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Figure 1.
In glaucoma, various risk factors are associated with optic nerve and/or retinal ganglion cell damage and lead to neuronal death. Lowering intraocular pressure (IOP) reduces the effect of the leading risk factor and can protect the optic nerve in some individuals. Neuroprotection is directed at preventing irreversible death of retinal ganglion cells and preserving their structural and functional characteristics.

In glaucoma, various risk factors are associated with optic nerve and/or retinal ganglion cell damage and lead to neuronal death. Lowering intraocular pressure (IOP) reduces the effect of the leading risk factor and can protect the optic nerve in some individuals. Neuroprotection is directed at preventing irreversible death of retinal ganglion cells and preserving their structural and functional characteristics.

Figure 2.
Several mechanisms have been hypothesized to have a role in causing retinal ganglion cell death in glaucoma. IOP indicate intraocular pressure.

Several mechanisms have been hypothesized to have a role in causing retinal ganglion cell death in glaucoma. IOP indicate intraocular pressure.

Figure 3.
Retinal ganglion cells are hypothesized to be dependent on a balance of positive (survival) and negative (death) stimuli. They fail to survive if the balance is disturbed. Enhancing survival stimuli (eg, neurotrophins) or inhibiting death stimuli (eg, glutamate) can be neuroprotective. cAMP indicates cyclic adenosine monophosphate.

Retinal ganglion cells are hypothesized to be dependent on a balance of positive (survival) and negative (death) stimuli. They fail to survive if the balance is disturbed. Enhancing survival stimuli (eg, neurotrophins) or inhibiting death stimuli (eg, glutamate) can be neuroprotective. cAMP indicates cyclic adenosine monophosphate.

