Journal of Postgraduate Medicine
 Open access journal indexed with Index Medicus & ISI's SCI  
Users online: 127  
Home | Subscribe | Feedback | Login 
About Latest Articles Back-Issues Article Submission Resources Sections Etcetera Contact
 
  NAVIGATE Here 
  Search
 
 :: Next article
 :: Previous article 
 :: Table of Contents
  
 RESOURCE Links
 ::  Similar in PUBMED
 ::  Search Pubmed for
 ::  Search in Google Scholar for
 ::Related articles
 ::  Article in PDF (598 KB)
 ::  Citation Manager
 ::  Access Statistics
 ::  Reader Comments
 ::  Email Alert *
 ::  Add to My List *
* Registration required (free) 

  IN THIS Article
 ::  Abstract
 ::  Neuroprotection
 ::  Mechanisms of re...
 ::  Neuroprotective ...
 ::  Ideal drug for t...
 ::  Gene therapy: fu...
 ::  References

 Article Access Statistics
    Viewed24318    
    Printed823    
    Emailed48    
    PDF Downloaded1115    
    Comments [Add]    
    Cited by others 66    

Recommend this journal


 


 
REVIEW ARTICLE
Year : 2003  |  Volume : 49  |  Issue : 1  |  Page : 90-5

Neuroprotection in glaucoma.


Department of Ophthalmology, Postgraduate Institute of medical education and Research, Chandigarh-160 012, India., India

Correspondence Address:
S Kaushik
Department of Ophthalmology, Postgraduate Institute of medical education and Research, Chandigarh-160 012, India.
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0022-3859.917

Get Permissions


 :: Abstract 

Currently, glaucoma is recognised as an optic neuropathy. Selective death of retinal ganglion cells (RGC) is the hallmark of glaucoma, which is also associated with structural changes in the optic nerve head. The process of RGC death is thought to be biphasic: a primary injury responsible for initiation of damage that is followed by a slower secondary degeneration related to noxious environment surrounding the degenerating cells. For example, retinal ishaemia may establish a cascade of changes that ultimately result in cell death: hypoxia leads to excitotoxic levels of glutamate, which cause a rise in intra-cellular calcium, which in turn, leads to neuronal death due to apoptosis or necrosis. Neuroprotection is a process that attempts to preserve the cells that were spared during the initial insult, but are still vulnerable to damage. Although not yet available, a neuroprotective agent would be of great use in arresting the progression of glaucoma. There is evidence that neuroprotection can be achieved both pharmacologically and immunologically. Pharmacological intervention aims at neutralising some of the effects of the nerve-derived toxic factors, thereby increasing the ability of the spared neurons to cope with stressful conditions. On the other hand, immunological interventions boost the body's own repair mechanisms for counteracting the toxic effects of various chemicals generated during the cascade. This review, based on a literature search using MEDLINE, focuses on diverse cellular events associated with glaucomatous neurodegeneration, and discusses some pharmacological agents believed to have a neuroprotective role in glaucoma.


Keywords: Apoptosis, Cytoprotection, Gene Therapy, Glaucoma, genetics,prevention &control,Human, Neuroprotective Agents, therapeutic use,Retinal Ganglion Cells, drug effects,physiology,


How to cite this article:
Kaushik S, Pandav S S, Ram J. Neuroprotection in glaucoma. J Postgrad Med 2003;49:90

How to cite this URL:
Kaushik S, Pandav S S, Ram J. Neuroprotection in glaucoma. J Postgrad Med [serial online] 2003 [cited 2016 May 3];49:90. Available from: http://www.jpgmonline.com/text.asp?2003/49/1/90/917


Glaucoma associated with distinctive changes in the disc and visual fields, is viewed as an optic neuropathy characterized by progressive loss of retinal ganglion cells (RGC). This concept emphasizes that several pressure-independent mechanisms are responsible for the development and progression of glaucomatous neuropathy and that high intra-ocular pressure (IOP) and vascular insufficiency in the optic nerve head are merely risk factors for the development of glaucoma. The central role of raised IOP is being questioned as many patients continue to demonstrate a clinically downhill course despite control of initially raised IOP.[1] In addition, up to one-sixth of patients with glaucoma develop it despite normal IOP.[2] A great deal of research is being conducted for the development of neurotropic agents that would help prevent RGC death. In addition, researchers are also looking at induction of cell rescue mechanisms as an alternative strategy for neuroprotection. This review, based on an extensive literature search using MEDLINE, provides information about the pathophysiological aspects of glaucomatous optic nerve damage and the state of research regarding the development of neuroprotective and antiapoptotic agents.

