Original Article Nepal Journal of Neuroscience 4:58-66, 2007

Neuroprotectors in Post Glaucoma Optic Neuropathy Parul Lakhanpal, MD Division of Pharmacology is the mechanisms and strategies used SSR Medical College to protect against neuronal injury or degeneration in the Central Mauritius Nervous System (CNS) following acute disorders (e.g. or nervous system injury/trauma) or as a result of chronic Deepak Kumar Rai, MD neurodegenerative diseases (e.g. Parkinson's, Alzheimer's, SHMO Department Of Pediatrics Multiple Sclerosis). The goal of neuroprotection is to limit Ministry Of Health & Quality Of Life neuronal dysfunction/death after CNS injury and attempt to Flacq Hospital Flacq, Mauritius maintain the highest possible integrity of cellular interactions in the brain resulting in an undisturbed neural function. There Address for correspodence is a wide range of neuroprotective agents used in many Parul Lakhanpal, MD neurodegenerative disorders including cerebrovascular Division of Pharmacology disorders, , spinal cord injury, Alzheimer's SSR Medical College disease, Parkinson's disease, Huntington's disease, Mauritius amyotrophic lateral sclerosis, multiple sclerosis, epilepsy and Email: [email protected] ischemic optic neuropathy as well as retinal degeneration. Currently, glaucoma is recognised as an optic neuropathy and selective death of retinal ganglion cells (RGC) is the hallmark Received, May 10, 2007 Accepted, May 25, 2007 of glaucoma, which is also associated with structural changes in the optic nerve head. The goal of neuroprotection in optic neuropathy (glaucoma) treatment is to employ agents that prevent or delay apoptosis of retinal ganglion cells (RGC) and facilitate regeneration of already damaged cells. The ganglion cell death in glaucoma due to apoptosis is a normal biologic process that initiates the death of cells through preprogrammed genetic signals. Several causes of ganglion cell apoptosis in glaucoma have been discovered, including deprivation of metabolic substrates, autoimmune reactions, neurotrophin deprivation and . The concept of neuroprotection in glaucoma therapy continues to intrigue researchers and clinicians. New research is targeted to develop (Neuroprotectors) that protect the optic nerve and retinal ganglion cells that have been damaged by a primary stimulus (i.e., high intra-ocular pressure). This review article mainly emphasized on the pharmacological agents believed to have neuroprotective role in “post glaucoma optic neuropathy”. Key Words: glaucoma, neuroprotectors, optic neuropathy

laucoma is a chronic progressive optic neuropathy is the only proven treatment so far. However, it is apparent characterized by typical morphological and that pressure-independent mechanisms are also associated Gfunctional changes in the optic nerve head in which with the development of glaucomatous optic neuropathy. there is a characteristic acquired loss of retinal ganglion The ganglion cell death in glaucoma may occur due to cells, at levels beyond normal age-related baseline loss, apoptosis, a normal biologic process that initiates the death and corresponding atrophy of the optic nerve. Although of cells through preprogrammed genetic signals. There has asymptomatic in its earlier stages, the disease is been considerable effort to develop therapeutics that nevertheless one of the leading global causes of irreversible rescues the retinal ganglion cells from undergoing blindness. Although elevated intraocular pressure (IOP) is secondary degeneration after the original insult has one of the most important risk factors and lowering of IOP occurred. This therapeutic strategy has been termed