1.
Schumer  RAPodos  SM The nerve of glaucoma! Arch Ophthalmol. 1994;11237- 44Article
2.
Kolker  AE Visual prognosis in advanced glaucoma: a comparison of medical and surgical therapy for retention of vision in 101 eyes with advanced glaucoma. Trans Am Ophthalmol. Soc. 1977;75539- 555
3.
Odberg  T Visual field prognosis in advanced glaucoma. Acta Ophthalmol. 1987;182(suppl 65)27- 29
4.
Mao  LKStewart  WCShields  MB Correlation between intraocular pressure control and progressive glaucomatous damage in primary open-angle glaucoma. Am J Ophthalmol. 1991;11151- 55
5.
Sommer  ATielsch  JMKatz  J  et al.  Relationship between intraocular pressure and primary open-angle glaucoma among white and black Americans. Arch Ophthalmol. 1991;1091090- 1095Article
6.
Not Available, Preferred Practice Pattern: Primary Open-Angle Glaucoma.  San Francisco, Calif American Academy of Ophthalmology1992;19- 22
7.
Collaborative Normal-Tension Glaucoma Study Group, Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressure. Am J Ophthalmol. 1998;126487- 497Article
8.
Fechtner  RDWeinreb  RN Mechanisms of optic nerve damage in primary open-angle glaucoma. Surv Ophthalmol. 1994;3923- 42Article
9.
Hernandez  MRPena  JDO The optic nerve head in glaucomatous optic neuropathy. Arch Ophthalmol. 1997;115389- 395Article
10.
Weinreb  RN Toward understanding the optic neuropathy of glaucoma. Arch Ophthalmol. 1998;1161102- 1103Article
11.
Levin  LA Intrinsic survival mechanisms for retinal ganglion cells. Eur J Ophthalmol. 1999;9S12- S16
12.
Wheeler  LALai  RWoldeMussie  E From the lab to the clinic: activation of an α2-agonist pathway is neuroprotective in models of retinal and optic nerve injury. Eur J Ophthalmol. 1999;9S17- S21
13.
Dreyer  EB A proposed role for excitotoxicity in glaucoma. J Glaucoma. 1998;762- 67Article
14.
Meyer-Franke  AKaplan  MRPfrieger  FWBarres  BA Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron. 1995;15805- 819Article
15.
Minckler  DSBunt  AHJohanson  GW Orthograde and retrograde axoplasmic transport during acute ocular hypertension in the monkey. Invest Ophthalmol Vis Sci. 1977;16426- 441
16.
Tatton  WG Apoptotic mechanisms in neurodegeneration: Possible relevance to glaucoma. Eur J Ophthalmol. 1999;9S22- S29
17.
Kroemer  GZamzami  NSusin  SA Mitochondrial control of apoptosis. Immunol Today. 1997;1844- 51Article
18.
Tatton  WGChalmers-Redman  RMJu  WYWadia  JTatton  NA Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription. J Neural Transm Suppl. 1997;49245- 268
19.
Quigley  HANickells  RWKerrigan  LA  et al.  Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci. 1995;36774- 786
20.
Kerrigan  LAZack  DJQuigley  HASmith  SDPease  ME TUNEL-positive ganglion cells in human open-angle glaucoma. Arch Ophthalmol. 1997;1151031- 1035Article
21.
Okisaka  SMurakami  AMizukawa  AIto  J Apoptosis in retinal ganglion cell decrease in human glaucomatous eyes. Jpn J Ophthalmol. 1997;4184- 88Article
22.
Yoles  ESchwartz  M Potential neuroprotective therapy for glaucomatous optic neuropathy. Surv Ophthalmol. 1998;42367- 372Article
23.
Caprioli  J Neuroprotection of the optic nerve in glaucoma. Acta Ophthalmol Scand. 1997;75361- 367
24.
Yoles  EMuller  SSchwartz  M NMDA-receptor antagonist protects neurons from secondary degeneration after partial optic nerve crush. J Neurotrauma. 1997;14665- 75Article
25.
Dreyer  EBZurakowski  DSchumer  RAPodos  SMLipton  SA Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma. Arch Ophthalmol. 1996;114299- 305Article
26.
Caprioli  JKitano  SMorgan  JE Hyperthermia and hypoxia increase tolerance of retinal ganglion cells to anoxia and excitotoxicity. Invest Ophthalmol Vis Sci. 1996;372376- 2381
27.
Levin  LA Direct and indirect approaches to neuroprotective therapy of glaucomatous optic neuropathy. Surv Ophthalmol. In press.
28.
Hickenbottom  SLGrotta  J Neuroprotective therapy. Semin Neurol. 1998;18485- 492Article
29.
Muir  KWGrosset  DG Neuroprotection for acute stroke: making clinical trials work. Stroke. 1999;30180- 182Article
30.
Mansour-Robaey  SClarke  DBWang  YC  et al.  Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. Proc Natl Acad Sci U S A. 1994;911632- 1636Article
31.
Bracken  MBShepard  MJHolford  TR  et al.  Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury: results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial: National Acute Spinal Cord Injury Study. JAMA. 1997;2771597- 1604Article
32.
Levin  LAClark  JAJohns  LK Effect of lipid peroxidation inhibition on retinal ganglion cell death. Invest Ophthalmol Vis Sci. 1996;372744- 2749
33.
Lindsey  JDWeinreb  RN Survival and differentiation of purified retinal ganglion cells in a chemically defined microenvironment. Invest Ophthalmol Vis Sci. 1994;353640- 3648
34.
Vorwerk  CKLipton  SAZurakowski  D  et al.  Chronic low-dose glutamate is toxic to retinal ganglion cells: toxicity blocked by memantine. Invest Ophthalmol Vis Sci. 1996;371618- 1624
35.
Pang  I-HWexler  EMNawy  SDeSantis  LKapin  MA Protection by eliprodil against excitotoxicity in cultured rat retinal ganglion cells. Invest Ophthalmol Vis Sci. 1999;401170- 1176
36.
Yoles  EWheeler  LASchwartz  M α2-Adrenoreceptor agonists are neuroprotective in a rat model of optic nerve degeneration. Invest Ophthalmol Vis Sci. 1999;4065- 73
37.
Morrison  JCMoore  CGDeppmeier  LM  et al.  A rat model of chronic pressure-induced optic nerve damage. Exp Eye Res. 1997;6485- 96Article
38.
Neufeld  AHSawada  ABecker  B Inhibition on nitric-oxide synthase 2 by aminoguanidine provides neuroprotection of retinal ganglion cells in a rat model of chronic glaucoma. Proc Natl Acad Sci U S A. 1999;969944- 9948Article
39.
Gaasterland  DKupfer  C Experimental glaucoma in the rhesus monkey. Invest Ophthalmol Vis Sci. 1974;13455- 457
40.
Sample  PABosworth  CFWeinreb  RN Short-wavelength automated perimetry and motion automated perimetry in glaucoma. Arch Ophthalmol. 1997;1151129- 1133Article
41.
Johnson  CAAdams  AJCasson  EJ  et al.  Blue-on-yellow perimetry can predict the development of glaucomatous visual field loss. Arch Ophthalmol. 1993;111645- 650Article
42.
Weinreb  RN Assessment of optic disc topography for diagnosing and monitoring glaucoma. Arch Ophthalmol. 1998;1161229- 1231Article
43.
Weinreb  RN Evaluating the retinal nerve fiber layer in glaucoma with scanning laser polarimetry. Arch Ophthalmol. 1999;1171403- 1406Article
44.
Eriksson  PSPerfilieve  EBojrk-Eriksson  T  et al.  Neurogenesis in the adult human hippocampus. Nat Med. 1998;41313- 1317Article
Special Article
November 1999