In humans, the optic nerve consists of approximately one million axons; whose cell bodies are primarily located in the ganglion cell layer.[3] RGC death, therefore, represents the final common pathway of virtually all diseases of the optic nerve including glaucomatous optic neuropathy. There is histological and electrophysiological evidence to suggest that ganglion cells are the sole neurons affected in glaucoma,[3] while the remainder of the inner and outer retina remain uninvolved. The excavated appearance of the optic nerve head in glaucoma is thought to be caused by death of the ganglion cells and subsequent loss of their axons.[4] Electroretinogram (ERG) is normal in glaucoma, indicating normal photoreceptor and bipolar/Muller’s cells.[5] Histopathological studies have shown that, in glaucoma, retinal ganglion cells and axons die, while no other neurons are visibly affected.[6]

It is necessary to understand certain concepts about cell death before discussing the pathophysiology of glaucomatous optic neuropathy. It is now understood that most mammalian cells die through apoptosis, which is a complex active cellular process that results in an orderly self-destruction. It is also known that whatever the inciting insult or injury, actual cell death occurs through a final common pathway. In addition, Kerr et al[7] described the process of secondary degeneration wherein neuronal damage continues even when the primary cause of damage is ameliorated or eliminated. They suggested that healthy neurons suffer progressive damage due to their close proximity to the dying neurons as the former are exposed to the noxious environment created by the latter and subsequently suffer the same fate of cell death. Thus, neuronal death can be thought to occur in three stages: axonal injury, death of the injured neuron and injury to and death of the neighbouring intact neurons through secondary degeneration.

The excessive loss of neurons has been attributed to the delayed biochemical processes that lead to neuronal death in excess of that caused by the primary injury.[9],[10] It appears that, regardless of the primary lesion (ischaemia, hypoxia, stroke, mechanical trauma, degenerative neuronal disease), the damage to neurons leads to similar changes in the extra-cellular milieu: alteration in the ionic concentrations, increased amounts of free radicals, release of neurotransmitters, depletion of growth factors and alterations in the immune system.[11],[12] The hostile milieu, therefore, allows for a self-perpetuating destructive cascade that remains active long after the initial or primary insult has abated. The extent of succeeding degeneration, however, remains a function of the severity of the initial insult, i.e. more severe the primary insult, more extensive is the secondary degeneration.

Yoles and Schwartz[13] hypothesised that this concept provided a plausible explanation for two important clinical observations in glaucoma. First, in some cases, progression of glaucomatous damage continues despite attenuation of the initial insult, viz. high IOP. Secondly, patients with severe pre-existing damage are more likely to deteriorate despite having the same or even lower IOPs than those who do not have visual field loss at the time of diagnosis. Neufield[14] described a model concept of the internal milieu of a glaucomatous eye as having RGCs in various conditions ranging from normal, sick, degenerating and dead. The fate of these cells is a function of their proximity to the original site of damage, coupled with individual susceptibility.

The strategy of treating a disease by preventing neuronal death is termed neuroprotection. The term is used more narrowly to describe therapies to address final common pathways of damage in many neurological diseases ranging from amyotrophic lateral sclerosis, Alzheimer’s disease and, in the context of the eye, glaucoma. The potential role of neuroprotective agents is to rescue of sick and dying cells and to maintain the integrity of healthy cells by providing resilience to a variety of hostile factors or agents.


  ::   Mechanisms of retinal ganglion cell death Top


Research into the actual events leading to the death of RGCs has delineated several mechanisms that may be responsible for RGC death:

1. Neurotrophin withdrawal due to retrograde axoplasmic transport block.

2. Glutamate induced excitotoxicity.

3. Free radical generation

4. Nitric oxide neurotoxicity

5. Apoptosis

Neurotrophin Withdrawal

The neurotrophic hypothesis holds that mammalian neuronal growth and maintenance depend upon the viability of retrograde axoplasmic transport of soluble growth factors called neurotrophins.[15] The neurotrophins supplied to the RGCs are small peptides that function to regulate cellular metabolism by attaching themselves to neuronal target-cell receptors. From there, they initiate a cascade of molecular enzymatic events and maintain cellular homeostasis. Ganglion cells appear to be particularly dependent upon the brain-derived neurotrophin factor (BDNF) which is necessary for their continued survival.[16],[17]. This factor can promote survival and prevent neuronal death after axotomy in the optic nerve.[18] Further support for the neurotrophic hypothesis comes from the findings of Gao et al[19] who showed an enhanced expression of BDNF in the RGC layer after optic nerve injury.

Glutamate Induced Excitotoxicity

Glutamate is the main excitatory neurotransmitter in the central nervous system and is present in neurons in very high concentrations. Glutamate induced excitotoxicity occurs when extra-cellular glutamate levels are increased, either due to increased release or decreased uptake from the synapse. High glutamate concentrations activate several types of cell receptors, including N-methyl-D-aspartate (NMDA) receptors that can allow entry of excessive amounts of calcium. Abnormally high Ca2+ concentration leads to inappropriate activation of complex cascades of nucleases, proteases and lipases. They directly attack cell constituents and lead to the generation of highly reactive free radicals and activation of the nitric oxide pathway.[20] The resulting interaction between intermediate compounds and free radicals leads to DNA nitrosylation, fragmentation and activation of the apoptotic programme.