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“neuroprotection”. Neuroprotection, a strategy to slow or the degeneration that occurs in glaucoma. prevent the death of retinal ganglion cells, offers the possibility of slowing the rate of glaucomatous progression Pathogenesis and preventing blindness. The failure of ganglion cell axons to transport nerve Although the pathophysiology of glaucoma is not fully growth factors, liberation of excitotoxic glutamate, rise of understood at the present time, there has been progress in intracellular calcium, initiation of inflammation and neuronal determining the process by which the damage occurs. death most probably due to apoptosis are the key events Clinically, there is a progressive loss of the nerve fiber 59 of optic neuropathy. Neuroprotection is a process that layer in glaucoma patients, that leads to the characteristic attempts to preserve the cells that were spared during the optic nerve head cupping and axonal degeneration in the 47 initial insult, but are still vulnerable to damage. optic nerve. The primary site of damage in glaucoma is 39, 48 A pressure-lowering strategy is probably effective for the retinal ganglion cell (RGC) layer. protecting the RGC in most patients. However, glaucoma There are several mechanisms which could be responsible continues to progress in many others despite well- for RGC death:1) Apoptosis 2)Excitotoxin Glutamate 3) controlled IOPs, thus normal or low-tension glaucoma neurotoxicity and Free radical generation (LTG). This suggests that pressure-independent 4)Neurotrophic withdrawal neuropathological mechanisms are at work. IOP reduction had been the primary goal for treating all glaucoma. The Apoptosis future of glaucoma therapy may well utilize a multi-faceted Apoptosis is a biological process in which a cell initiates approach, beginning with IOP-lowering agents, progressing its own death through a preprogrammed genetic signal. to optic nerve head blood-flow enhancers, and ultimately The generation of “suicide triggers” could be one of the ending or getting supplemented with neuroprotectants that consequences of these processes and interactions and prevent apoptosis and/or block the apoptotic pathway. these molecules may start the process of Apoptosis which is characterized by an orderly pattern of inter- nucleosomal Potential Approaches to Neuroprotection DNA fragmentation, Chromosome clumping, cell shrinkage and membrane blebbing.12 This is followed by disassembly The following are the important approaches to of cells into multiple membrane enclosed vesicles that are neuroprotection: engulfed by neighboring cells without inciting inflammation. It is conceivable that the first dying cells 1) Blood flow enhancers undergo necrosis, thus spilling their contents into the extracellular milieu, which then could initiate apoptosis in 2) Sodium channel blockers adjacent cells.21 Nevertheless, it is widely held that after 3) Glutamate inhibitors the initial insult in glaucoma, there are cellular factors present that are capable of initiating the apoptotic machinery within 4) Neurotrophic factors the RGC’s. Because these factors induce each cell to commit to its own death, apoptosis has been commonly referred to 5) Nitric oxide inhibitors as “cell suicide”. Perhaps this analogy is not completely accurate because the cell does not decide to die but rather 6) Free-radical scavengers/antioxidants it receives a signal that it must die-more like a forced suicide. The hope for neuroprotection is that it may be possible to 7) Apoptosis-related protease inhibitors prevent the secondary degeneration from occurring by targeting cellular events that are involved in the pathway 8) New protein synthesis inducers that ultimately ends in RGC death.35, 69, 71 9) Genetic modulators Excitotoxin Glutamate 10) Ocular hypotensive agents The vascular hypothesis suggests that optic nerve head perfusion may be compromised secondary to increased IOP Etiology and vascular abnormalities such as dysfunctional autoregulatory mechanisms. Localized ischemia may result The etiology of glaucoma appears to be complex with a in decreased metabolic activity and accumulation of number of mechanisms that can lead to glaucomatous optic extracellular excitotoxin glutamate...... nerve damage. It is becoming more likely that there are Lucas and Newhouse, 27 two ophthalmologists in 1950 several risk factors, of which raised IOP is one, that can injected glutamate into mice to evaluate it as a potential contribute to the clinical manifestations of primary open- therapy for retinal degeneration. Unexpectedly, the injection angle glaucoma.1, 13, 40, 70 If glaucoma is actually a collection of glutamate resulted in the selective destruction of the of diseases that all result in a common optic neuropathy, a inner retinal layer of the mice.27 Further research showed therapy aimed at preventing the process of damage (rather that excess glutamate induces neuronal changes leading than reducing a risk factor) would show enormous to retinal ganglion cell death, 41 and this paradoxical therapeutic potential. Such is the goal for neuroprotection, phenomenon was later termed excitotoxicity. The toxic a concept that focuses on protecting the optic nerve from effects of this excitatory neurotransmitter do not appear

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under normal conditions because the extracellular concentration is kept low by a powerful reuptake system in the retinal glial (Muller) cells.28, 34 There are at least four classes of glutamate receptors.28 One class, the NMDA receptor, is commonly believed to be the primary one involved in excitotoxicity both in central nervous system and the retina .7,10,44,58 Activation of the NMDA receptor leads to an increased influx of calcium within the neuron through ion channels. 10,24,63 Studies have shown that activation of the NMDA receptors will kill RGC’s both in vivo and in vitro, and this death can be prevented by blocking the receptors with a potent glutamate antagonist such as MK801. 11,53,58,62