Is Neuroprotection a Viable Therapy for Glaucoma?

Author Affiliations

From the Glaucoma Center and Department of Ophthalmology, University of California, San Diego, La Jolla (Dr Weinreb); and Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison (Dr Levin). Both authors are consultants for several pharmaceutical companies involved with potential neuroprotective drugs. Dr Weinreb has served as a consultant or received research support from companies including Alcon Laboratories Inc, Allergan Inc, Merck & Co Inc, and Pharmacia & Upjohn.

Arch Ophthalmol. 1999;117(11):1540-1544. doi:10.1001/archopht.117.11.1540
Abstract

Treatment of glaucoma continues to be directed at lowering intraocular pressure to decrease the likelihood of disease progression. In the future intraocular pressure reduction might be augmented by other therapeutic approaches. Interest has been increasing in preventing progression of glaucomatous optic neuropathy using approaches based on the premise that glaucoma is a neurodegenerative disease. Neuroprotection of the glaucomatous optic nerve therefore would be an adjuctive therapeutic paradigm for use with conventional intraocular pressure–lowering treatments or by itself.

Treatment of glaucoma continues to be directed at lowering intraocular pressure (IOP)to decrease the likelihood of disease progression. The possibility that this emphasis on IOP reduction might be augmented in the future by other therapeutic approaches was discussed in the ARCHIVES more than 5 years ago.1 Since then, there has been increasing interest in preventing progression of glaucomatous optic neuropathy using approaches based on the premise that glaucoma is a neurodegenerative disease. Neuroprotection of the glaucomatous optic nerve therefore would be an adjunctive therapeutic paradigm for use with conventional IOP-lowering treatments or by itself.

CURRENT TREATMENT OF GLAUCOMA

Reduction of IOP has been the primary, and often the only, treatment modality for patients with ocular hypertension who are considered to be at risk for developing glaucoma, and for virtually all patients with glaucoma. In clinical practice, reduction of IOP is expected to halt or delay optic nerve damage in these patients. Once initiated, IOP-lowering treatment of both patients with ocular hypertension and glaucoma, usually with eye drops, is generally lifelong unless superseded by surgical intervention. The results of the Ocular Hypertensive Treatment Study, an ongoing randomized trial of medical IOP lowering vs observation, are expected within the next 5 years. Until recently, support for the role of IOP-lowering therapy in patients with glaucoma has derived mainly from uncontrolled or nonrandomized studies.26

Intraocular pressure–lowering treatment recently has been demonstrated to be beneficial in many, but not all, patients with normal-tension glaucoma. There is a lower rate of progression of visual field loss in patients with normal-tension glaucoma achieving a 30% reduction of IOP by medical or surgical treatment, compared with those in whom it was not lowered.7 Seven (12%) of the 61 treated patients reached end points (ie, specifically defined criteria of glaucomatous optic disc progression or visual field loss) compared with 28 (35%) of the 79 untreated control patients, when analyzed on an intention-to-treat basis. That those 7 patients had progressive glaucoma despite a 30% reduction of IOP by medical or surgical treatment is not surprising to many clinicians, particularly those in practice for many years.