Free Radical Generation

Free radicals are generated not only through the activation of glutamate receptors but also as an inevitable by-product of normal oxidative mechanisms.[21] This is especially true in the retina which has a very high metabolic rate. Endogenous antioxidants such as superoxide dismutase, Vitamins E and C, and glutathione normally inactivate these free radicals. However, when not inactivated sufficiently, they can react detrimentally with most macromolecular cellular constituents and may lead to protein conversion, lipid peroxidation and nucleic acid breakdown.

Nitric Oxide Neurotoxicity

Nitric oxide neurotoxicity occurs through the reaction of nitric oxide with superoxide anion to form peroxynitrite and other more reactive free radical species. Peroxynitrite acts by S-nitrosylating both proteins and nucleic acids, thus destroying them.[22]

Apoptosis

All animal cells are programmed for carrying out self-destruction when they are not needed, or when damaged. Apoptosis is a process rather than an event. It has been labelled a programmed cell death, or cell suicide. It is not unique to RGCs or glaucoma alone. Following an initial insult, the cells try to minimize or buffer the damage done through a variety of processes. Generation of “suicide triggers” could be one of the consequences of these processes and interactions and these molecules may start the process of apoptosis which is characterized by an orderly pattern of inter-nucleosomal DNA fragmentation, chromosome clumping, cell shrinkage and membrane blebbing.[22] This is followed by disassembly of cells into multiple membrane-enclosed vesicles, that are engulfed by neighbouring cells without inciting inflammation. Cell death with apoptosis is often contrasted with death by necrosis. Necrosis is classically marked by cellular swelling, disruption of organelle and plasma membranes, random DNA fragmentation, and uncontrolled release of cellular constituents into extra-cellular space usually resulting in inflammation.


  ::   Neuroprotection Top


The objective of neuroprotective therapy is to employ pharmacologic or other means to attenuate the hostility of the environment or to supply the cells with the tools to deal with these changes.[23] According to this approach, any chronic degenerative disease may be viewed to have, at any given time, some neurons undergoing an active process of degeneration which contributes to the hostility of the environment surrounding it. The exponential loss of cells after secondary degeneration stems from the damage brought on other neurons that either escaped or were only marginally damaged by the primary injury.[24] Neuroprotection attempts to provide protection to such neurons that continue to remain at risk.[25]

The inherent attractiveness of neuroprotection lies in absence of the need to treat the cause of the disease. Regardless of whether pressure-dependent or pressure-independent factors are at work, neuroprotection attempts to address the final common pathway of a variety of insults leading to RGC death.


  ::   Neuroprotective agents Top


The loss of RGCs in glaucoma appears progressively over many years. A neuroprotective drug should enhance the survival of RGCs in the presence of chronic stress/injury. Wheeler and WoldeMussie[26] proposed four criteria to assess the likely therapeutic utility of neuroprotective drugs with demonstrated utility in animal studies: The drug should have a specific receptor target in the retina/ optic nerve; activation of the target must trigger pathways that enhance a neuron’s resistance to stress or must suppress toxic insults, the drug must reach the retina/ vitreous in pharmacologically effective concentrations and the neuroprotective activity must be demonstrated in clinical trials.

A host of pharmacological drugs, growth factors, and other compounds have been reported to be neuroprotective in vitro, and in a number of neurologic and neurodegenerative disorders. Numerous clinical trials in stroke,  Parkinsonism More Details and Alzheimer’s disease are underway at the present time. However, no clinical trials of neuroprotection in glaucoma have yet been reported. Nevertheless, the variety of biochemical processes taking place present potential avenues for neuroprotective intervention. Some of the agents reported to have neuroprotective activity in the optic nerve are presented.

Ca2+ channel blockers (CCB): They have been shown to neutralize glutamate-NMDA-induced intracellular Ca2+ influx. In a retrospective study of normal-tension and open-angle glaucoma patients who happened to be taking calcium channel blockers, Netland et al[27] demonstrated a decrease in glaucoma progression relative to controls. Kittazawa et al[28] suggested visual improvement in a significant number of patients who took nifedipine in a 6-month prospective study. Flunarizine, a potent CCB has been demonstrated to enhance RGC survival after optic nerve transection in mice.[29] Although seemingly beneficial, one concern is that the blood-pressure lowering properties that make them useful in cardiovascular diseases might also decrease perfusion in the optic nerve and result in further ischemia.[30]

Antiglaucoma medications: Betaxolol is thought to possess some calcium-channel blocking activity, which could explain tis apparent vasodilating activity. [31] Additionally, Gross et al [32] have shown that it exerts actions on the retinal ganglion cells by reversibly blocking glutamate-gated currents and subsequent firing of ganglion cells. Recently, Brimonidine has been demonstrated to have neuroprotective attributes by virtue of its ability to reduce the rate of RGC loss in a rat optic nerve injury model.[24] Gao et al[33] also demonstrated that intra-vitreal brimonidine significantly increased endogenous BDNF expression in rat RGCs. A clinical trial has been instituted to determine brimonidine’s neuroprotective activity in patients with non-arteritic ischaemic neuropathy.