Nitric Oxide and Free Radicals After the increase in neuronal intracellular calcium, there is an increased production of free radicals including nitric oxide (NO). As a free radical, however, NO· can start a chain Figure 1. Stages of Glaucoma.37 of reactions including activation of the p53 protein, disruption of mitochondria function, and the degradation · In order to appreciate how neuroprotectants may be used of DNA that ultimately results in apoptosis. NO rapidly to treat glaucoma, it is must to know that this disease has reacts with superoxide to form peroxynitrate, which is a three separate stages that are intimately linked together toxic free radical capable of extensive neurodegeneration. Figure 1).37 24, 25 like a row of dominos ( The first stage is the primary event, which for many people is probably a defect Oxygen-derived free radicals have been shown to 33 in the production/outflow of aqueous fluid leading to an increase in the retina during acute ischemia. Oxygen free increase in IOP. In susceptible individuals, this increased radicals are oxygen-containing molecules carrying one or pressure leads to Stage 2, which is a “damaging stimulus.” more unpaired electrons that react with proteins, lipids and Basically, an increased IOP leads to molecular changes in nucleic acids. These highly reactive compounds may be the retinal ganglion cells and surrounding tissues that important mediators in secondary RGC degeneration. activate Stage 3, which is the actual death of the ganglion cells. Seeing the progression of glaucoma as a row of falling Neurotrophins Generation dominos, pressure management therapy as being akin to Neurotrophins are the “survival factors” that the brain remove some of the dominos early in the chain. At face transports to RGC axons and their cell bodies. Deprivation value, this is a terrific strategy because if done early enough of these growth factors may ultimately result in RGC death. the progression of this chain reaction could be blocked. The family of neurotrophins includes fibroblast growth Unfortunately, there is no good way of knowing if the chain factor (FGF), ciliary neurotrophic factor, nerve growth factor, reaction has already passed this critical point of treatment brain-derived neurotrophic factor (BDNF), and 14, 65 and this is probably why pressure management therapy is neurotrophins 3, 4/5, and 6. Experimental studies have associated with variable success.38, 49 The advent of new shown that growth factors such as bFGF (basic fibroblastic neuroprotective agents, however, means that it may soon growth factor), brain-derived neurotrophic factor (BDNF), be possible to start taking dominos out further down the neurotrophin-4 and ciliary neurotrophic factor (CNTF) chain, and at multiple sites, thus maximizing chances of 29, 45 greatly reduce RGC death rates after axotomy. stopping the chain reaction before the irreversible death of the cells.38 The goal of neuroprotection in glaucoma Concept of Neuroprotectors treatment is to employ agents that prevent or delay The ultimate goal of glaucoma treatment is to delay or apoptosis of RGC and facilitate the regeneration of already stop or sometimes reverse the glaucomatous changes to damaged cells (Figure 2). the optic nerve and ganglion cell layer caused by raised There are different approaches for neuroprotection (Table 1): IOT. Although a number of medications are available that would directly protect the optic nerve or reverse the damage Blood Flow Enhancers from glaucoma, no such has yet been proven to Blood flow enhancers (Naftidrofuryl, minoxidil, gingko be effective. Current Medicinal therapy for Glaucoma biloba) by virtue of their vasodilating property prevent focuses on protecting the optic nerve indirectly through ischemia induced retinopathy. In one clinical study it was lowering of the IOP. Neuroprotective drug should enhance demonstrated that low dose, short term treatment with the survival of retinal ganglionic cells in the presence of gingko biloba in healthy volunteers increased ophthalmic chronic stress/injury. There are numerous agents claimed artery blood flow by a mean of 24%.8 Another blood flow to be neuroprotectives in vitro and number of enhancer Naftdrofuryl, a serotonin receptor antagonist neurodegenerative disorders (however no clinical trial yet improves visual acuity, inhibits platelet aggregation and been reported). increases oxidation.66

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Mechanism of Protection Possible Protective Agents

