don't get glaucomatous damage.  So it can't be that easy.  Perhaps chronic low-grade ischemia has to suspected as a cause, but we just don't know yet.  There are good data to suggest that low blood pressure is related to glaucoma and the mechanism isn't known, but ischemia has to be a suspicious cause.

P:  How important for developing neuroprotective strategies is knowing the cause of optic nerve damage? 

Dr. Jeff Henderer:  That is a bit of a mystery.  The cause of apoptosis (the trigger) can be any one of ten or more things, such as ultraviolet light, toxic chemicals, etc.  The cause may not be easy to fix, but if we can block the cells' response -- this stimulus to commit suicide --then perhaps we can block the death, regardless of the insult.

P:  Can apoptosis be prevented?

Dr. Jeff Henderer:  That would be hard to do selectively in one tissue only.  Might be able to block the receptor for a certain chemical toxic stimulus.  That is the thinking behind the NMDA (N-Methyl-D-Asparate) receptor antagonists for glutamate and glaucoma.

P:  If glutamate is part of the memory encoding process, would regulating the NMDA channel modify the memory ability?

Dr. Jeff Henderer:  It might! That is the problem with blocking apoptosis.

P:  Is glutamate the same as monosodium glutamate?  In other words, does ingestion of glutamates increase the level in the body and the triggering mechanism you mentioned?

Dr. Jeff Henderer:  I believe the answer is yes, but I am not aware that eating MSG is bad for glaucoma.

P:  Does IOP affect blood flow?

Dr. Jeff Henderer:  Yes, the higher the IOP, the less the blood flow.

P:  Can the optic nerve be protected independent of lowering the IOP?

Dr. Jeff Henderer:  That is not easy.  The current strategies are aimed at blocking the actions of a particular chemical, glutamate, and its triggering effects.  Other strategies are in the works, but that one is in clinical trial.  (Editor's note:  Memantine Study, Allergan).  

P:  Can the optic nerve be affected by necrosis along with apoptosis?  And if apoptosis is natural or programmed, can it be de-programmed? 

Dr. Jeff Henderer:  The pathologic studies I've seen really seem to find apoptosis, not necrosis, as the pathologic change.  Deprogramming apoptosis is tricky, as you want to be selective.  It is possible to block the actual suicide molecules, but these haven't made it to human trial that I know of, so I don't know the safety of them.

P:  Would low blood flow be more likely to cause apoptosis or necrosis?

Dr. Jeff Henderer:  The answer is both.  Perhaps the best model is in the brain that has suffered a stroke.  The immediate cell response is necrosis, but there is also the release of toxic chemicals from the dying cells that then go on to trigger cell death in neighboring cells. This is by apoptosis.  A similar situation is thought to occur in the ganglion cells of the retina.  There's no necrosis, but dying cells release toxic chemicals that then trigger more cell death.

P:  Is pallor of the optic nerve indicative of decreased blood flow?

Dr. Jeff Henderer:  Sometimes.  If it follows a stroke, yes.  But there are other causes of nerve pallor that are not thought to be related to blood flow -- say, methanol toxicity or nutritional deficiency.

P:  So when the doctor says the optic nerve looks "pink," is that good?  

Dr. Jeff Henderer:  Yes, pink is healthy.  Glaucomatous nerves in the end stage are pale.  But early glaucoma can have a pink nerve, and also thinning of the nerve rim.  So pink is great, but it doesn't get you off the hook, in my opinion.

P:  If high IOP reduces blood flow to the optic nerve, what is the effect of low IOP on the optic nerve?

Dr. Jeff Henderer:  Well, I assume that the flow is increased, but you have to understand that there is a process of autoregulation of blood pressure in most organ tissues to try to maintain a stable flow.  

P:  Can aerobics or other forms of exercise help to increase the blood flow to the nerve?

Dr. Jeff Henderer:  Yes, I believe that is true.  Exercise also temporarily lowers eye pressure.  Seems like a win-win situation.

P:  What about natural ways to protect the optic nerve, such as herbs, etc?

Dr. Jeff Henderer:  Ginkgo is thought to provide protection by increasing blood flow.  Vitamins such as C and E are antioxidants and may prevent cell death induced by free radicals.  

P:  Have you heard of the drug, Semax (heptapeptid), which is a proven neuroprotector for the optic nerve?  Semax is a nasal spray that has been approved for human use in Russia, Indonesia, and other places since 1996.  

Dr. Jeff Henderer:  No, I have not heard of it, but I'll look into it. 

P:  Are there any proven neuroprotective agents?

Dr. Jeff Henderer:  Lowering IOP is proven to be neuroprotective.

Dr. Jeff Henderer:  Thank you all.  I should go.  A patient might be calling soon.  E-mail me if you need to.

End of highlights for June 19, 2002.

On June 26, Dr. Wilson discussed " Glaucoma Research" in the Chat room. Click here for highlights of that meeting.

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