NMDA Antagonists: NMDA antagonists can inhibit over-stimulation of the NMDA receptor, which then provides neuroprotection by preventing excessive calcium influx. One NMDA antagonist, memantine, is presently undergoing testing in a placebo-controlled prospective, randomised, multi-centric trial in the US. Memantine effectively blocks the excitotoxic response of retinal ganglion cells both in culture and in vivo.[34] In a rat model of retinal ischemia created by elevating IOP to 120 mm Hg, memantine reduced ganglion cell loss when given systemically.[35]

Antioxidants: Antioxidants neutralise other suicide triggers such as reactive oxygen species emanating from the glutamate cascade. Free radical scavengers like catalase, superoxide dismutase, and vitamins C and E are useful for mopping up loose by-products generated during secondary degeneration.

Nitric Oxide synthase (NOS-2) inhibitors: NO in significant amounts plays a significant role in DNA nitrosylation and fragmentation that precedes apoptosis.[20] Neufield et al[36] examined the use of oral aminoguanidine, an inhibitor of NOS-2, for its effect in preventing glaucomatous cupping in a rat model created by cauterising three episcleral vessels. After 6 months of treatment, the optic nerve heads of the untreated animals had pallor and cupping, while those of the treated animals appeared normal. In histological specimens, the untreated eyes had lost a mean of 36% of their retinal ganglion cells, whereas those in the treated group had lost less than 10%.

Neurotrophins: Neurotrophic support through endogenous and exogenous sources is being evaluated. BDNF, ciliary neurotrophin factor, and basic fibroblastic growth factor have been shown to promote human retinal ganglion cell survival in culture and in vivo.[37] One suggested approach is to deliver these substances by creation of a fistula between the anterior chamber and vitreous cavity through which neurotrophins from the iris can reach the retina.

Ginkgo biloba extract (GBE): This is freely available as a nutritional supplement in the US. It is claimed to be effective in a variety of disorders associated with ageing, including cerebrovascular disease, peripheral vascular disease, dementia, tinnitus, bronchoconstricition and sexual dysfunction.[38] GBE exerts protective effects against free radical damage and lipid peroxidation in various tissue and experimental systems. It preserves mitochondrial metabolism and ATP production in various tissues. It is also a scavenger of superoxide radicals and nitric oxide.[39]

GBE has been found to improve both peripheral and cerebral blood flow. In one clinical study by Chung et al,[40] it was demonstrated that low-dose, short-term treatment with GBE in healthy volunteers, increased ophthalmic artery blood flow by a mean of 24%.


  ::   Ideal drug for the treatment of glaucoma Top


The ideal anti-glaucoma drug would be one that prevents ganglion cell death and has no adverse effects on the patient. Should the patient also have increased IOP, this can be treated separately.[41] However, in reality, any drug targeted specifically to the retina to prevent ganglion cell death is likely to have appreciable side effects. Therefore, at the present time, a more realistic ideal drug would be one that when applied topically, reduces IOP, and reaches the retina in appropriate amounts to attenuate retinal ganglion cell death.


  ::   Gene therapy: future possibilities Top


Intense research in gene therapy has made it an emerging therapeutic possibility in glaucoma management. Advances in the expression of apoptosis-involved genes or their protein products have demonstrated neuroprotective capacity in vitro. Several gene families have been identified that play either positive or negative roles in determining whether a cell will undergo apoptosis. Caspases are cysteine proteins that both propagate apoptotic signals as well as carry out disassembly of the cell.[42] Many triggers activate caspases including increased intracellular calcium, free radicals and adenosine 3’5'- cyclic phosphate.[43] The prototype of the mammalian caspase is interleukin-1b converting enzyme (ICE).

The main inhibitors of apoptosis are Bcl-2 and related proteins. They have multiple complex functions, such as inhibiting intermediate proteins that activate caspases.[44] One of the primary regulatory steps in apoptosis is the activation of tumour suppression protein, p53.[45] This protein functions as a transcription factor that can up-regulate the expression of the pro-apoptotic gene bax and down-regulate the expression of the anti-apoptotic gene bcl-2.

Martinou et al[46] have successfully generated a transgenic mouse line that allowed expression of the apoptosis-inhibiting gene Bcl-2 in rat neurons. The result was a 50% increase in retinal ganglion cell numbers accompanied by an increase in the thickness of the inner plexiform layer. Deprenyl, a monoamine oxidase inhibitor used in Parkinson’s disease, is an example of a compound capable of increasing gene expression that inhibits apoptosis. Other promising compounds include flunarizine and aurintricarboxylic acid, which apparently delay apoptosis after light-induced photoreceptor cell death.[47]

An understanding of the genetic pathways of apoptosis may lead to the design of new treatments that could prevent its activation or arrest the process when started. A gene could be delivered to the relevant tissue via several possible mechanisms including viruses, artificial liposomes, and direct transfer. Alternatively, one could induce the cell to express the requisite gene by its own regulatory pathways. Ultimately, gene therapy could replace the mutant gene with a normal one before visual loss has occurred.