Blood flow enhancers Naftidrofuryl, minoxidil, gingko biloba

Sodium channel blockers , , riluzole

Glutamate inhibitors Lifarazine,riluzole,,eliprodil,

Neurotrophins Various neural growth factors

Nitric oxide inhibitors Nitroglycerine,Aminoguanidine,gingko biloba

Free radical scavengers/ Antioxidants VitaminsC, Vit E, catalase, superoxide dismutase

Apoptosis-relared prorease inhibitors Invirase,Norvir,crixivan,viracept,AIDS medicines

New protein synthesis inducers MAO-B inhibitor

Genetic modulators bcl-x and bcl-2

Table1.Various potential Neuroprotective Agents38

Sodium Channel Blockers eye. Memantine belongs to a class of drugs known as Sodium channel blockers like Lamotrigine, topiramate “open-channel blockers.” These agents attenuate glutamate and riluzole achieve neuroprotection by blocking the release by entering and binding to NMDA receptor sodium channels so that the further cascade of excitotoxin channels, thus blocking calcium entry. Memantine, like glutamate induced insults are prevented.46 With or however, may hold promise in glaucoma neuroprotection. without NMDA receptor-blocking activity, these agents It interacts noncompetitively with NMDA receptors and may decelerate the RGC’s death process. Sodium channel binds to them only when their channels are open. Thus, it blockers (SCBs) are thought to inhibit sodium channel blocks toxic glutamate levels without significantly affecting action at the time of RGC injury, decreasing consumption normal cell function.5, 6 Also by virtue of its ability to rapidly of adenosine triphosphate (ATP). block and unblock NMDA channels, memantine may ensure normal NMDA receptor function and ultimate RGC survival Glutamate Inhibitors in areas of diminished glutamate levels. Memantine is in Excessive glutamate levels may trigger apoptosis of phase III clinical trials here for glaucoma. Memantine RGCs, so researchers have focused on drugs that either displays neuroprotective properties both in vitro in RGC’s block glutamate release at pre-NMDA receptor sites or exposed to glutamate and in vivo in rabbits that have retinal inhibit glutamate interaction at the NMDA receptor (Table ischemia induced by a rapid elevation in IOP. Another 2). Studies have shown that activation of the NMDA potential neuroprotective compound is L-Kyn, which serves receptors will kill RGC’s both in vivo and in vitro, and this as a biochemical precursor to an endogenous NMDA death can be prevented by blocking the receptors with a antagonist. It also has been shown to protect against potent glutamate antagonist such as MK801.11, 53, 58, 62 excitotoxic RGC death and seemed to improve visual Lifarazine and riluzole have been shown to block glutamate brightness discrimination in rats injected with NMDA.68 before synapses, attenuating the release of excitotoxin at An elevated extracellular concentration of glutamate will the NMDA receptor.17, 38 Compounds thought to inhibit lead to an increased inflow of calcium into the RCG’s through glutamate at the NMDA receptor include felbamate an activation of voltage-gated calcium channels.34, 43 An (Felbatol), eliprodil and memantine. Felbamate is an FDA- excessive intracellular concentration of calcium leads to approved anti-convulsant that may act as an antagonist at neuron damage, 24, 44 and therefore a therapeutic that blocks the binding site of the NMDA receptor.38 Eliprodil, these calcium channels could be neuroprotective. Eliprodil a noncompetitive NMDA antagonist, has shown and , both already mentioned as NMDA receptor neuroprotective capacity in rat and rabbit studies.4, 51 antagonists, also seem to block the N- and P-type channels, Eliprodil binds at the polyamine site on the NMDA receptor; 2 which may contribute to their established neuroprotective it can also block the voltage-operated calcium channels.55 qualities in animal and culture models. Human retinal ganglion cells do possess this polyamine- binding site, and the site does show affinity for eliprodil Neurotrophins and the related ifenprodil.57 Eliprodil may have less CNS Neurotrophin (BDNF) protects RGC’s from secondary effects than other NMDA antagonists,55 and it is currently degeneration due to ischemia, axotomy, and glutamate being examined as a potential neuroprotective agent in the excitotoxicity29,.45,52,65 Further evidence that RGC’s

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Site of Action Compound Mode of Action

Pre-NMDA Receptor Riluzole Attenuates glutamate release Lifarazine Attenuates glutamate release