Glaucoma can worsen despite careful follow-up and good patient compliance with seemingly adequate IOP-lowering therapy. Medical therapy alone fails to prevent progressive glaucoma damage in many patients. Surgery may succeed more often, but has greater risk associated with its use. In some of these patients with progressive glaucoma, it is possible that IOP has not been sufficiently reduced. In this situation, a lower target IOP range would be more effective. However, it is likely that there are other risk factors, in addition to IOP, that either modify the effects of elevated IOP or independently cause disease progression. Delineation of these risk factors, understanding how they influence optic nerve function and structure, and ameliorating them is necessary to comprehensively treat glaucoma. As the relationship between various risk factors and glaucoma onset or progression is not well understood, and it can be difficult or impossible to ameliorate the risk factors, a more global therapeutic approach may be useful. Neuroprotection, achieved with either current or future drugs, is such an approach and may provide a more encompassing mechanism for treating both nonpressure-dependent risk factors and the effects of elevated pressure (Figure 1).

WHAT IS NEUROPROTECTION?

Neuroprotection is a therapeutic paradigm for slowing or preventing death of neurons, in this case retinal ganglion cells and their axons (optic nerve fibers), to maintain their physiological function. Independent of cause, neuroprotection is aimed at blocking primary destructive events or enhancing survival mechanisms of the retinal ganglion cells or optic nerve fibers. In glaucoma, neuroprotection offers a method for preventing the irreversible loss of those cells. An important advantage of the neuroprotective strategy is that it allows treatment of a disease for which the specific etiology is either unknown or differs among patients. This is particularly relevant to glaucoma, a heterogeneous group of disorders that share common characteristic morphological features of the optic nerve head and patterns of visual loss. Theoretically, neuroprotection should be effective independently of whether a particular patient's glaucoma is due to primary or secondary disease mechanisms.

WHAT DAMAGES THE OPTIC NERVE IN GLAUCOMA?

Several pathophysiological mechanisms have been hypothesized to have a role in causing retinal ganglion cell death in glaucoma (Figure 2).1,810 Retinal ganglion cell viability is hypothesized to be dependent on a balance of positive (survival) and negative (death) stimuli, and they fail to survive if this balance is disturbed (Figure 3).11,12 One specific trigger of retinal ganglion cell death is excitotoxicity.13 Certain excitatory neurotransmitters, such as glutamate, can overexcite a cell via activation of the N-methyl-D-aspartate subclass of receptors. Retinal ganglion cell survival also may depend on certain neuronal growth factors (neurotrophins), such as brain-derived neurotrophic factor and ciliary neurotrophic factor.14 Axonal compression at the lamina cribrosa may cause blockade of retrograde axoplasmic flow from the lateral geniculate nucleus and other retinal ganglion cell targets (eg, superior colliculus, suprachiasmatic nucleus, or pretectal nuclei).15 Death of retinal ganglion cells could thus result from deprivation of these target-derived growth factors.8 Although the actual mechanisms leading to retinal ganglion cell death in glaucoma are still unclear, it would not be surprising if they shared common features with other types of neuronal injury, eg, signaling by reactive oxygen species,11 depolarization of mitochondria,16,17 or induction of transcriptionally regulated cell death.18

RATIONALE FOR NEUROPROTECTION

Experimental and pathophysiological studies suggest that the death of retinal ganglion cells in glaucoma occurs by a process of cell suicide or apoptosis.1921 At the present stage of biomedical research, it seems as if dead retinal ganglion cells cannot be replaced. This suggests that protecting a retinal ganglion cell from death is necessary to prevent its irreversible loss of function.

Successful neuroprotection requires that both the functional and structural characteristics of the retinal ganglion cells be preserved to maintain useful vision. Hence, in addition to slowing or preventing death of retinal ganglion cells, the electrical and biochemical requirements needed for function and the integrity of their structural relationships with surrounding cells need to be maintained.

Several approaches to neuroprotection in glaucoma are being evaluated (Figure 3).22,23 One possibility is to interrupt the excitotoxic cascade via blockade of the N-methyl-D-aspartate receptors–mediating cell death when retinal ganglion cells are exposed to glutamate.24,25 Dreyer et al25 have demonstrated elevated levels of glutamate in the vitreous of patients and animals with glaucoma, suggesting a possible causal relationship. Blockade of these receptors may interrupt the effects of axonal injury.13,22 Another neuroprotective approach relies on delivering neurotrophins to the retina to compensate for the deprivation of target-derived neurotrophins resulting from blockade of retrograde axoplasmic transport. This might require repeated intravitreal injections in a chronic disease like glaucoma since neurotrophins, which are large molecules, cannot readily cross the blood-retinal barrier. Alternatively, sustained release of a neurotrophin from an intraocular implant might be considered. Another approach to neuroprotection in glaucoma could take advantage of the inherent ability of the retinal ganglion cell to survive after sublethal injury.26 Neuroprotective agents that potentiate this survival cascade might maintain cellular function without altering the metabolic and/or proliferative characteristics of uninjured cells.27