 
 :: References Top

1.Brubaker RF. Delayed functional loss in glaucoma. LII Edward Jackson Memorial Lecture. Am J Ophthalmol 1996;121:473-83.  Back to cited text no. 1    
2.Lisegang TJ. Glaucoma: changing concepts and future directions. Mayo Clin Proc 19967;689-94.  Back to cited text no. 2    
3.Osborne NN, Ugarte M, Chao M, Chidlow G, Bae JH, Wood JP, et al. Neuroprotection in relation to retinal ischemia and relevance to glaucoma. Surv Ophthalmol 1999;43(Suppl):102-28.  Back to cited text no. 3    
4.Quigley HA, Green WR. The histology of human glaucoma cupping and optic nerve damage: clinicopathologic correlation in 21 eyes. Ophthalmology 1979;86:1803-30.  Back to cited text no. 4    
5.Korth M, Horn F, Stork B, Jonas J. The pattern evoked electroretinogram: age related alterations and changes in glaucoma. Graefes Arch Clin Exp Ophthalmol 1989;227:123-30.  Back to cited text no. 5    
6.Quigley HA, Addicks EM, Green WR, Maumenee AE. Optic nerve damage in human glaucoma II. The site of injury and susceptibility to damage. Arch Ophthalmol 1981;99:635-49.  Back to cited text no. 6    
7.Wein FB, Levin LA. Current understanding of neuroprotection in glaucoma. Curr Opin Ophthalmol 2002;13:61-7.  Back to cited text no. 7    
8.Kerr JF, Wyilie AH, Currle AR. Apoptosis: a basic biologic phenomenon with wide-ranging complications in tissue kinetics. Br J Cancer 1972;26:239-57.  Back to cited text no. 8    
9.Faden AI. Pharmacotherapy in spinal cord injury: a critical review of recent developments. Clin Neuropharmacol 1987;10:193-204.  Back to cited text no. 9    
10.Lynch DR, Dawson TM. Secondary mechanisms in neuronal trauma. Curr Opin Neurol 1994;7:510-6.  Back to cited text no. 10    
11.Choi DA. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1988;1:623-34.  Back to cited text no. 11    
12.Siesjo BK. Mechanisms of ischaemic brain damage. Crit Care Med 1988;16:954-63.  Back to cited text no. 12    
13.Yoles E, Schwartz M. Potential neuroprotective therapy for glaucomatous optic neuropathy. Surv Ophthalmol 1998;42:367-72.  Back to cited text no. 13    
14.Neufield AH. New conceptual approaches for pharmacological neuroprotection in glaucomatous neuronal degeneration. J Glaucoma 1998;7:434-8.  Back to cited text no. 14    
15.Mckinnon SJ. Glaucoma, apoptosis and neuroprotection. Curr Opin Ophthalmol 1997;8:28-37.  Back to cited text no. 15    
16.Nickells RW. Retinal ganglion cell death in glaucoma: the how, the witty and the maybe. J Glaucoma 1996;5:345-56.  Back to cited text no. 16    
17.Nickells RW, Zack DJ. Apoptosis in ocular disease: a molecular review. Ophthalmic Genet 1996;17:145-65.  Back to cited text no. 17    
18.Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ, Zach DJ. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vi Sci 1995;36:774-86.  Back to cited text no. 18    
19.Gao H, Qiaou X, Hefti F, Holyfield JG, Knusel B. Elevated mRNA expression of brain-derived neurotrophic factor in retinal ganglion cell layer after optic nerve injury. Invest Ophthalmol Vis Sci 1997;38:1840-7.  Back to cited text no. 19    
20.Naskar R, Dreyer EB. New horizons in neuroprotection. Surv Ophthlamol 2001;45(Suppl 3):S250-6.  Back to cited text no. 20    
21.Boveris A, Chance B. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 1973;134:707-16.  Back to cited text no. 21    
22.Farkas RH, Grosskreutz CL. Apoptosis, neuroprotection and retinal ganglion cell death: An overview. Int Ophthalmol Clin 2001;41:111-30.  Back to cited text no. 22    
23.Kaufman PL, Gabelt BT, Cynader M. Introductory comments on neuroprotection. Surv Ophthalmol 1999;43(Suppl):S89-90.  Back to cited text no. 23    
24.Schwartz M, Belkin M, Yoles E, Solomon A. Potential treatment modalities for glaucomatous neuropathy: neuroprotection and neuroregeneration. J Glaucoma 1996;5:427-32.  Back to cited text no. 24    
25.Chew SJ, Ritch R. Neuroprotection: the next break through in glaucoma? Proceedings of the third Annual Optic Nerve Rescue and Restoration Think Tank. J Glaucoma 1997;6:263-66.  Back to cited text no. 25    