NMDA Receptor CGS19755 Glutamate binding-site antagonist Felbamate Glycine binding-site antagonist Open-channel blocker Memantine Open-channel blocker Nitroglycerin Redox site

Table 2. Glutamate antagonists37

upregulate gene expression of BDNF in response to This class of drugs may enhance RGC survivability by axotomy 14 supports the role of this neurotrophin as a scavenging free radicals and ultimately preventing ischemic protective strategy within the eye after insult. The damage.20 Examples include nitroglycerine, which provides neuroprotective effect of BDNF has been attributed to its oxidized nitric oxide, 49 and possibly ginkgo biloba.30 ability to delay apoptosis. Other neurotrophins such as ciliary neurotrophic factor, basic fibroblast growth factors Free radical scavengers 65 45 (bFGF), and Neurotrophin-4(NT-4) have also been Oxygen free radicals may be important mediators in shown to have protective properties. secondary RGC degeneration. Potential free radical scavengers include vitamins C and E, enzymes catalase Nitric oxide synthase inhibitors and superoxide dismutase (SOD), ginkgo biloba and lipid Nitric oxide is produced by the enzyme nitric oxide peroxidation inhibitors.3, 22 synthase (NOS), of which there are three types. NOS-1 is a constitutive type that is found in normal neuronal cells, Apoptosis-related Protease Inhibitors NOS-2 is an inducible isoform that is only present under Proteases are enzymes critical to protein synthesis, and a conditions of stress, and NOS-3 is found in the endothelium subset of this chemical family is involved in apoptosis. So, of blood vessels.36 All three of these isoforms seem to be due to the success of the protease inhibitors saquinavir present in increased amounts at the nerve heads of human mesylate (Invirase), ritonavir (Norvir), indinavir (Crixivan) glaucoma patients compared with control patients.36 Mice and nelfinavir mesylate (Viracept) in treating AIDS, similar that have been genetically engineered to be deficient in agents may aid in treating glaucoma. There are several drugs NOS-1 were shown to possess RGC’s that were relatively that are proving extremely useful at blocking apoptosis. resistant to excitotoxicity or vascular insult.67 The Many of these are grouped as anti-oxidants, which may nonspecific NOS inhibitor N-nitro-l-arginine offered partial function to block the initial stages of the apoptotic program. protection to rat RGC’s in vitro exposed to anoxia or One class of compounds that block lipid peroxidation glutamate,32 and for RGC death after axotomy of the optic (collectively known as “Lazaroids”) has been shown to nerve.19 However, NOS-1 and NOS-3 are found in normal delay retinal ganglion cell death in culture .22 tissue and are necessary for normal physiological function. Many other drugs also exist that blocks the actions of NOS-3 causes vasodilation31 and increases blood flow, and the proteases. They are known as “protease inhibitors”. therefore it could actually reduce any ischemic insult to the Currently, these drugs are still being characterized and optic nerve. tested in the laboratory.26 It is now clear that different Even though elevated levels of NOS-1 do seem to members of a family of apoptosis-related proteases are active contribute to RGC death,19, 67 NOS-2 is an attractive target in different cells and future treatments may first require because it is not present in normal cells.36 NOS-2 is capable identifying which are active in target cells. Given the recent 9 of producing large amounts of the NO· free radical success of protease inhibitors in treating AIDS. However, continuously for long periods of time.18 A specific NOS-2 this class of molecules may prove to be very powerful inhibitor, aminoguanidine, was found to significantly neuroprotectants. increase RGC survival in rats with chronic, moderately New Protein Synthesis Inducers elevated IOP.36 Because this compound is already in clinical trials for treatment of complications due to diabetes, its Researchers have reported that the monoamine oxidase value as an antiglaucoma agent has gained considerable (MAO)-B inhibitor selegiline has also shown promise in attention and is currently being investigated. experimental studies as an inhibitor of RGC apoptsis.50,

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Figure 2. A Simplified outline of the cascade of stages thought to be involved in retinal ganglion cell death in glaucoma. Potential therapies along with their targets along the cascade are indicated in the circles. 16