DIFFERENCES BETWEEN NEUROPROTECTING THE BRAIN AND THE RETINAL GANGLION CELL

Neuroprotection already has been a goal of neurologists and neurosurgeons for several years, as a strategy for dealing with the irreversible effects of central nervous system (CNS) infarction or trauma. Unfortunately, there have been few randomized, double-masked, controlled (phase 3) clinical trials that have shown that any drug can have a significantly beneficial effect compared with no intervention.28,29 Therefore, it is reasonable to question why should neuroprotection for glaucoma, a disease affecting the retinal ganglion cell, be effective when it has been unsuccessful in so many other CNS trials so far. This question is of particular concern, as the retinal ganglion cell is itself a CNS neuron, and its axon is insulated and maintained by CNS oligodendrocytes and astrocytes.

One major difference between optic neuropathies (including glaucomatous optic neuropathy) and CNS infarction or trauma is the location of the injury. In optic nerve disease, only the retinal ganglion cell axons may be injured early, and the cell bodies die hours to days later.30 In most CNS infarctions and trauma, there is immediate injury directly to the cell bodies, and irreversible loss may occur much more quickly. Therefore, the window of opportunity for successful neuroprotection in axonal injuries may be much longer than for cell body injuries. This means that results of trials for neuroprotective agents in CNS diseases in general are not necessarily applicable to glaucomatous optic neuropathies. One of the few successful trials of a neuroprotective agent for CNS injury involved spinal cord injury, which is predominantly a disruption of long myelinated CNS axons.31

IMPLEMENTATION OF NEUROPROTECTION

The underlying theoretical basis for a neuroprotective strategy in glaucoma appears sound. Further, considerable data from retinal ganglion cell culture3235 and animal models of optic nerve injury24,3638 support a neuroprotective strategy. No randomized controlled trial has been completed that evaluates patients with glaucoma or any other optic neuropathy. For neuroprotection to become an integral part of our therapy for glaucoma, it is necessary that clinical research complement and extend available basic research.

One development that will surely have an influence on glaucoma treatment in the next several years is the delineation of which current and future drugs can best preserve visual function and the structural integrity of the optic nerve. Drugs approved to treat glaucoma are used to lower IOP. Whether the use of these drugs also results in preservation of visual function and structural integrity of the optic nerve was not an important consideration in their approval by the Food and Drug Administration. However, it is clear that each IOP-lowering medication has distinct biological activities and, therefore, that their IOP-lowering ability may not correlate fully with their ability to preserve visual function and optic nerve structure. For example, it is possible that 2 drugs that cause equivalent lowering of IOP may lead to different outcomes in retaining visual function. If one of them also can maintain (either directly or indirectly) the health of retinal ganglion cells and their axons, then that drug might be associated with a better visual outcome despite equivalent IOP lowering.

Pharmaceutical companies worldwide have made substantial investments to determine whether their drugs have a salutary effect on visual function and optic nerve structure. The modification of possible risk factors associated with glaucoma progression, such as conditions that lead to ischemia, also have been studied. However, unless these adjunctive measures correlate with enhanced visual function or maintenance of the optic disc and retinal nerve fiber layer, they might not provide justification for a claim for the drug of neuroprotection in glaucoma. The same issues are relevant to the study of drugs that may protect the optic nerve independent of lowering IOP. Regardless of what else it does, a drug should preserve visual function or maintain the structural integrity of the optic nerve if it is to be useful as a neuroprotective agent in glaucoma.

CONSIDERATIONS FOR IDENTIFICATION OF A PUTATIVE NEUROPROTECTIVE AGENT

With our current state of knowledge, candidate neuroprotective drugs should be sought that rescue injured retinal ganglion cells and/or protect healthy retinal ganglion cells. These drugs should be studied in appropriate models. As an example, one might screen drugs by looking at an in vitro model using cultured retinal ganglion cells33 that have sustained axonal injury. The optic nerve crush model in the rat22 may mimic some, but not all, aspects of glaucoma pathophysiology, and can also be used to screen compounds. More relevantly, candidate drugs can be studied in experimental ocular hypertensive models of glaucoma in the rat37,38 or monkey.39 Human optic neuropathies other than glaucoma (eg, anterior ischemic optic neuropathy or traumatic optic neuropathy) also can be studied as models for rescuing retinal ganglion cells.