26.Wheeler LA, Gil DW, WoldeMussie E. Role of alpha-2 adrenergic receptors in neuroprotection and glaucoma. Surv Ophthalmol 2001;45(Suppl)3:S290-6.  Back to cited text no. 26    
27.Netland PA, Chaturvedi N, Dreyer EB. Calcium channel blockers in the management of low tension and open angle glaucoma. Am J Ophthalmol 1993;115:608-13.  Back to cited text no. 27    
28.Kittazawa Y, Shirai H, Go FJ. The effect of ca2+ antagonist on visual field in low-tension glaucoma. Graefes Arch Clin Exp Ophthalmol 1989;227:408-12.  Back to cited text no. 28    
29.Eschweiler GW, Bahr M. Flunarizine enhances rat retinal ganglion cell survival after axotomy. J Neurol Sci 1993;116:34-40.  Back to cited text no. 29    
30.Caprioli J. Neuroprotection of the optic nerve in glaucoma. Acta Ophthalmol Scand 1997;75:364-7.  Back to cited text no. 30    
31.Bautista RD. Glaucomatous neurodegeneration and the concept of neuroprotection. Int Ophthalmol Clin 1999;39:57-70.  Back to cited text no. 31    
32.Gross RL, Hensley SH, Gao F, Wu SM. Retinal ganglion cell dysfunction induced by hypoxia and glutamate: potential neuroprotective effects of beta-blockers. Surv Ophthalmol 1999;43(Suppl 1):S162-70  Back to cited text no. 32    
33.Gao H, Qiao X, Cantour LB, Wu Dunn D. Up-regulation of brain-derived neurotrophic factor expression by brimonidine in rat retinal ganglion cells. Arch Ophthalmol 2002;120:797-803.  Back to cited text no. 33    
34.Vorwerk CK, Lipton SA, Zurakowski D, Hyman BT, Sobel BA, Dreyer EB. Chronic low-dose glutamate is toxic to retinal ganglion cells: toxicity blocked by memantine. Invest Ophthalmol Vis Sci 1996;37:1618-24.  Back to cited text no. 34    
35.Lagreze WA, Knorle R, Bach M, Feuerstein TJ. Memantine is neuroprotective in a rat model of pressure-induced retinal ischemia. Invest Ophthalmol Vis Sci 1998;39:1063-6.  Back to cited text no. 35    
36.Neufeld AH, Sawada A, Becker B. Inhibition of nitric oxide synthase-2 by aminoguanidine provides neuroprotection of retinal ganglion cells in a rat model of chronic glaucoma. Proc Nat Acad Sci USA 1999;96:9944-8.  Back to cited text no. 36    
37.Rabacchi SA, Ensini M, Bonfanti I, Grarina A, Maffei L. Nerve growth factor reduces apoptosis of axotomized retinal ganglion cells in the neonatal rat. Neuroscience 1994;63:969-73.   Back to cited text no. 37    
38.Ritch R. Neuroprotection: Is it already applicable to glaucoma therapy? Curr Opin Ophthalmol 2000;11:78-84.  Back to cited text no. 38    
39.Janssens D, Michiels C, Delaive E, Eliaers F, Drieu K, Remacle J. Protection of hypoxia induced ATP decrease in endothelial cells by Ginkgo biloba extract and bilobalide. Biochem Pharmacol 1995;50:991-9.  Back to cited text no. 39    
40.Chung HS, Harris A, Kristinsson JK, Ciulla TA, Kagemann C, Ritch R. Ginkgo biloba extract increased ocular blood flow velocity. J Ocul Pharmacol Ther 1999;15:233-40.  Back to cited text no. 40    
41.Sood NN, Sood D. Primary glaucomas: current concepts and management. J Indian Med Assoc 2000;98:763-7.  Back to cited text no. 41    
42.Hetts SW. To die or not to die: an overview of apoptosis and its role in disease. JAMA 1998;279:300-7.  Back to cited text no. 42    
43.GarrielI Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell-death in situ via labeling of nuclear DNA fragmentation. J Cell Biol 1992;119:493-501.  Back to cited text no. 43    
44.Adams JM, Cory S. The Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Science 1998;281:1322-6.  Back to cited text no. 44    
45.Nickells RW. Apoptosis of retinal ganglion cells in glaucoma: an update of the molecular pathways involved in cell death. Surv Ophthalmol 1999;43:S151-61.  Back to cited text no. 45    
46.Martinou JC, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski M, Missotten M, et al. Overexpression of Bcl-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 1994;13:1017-30.  Back to cited text no. 46    
47.Lam TT, Fu J, Hyrnewycz M, Tso MO. The effect of aurintricarboxylic acid, an endonuclease inhibitor, on ischemia/ reperfusion damages in rat retina. J Ocular Pharmacol Ther 1995;11:253-9.  Back to cited text no. 47    