73This drug’s neuroprotective mechanism for inhibiting clonidine, á2-adrenoreceptor agonists, delay the secondary apoptosis in RGCs; however is not a true MAO inhibition, degeneration of axons after a partial optic crush in rats, and instead thought to be related to stimulation of new protein the neuroprotective effect could be blocked by an á2- synthesis. antagonist. 72 The â blocker betaxolol has been shown to be neuroprotective both in vitro and in vivo in rats exposed Genetic Modulators to ischemia.42

Under-standing the basis of genetic forms of glaucoma Which is the Ideal Drug? may eventually allow researchers to create compounds that 54, 60, 61 modulate expression of apoptotic genes. Molecular It is difficult to say that which drug should be used for genetic technology has identified the bax and bad genes the treatment of glaucoma as number of mechanisms are as stimulators, and the bcl-x and bcl-2 genes as suppressors involved in glaucomatous damage and RGC’s death. This of RGC apoptosis. The compounds selegiline and should not be surprising because there is not one universal brimonidine, and the tumor suppressor gene p53, may apoptotic pathway, but rather a complex web of biochemical prevent RGC apoptosis by increasing expression of the life vs. death controls that are dependent on numerous bcl-x and bcl-2 genes and/or suppressing detrimental genes. cellular functions.23 Secondly, there are many unanswered Ocular Hypotensive Agents questions about glaucomatous ganglion damage like what exactly are the factors that set off this cascade of Lowering IOP may be one aspect of neuroprotection. degeneration? Are there multiple causes of the initial insult Ocular hypotensive agents may improve neurotrophin flow (i.e., IOP, vascular insufficiency, and genetic or autoimmune to RGC bodies, aiding those cells in metabolizing glutamate factors), and if so, do they follow different pathways with and normalizing autoregulatory mechanisms of the optic the same end result? Are there common checkpoints along nerve vasculature.15,56 Present day therapy aims to achieve the degenerative pathway irrespective of the initiating step? this, with beta blockers, latanoprost (Xalantan) and It is tempting to suggest that excitotoxicity could play a brimonidine (Alphagan) exhibiting the greatest IOP- bigger role in damage due to ischemia because there is lowering effect . It has been shown that brimonidine and extensive research linking excitotoxicity to hypoxic

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conditions 34 or it is the deprivation of neurotrophins, which 7. Choi DW: Glutamate neurotoxicity and diseases play a major role in RGC’s death.13 of the nervous system. Neuron 1:623-34, 1988 The ideal anti-glaucoma drug would be one that prevents 8. Chung HS, Harris A, Kristinsson JK, et al: Gingko ganglion cell death and has no adverse effects on the biloba extract increased ocular blood flow velocity. patient. Should the patient also have increased IOP, this Ocul Phrmacol Ther 15:233-240, 1999 can be treated separately.64 However, in reality, any drug targeted specifically to the retina to prevent ganglion cell 9. Cohen J. Protease inhibitors: A tale of two death is likely to have appreciable side effects. Therefore, companies. Science 272:1882-1883, 1996 at the present time, a more realistic ideal drug would be one that when applied topically, reduces IOP, and reaches the 10. Dreyer EB. 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Bath CP, Farrell LN, Gilmore J, Ward MA, Hicks contribute to up regulation of retinal nitric oxide CA, O’Neill MJ, Bleakman D: The effects of synthase activity by brain-derived neurotrophic ifenprodil and eliprodil on voltage-dependent Ca2+ factor. J Neurosci 19:8517-27, 1999 channels and in gerbil global cerebral ischemia. 19. Koeberle PD, Ball AK: Nitric oxide synthase Eur J Pharmacol 299:103-121,996 inhibition delays axonal degeneration and promotes 3. Benjamin SA, Duke JA: Herbal medicine: What the survival of axotomized retinal ganglion cells. works, what’s safe? Patient Care 31:49-68, 1997 Exp Neurol 158:366-81, 1999 4. Chandler ML, Pang I-H, Doshi R, et al: In vitro and 20. Koseki Y, Kitano S, Podos SM, et al: A nitric oxide in vivo protective effects of eliprodil in the retina. synthase inhibitor protects against anoxia in Invest Ophthalmol Vis Sci 38: S147. Abstract 725, cultured rat retinal ganglion cells. Invest 1997 Ophthalmol Vis Sci 35:1968, 1994 21. 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