As a topically administered drug does not necessarily achieve an appreciable concentration at the retinal ganglion cell or optic disc, whether a topical eye drop can affect retinal ganglion cells, either directly or indirectly, needs to be ascertained. This also is the case for a systemic agent, which would need to be shown to penetrate the blood-retinal barrier.

Finally, it is necessary to ascertain the feasibility of preventing retinal ganglion cell injury and repairing the effects of injury. Prevention is difficult to achieve in glaucoma, as significant damage occurs before detection can be achieved with current methods of visual field testing and optic disc or retinal nerve fiber layer examination. Although the beneficial effect might be limited, repair would appear to be feasible in eyes with known glaucoma.

CONSIDERATIONS FOR CLINICAL TRIALS WITH A NEUROPROTECTIVE AGENT

Clinical pharmacological 21 studies in glaucoma have been directed, for the most part, at determining whether a medication adequately reduces IOP with a tolerable side effect profile. Studies to demonstrate efficacy and obtain regulatory approval have been largely short-term and have employed few patients. Unfortunately, there is no simple single parameter to measure neuroprotection. Whether a drug can prevent or delay the progression of glaucomatous optic neuropathy cannot be readily addressed without use of visual function and/or optic nerve structural measures. However, few clinical trials have used visual function or optic nerve structure as an end point for determining treatment effect.

As glaucomatous optic neuropathy is a slowly progressive disease, clinical trials of neuroprotection will necessarily be of much longer duration than is required for determining IOP-lowering effect. In addition, large numbers of patients will be needed. The length of these studies and the large number of patients needed might be reduced by recruiting only those patients who are at higher risk for progressive disease. The use of more sensitive diagnostic techniques for determining visual function40,41 and optic nerve structure42,43 also may be helpful.

FUTURE APPROACHES

Although retinal ganglion cells cannot be replaced now, this may change in the future. Recent work suggests that the mammalian CNS has a much greater potential for producing new neurons and repairing damaged regions than previously thought.44 It may therefore be possible to trace the molecular cascades that lead from a specific stimulus, whether it be mechanical, ischemic, or excitotoxic, to particular alterations in gene expression, and thereby enhance regeneration and/or neurogenesis. Finally, the possibility that stem cell implantation may allow reconstitution of lost retinal ganglion cells could be a powerful method for amelioration of the otherwise irreversible effects of glaucoma on the optic nerve.

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Article Information

Accepted for publication September 13, 1999.

This investigation was supported in part by grants EY11158 (Dr Weinreb) and EY00340 (Dr Levin) from the National Eye Institute, National Institutes of Health, Bethesda, Md, the Glaucoma Foundation, New York, NY (Dr Levin), the Joseph Drown Foundation, Los Angeles, Calif (Dr Weinreb), and unrestricted departmental grants from Research to Prevent Blindness Inc, New York, NY, to the University of California, San Diego, and University of Wisconsin, Madison.

Dr Weinreb is a Research to Prevent Blindness Senior Scientific Investigator. Dr Levin is a Research to Prevent Blindness Dolly Green Scholar.

Corresponding author: Robert N. Weinreb, MD, Glaucoma Center (0946), University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0946.