This article has been cited by
1 Neuroprotective effects of intravitreally transplanted adipose tissue and bone marrow–derived mesenchymal stem cells in an experimental ocular hypertension model
Esra Emre,Nursen Yüksel,Gökhan Duruksu,Dilara Pirhan,Cansu Subasi,Gülay Erman,Erdal Karaöz
Cytotherapy. 2015; 17(5): 543
[Pubmed] | [DOI]
2 Anti-glaucoma potential of Heliotropium indicum Linn in experimentally-induced glaucoma
Samuel Kyei,George Asumeng Koffuor,Paul Ramkissoon,Osei Owusu-Afriyie
Eye and Vision. 2015; 2(1)
[Pubmed] | [DOI]
3 Visual improvement following glaucoma surgery: a case report
William S Foulsham,Lanxing Fu,Andrew J Tatham
BMC Ophthalmology. 2014; 14(1): 162
[Pubmed] | [DOI]
4 What can we learn about stroke from retinal ischemia models?
Philippe M DæOnofrio, Paulo D Koeberle
Acta Pharmacologica Sinica. 2013; 34(1): 91
[VIEW] | [DOI]
5 Adenosine, adenosine receptors and glaucoma: An updated overview
Yisheng Zhong,Zijian Yang,Wei-Chieh Huang,Xunda Luo
Biochimica et Biophysica Acta (BBA) - General Subjects. 2013; 1830(4): 2882
[Pubmed] | [DOI]
6 Neuroprotective Effect of Protease-Activated Receptor-2 in the Hypoxia-Induced Apoptosis of Rat RGC-5 Cells
Yanli Peng,Jiaping Zhang,Haiwei Xu,Jianrong He,Xi Ying,Yi Wang
Journal of Molecular Neuroscience. 2013; 50(1): 98
[Pubmed] | [DOI]
7 Protective effects of the compounds isolated from the seed of Psoralea corylifolia on oxidative stress-induced retinal damage
Kyung-A Kim,Sang Hee Shim,Hong Ryul Ahn,Sang Hoon Jung
Toxicology and Applied Pharmacology. 2013; 269(2): 109
[Pubmed] | [DOI]
8 Magnetic resonance in studies of glaucoma
Michal Fiedorowicz,Wojciech Dyda,Robert Rejdak,Pawel Grieb
Medical Science Monitor. 2011; 17(10): RA227
[Pubmed] | [DOI]
9 Topographic relationship between frequency-doubling technology threshold values : Acta Ophthalmologica 2011
Isabel Fuertes-Lazaro, Ana Sanchez-Cano, Antonio Ferreras, Jose M. Larrosa, Elena Garcia-Martin, Luis E. Pablo
Acta Ophthalmologica. 2011; : no
[VIEW] | [DOI]
10 SUN N8075, a novel radical scavenger, protects against retinal cell death in mice
Mai Akane, Masamitsu Shimazawa, Yuta Inokuchi, Kazuhiro Tsuruma, Hideaki Hara
Neuroscience Letters. 2011; 488(1): 87
[VIEW] | [DOI]
11 The role of melatonin in glaucoma: implications concerning pathophysiological relevance and therapeutic potential : Melatonin in glaucoma
Agorastos Agorastos, Christian G. Huber
Journal of Pineal Research. 2011; 50(1): 1
[VIEW] | [DOI]
12 Nanotechnology applications and approaches for neuroregeneration and drug delivery to the central nervous system : Nanotechnology approaches for CNS neuroregeneration
Gabriel A. Silva
Annals of the New York Academy of Sciences. 2010; 1199(1): 221
[VIEW] | [DOI]
13 Melatonin: a novel neuroprotectant for the treatment of glaucoma
Nicolás A. Belforte, María C. Moreno, Nuria de Zavalía, Pablo H. Sande, Mónica S. Chianelli, María I. Keller Sarmiento, Ruth E. Rosenstein
Journal of Pineal Research. 2010; 48(4): 353-364
[Pubmed] | [DOI]
14 Rapid and Noninvasive Imaging of Retinal Ganglion Cells in Live Mouse Models of Glaucoma
Joaquin Tosi, Nan-Kai Wang, Jin Zhao, Chai Lin Chou, J. Mie Kasanuki, Stephen H. Tsang, Takayuki Nagasaki
Molecular Imaging and Biology. 2010; 12(4): 386
[VIEW] | [DOI]
15 Agmatine protects cultured retinal ganglion cells from tumor necrosis factor-alpha-induced apoptosis
Samin Hong,Chan Yun Kim,Jong Eun Lee,Gong Je Seong
Life Sciences. 2009; 84(1-2): 28
[Pubmed] | [DOI]
16 A Na+/Ca2+ exchanger isoform, NCX1, is involved in retinal cell death after N-methyl-D-aspartate injection and ischemia-reperfusion
Y. Inokuchi, M. Shimazawa, Y. Nakajima, I. Komuro, T. Matsuda, A. Baba, M. Araie, S. Kita, T. Iwamoto, H. Hara
Journal of Neuroscience Research. 2009; 87(4): 906-917
[Pubmed] | [DOI]
17 Retinal cell apoptosis