References
1.
Schumer  RAPodos  SM The nerve of glaucoma! Arch Ophthalmol. 1994;11237- 44Article
2.
Kolker  AE Visual prognosis in advanced glaucoma: a comparison of medical and surgical therapy for retention of vision in 101 eyes with advanced glaucoma. Trans Am Ophthalmol. Soc. 1977;75539- 555
3.
Odberg  T Visual field prognosis in advanced glaucoma. Acta Ophthalmol. 1987;182(suppl 65)27- 29
4.
Mao  LKStewart  WCShields  MB Correlation between intraocular pressure control and progressive glaucomatous damage in primary open-angle glaucoma. Am J Ophthalmol. 1991;11151- 55
5.
Sommer  ATielsch  JMKatz  J  et al.  Relationship between intraocular pressure and primary open-angle glaucoma among white and black Americans. Arch Ophthalmol. 1991;1091090- 1095Article
6.
Not Available, Preferred Practice Pattern: Primary Open-Angle Glaucoma.  San Francisco, Calif American Academy of Ophthalmology1992;19- 22
7.
Collaborative Normal-Tension Glaucoma Study Group, Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressure. Am J Ophthalmol. 1998;126487- 497Article
8.
Fechtner  RDWeinreb  RN Mechanisms of optic nerve damage in primary open-angle glaucoma. Surv Ophthalmol. 1994;3923- 42Article
9.
Hernandez  MRPena  JDO The optic nerve head in glaucomatous optic neuropathy. Arch Ophthalmol. 1997;115389- 395Article
10.
Weinreb  RN Toward understanding the optic neuropathy of glaucoma. Arch Ophthalmol. 1998;1161102- 1103Article
11.
Levin  LA Intrinsic survival mechanisms for retinal ganglion cells. Eur J Ophthalmol. 1999;9S12- S16
12.
Wheeler  LALai  RWoldeMussie  E From the lab to the clinic: activation of an α2-agonist pathway is neuroprotective in models of retinal and optic nerve injury. Eur J Ophthalmol. 1999;9S17- S21
13.
Dreyer  EB A proposed role for excitotoxicity in glaucoma. J Glaucoma. 1998;762- 67Article
14.
Meyer-Franke  AKaplan  MRPfrieger  FWBarres  BA Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron. 1995;15805- 819Article
15.
Minckler  DSBunt  AHJohanson  GW Orthograde and retrograde axoplasmic transport during acute ocular hypertension in the monkey. Invest Ophthalmol Vis Sci. 1977;16426- 441
16.
Tatton  WG Apoptotic mechanisms in neurodegeneration: Possible relevance to glaucoma. Eur J Ophthalmol. 1999;9S22- S29
17.
Kroemer  GZamzami  NSusin  SA Mitochondrial control of apoptosis. Immunol Today. 1997;1844- 51Article
18.
Tatton  WGChalmers-Redman  RMJu  WYWadia  JTatton  NA Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription. J Neural Transm Suppl. 1997;49245- 268
19.
Quigley  HANickells  RWKerrigan  LA  et al.  Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci. 1995;36774- 786
20.
Kerrigan  LAZack  DJQuigley  HASmith  SDPease  ME TUNEL-positive ganglion cells in human open-angle glaucoma. Arch Ophthalmol. 1997;1151031- 1035Article
21.
Okisaka  SMurakami  AMizukawa  AIto  J Apoptosis in retinal ganglion cell decrease in human glaucomatous eyes. Jpn J Ophthalmol. 1997;4184- 88Article
22.
Yoles  ESchwartz  M Potential neuroprotective therapy for glaucomatous optic neuropathy. Surv Ophthalmol. 1998;42367- 372Article
23.
Caprioli  J Neuroprotection of the optic nerve in glaucoma. Acta Ophthalmol Scand. 1997;75361- 367
24.
Yoles  EMuller  SSchwartz  M NMDA-receptor antagonist protects neurons from secondary degeneration after partial optic nerve crush. J Neurotrauma. 1997;14665- 75Article
25.
Dreyer  EBZurakowski  DSchumer  RAPodos  SMLipton  SA Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma. Arch Ophthalmol. 1996;114299- 305Article
26.
Caprioli  JKitano  SMorgan  JE Hyperthermia and hypoxia increase tolerance of retinal ganglion cells to anoxia and excitotoxicity. Invest Ophthalmol Vis Sci. 1996;372376- 2381
27.
Levin  LA Direct and indirect approaches to neuroprotective therapy of glaucomatous optic neuropathy. Surv Ophthalmol. In press.
28.
Hickenbottom  SLGrotta  J Neuroprotective therapy. Semin Neurol. 1998;18485- 492Article
29.
Muir  KWGrosset  DG Neuroprotection for acute stroke: making clinical trials work. Stroke. 1999;30180- 182Article
30.
Mansour-Robaey  SClarke  DBWang  YC  et al.  Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. Proc Natl Acad Sci U S A. 1994;911632- 1636Article
31.
Bracken  MBShepard  MJHolford  TR  et al.  Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury: results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial: National Acute Spinal Cord Injury Study. JAMA. 1997;2771597- 1604Article
32.
Levin  LAClark  JAJohns  LK Effect of lipid peroxidation inhibition on retinal ganglion cell death. Invest Ophthalmol Vis Sci. 1996;372744- 2749
33.
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