Sarah Catherine Borrie, James Duggan, M Francesca Cordeiro
Expert Review of Ophthalmology. 2009; 4(1): 27
[VIEW] | [DOI]
18 Glaucoma alters the expression of NGF and NGF receptors in visual cortex and geniculate nucleus of rats: Effect of eye NGF application
Valentina Sposato,Vincenzo Parisi,Luigi Manni,Maria Teresa Antonucci,Veronica Di Fausto,Federica Sornelli,Luigi Aloe
Vision Research. 2009; 49(1): 54
[Pubmed] | [DOI]
19 Current concepts in the pathophysiology of glaucoma
Agarwal, R., Gupta, S.K., Agarwal, P., Saxena, R., Agrawal, S.
Indian Journal of Ophthalmology. 2009; 57(4): 257-266
[Pubmed]
20 Agmatine protects cultured retinal ganglion cells from tumor necrosis factor-alpha-induced apoptosis
Hong, S., Kim, C.Y., Lee, J.E., Seong, G.J.
Life Sciences. 2009; 84((1-2)): 28-32
[Pubmed]
21 Glaucoma alters the expression of NGF and NGF receptors in visual cortex and geniculate nucleus of rats: Effect of eye NGF application
Sposato, V., Parisi, V., Manni, L., Antonucci, M.T., Fausto, V.D., Sornelli, F., Aloe, L.
Vision Research. 2009; 49(1): 54-63
[Pubmed]
22 Progressive damage along the optic nerve following induction of crush injury or rodent anterior ischemic optic neuropathy in transgenic mice
Dratviman-Storobinsky, O., Hasanreisoglu, M., Offen, D., Barhum, Y., Weinberger, D., Goldenberg-Cohen, N.
Molecular Vision. 2008; 14: 2171-2179
[Pubmed]
23 Reduced NGF level and TrkA protein and TrkA gene expression in the optic nerve of rats with experimentally induced glaucoma
Sposato, V., Bucci, M.G., Coassin, M., Russo, M.A., Lambiase, A., Aloe, L.
Neuroscience Letters. 2008; 446(1): 20-24
[Pubmed]
24 Regulation of retinal morphology and posterior segment amino acids by 8-isoprostaglandin E2 in bovine eyes ex vivo
Zhao, M., Destache, C.J., Zhan, G., Liu, H., Zhang, Y., Govindarajan, V., Opere, C.A.
Methods and Findings in Experimental and Clinical Pharmacology. 2008; 30(8): 615-626
[Pubmed]
25 Oxidative stress in primary open-angle glaucoma
Zanon-Moreno, V., Marco-Ventura, P., Lleo-Perez, A., Pons-Vazquez, S., Garcia-Medina, J.J., Vinuesa-Silva, I., Moreno-Nadal, M.A., Pinazo-Duran, M.D.
Journal of Glaucoma. 2008; 17(4): 263-268
[Pubmed]
26 Assessment of neuroprotection in the retina with DARC
Guo, L., Cordeiro, M.F.
Progress in Brain Research. 2008; 173: 437-450
[Pubmed]
27 Agmatine inhibits hypoxia-induced TNF-α release from cultured retinal ganglion cells
Hong, S., Park, K., Kim, C.Y., Seong, G.J.
Biocell. 2008; 32(2): 201-205
[Pubmed]
28 Effect of crocus sativus on SOD and MDA alterations in the retina of rabbits with chronic ocular hypertension
Yang, X.-G., Sun, D.-J., Wang, Y.-W., Jin, W.-L., Wang, X.-J., Duan, X.-L.
International Journal of Ophthalmology. 2008; 8(1): 47-49
[Pubmed]
29 Effect of ocular hypertension on retinal GABAergic activity
Moreno MC, de Zavalia N, Sande P, et al.
NEUROCHEMISTRY INTERNATIONAL. 2008; 52(4-5): 675-682
[Pubmed]
30 Reduced NGF level and TrkA protein and TrkA gene expression in the optic nerve of rats with experimentally induced glaucoma
Valentina Sposato,Massimo Gilberto Bucci,Marco Coassin,Matteo Antonio Russo,Alessandro Lambiase,Luigi Aloe
Neuroscience Letters. 2008; 446(1): 20
[Pubmed] | [DOI]
31 Oxidative Stress in Primary Open-angle Glaucoma
Vicente Zanon-Moreno,Pilar Marco-Ventura,Antonio Lleo-Perez,Sheila Pons-Vazquez,Jose J. Garcia-Medina,Ignacio Vinuesa-Silva,Maria A. Moreno-Nadal,Maria Dolores Pinazo-Duran
Journal of Glaucoma. 2008; 17(4): 263
[Pubmed] | [DOI]
32 Effect of ocular hypertension on retinal GABAergic activity
María Cecilia Moreno,Nuria de Zavalía,Pablo Sande,Carolina O. Jaliffa,Diego C. Fernandez,María Inés Keller Sarmiento,Ruth E. Rosenstein
Neurochemistry International. 2008; 52(4-5): 675
[Pubmed] | [DOI]
33 Glaucoma is a neuronal disease
Caprioli J
EYE. 2007; 21((SUPPL 1)): S6-S10
[Pubmed]
34 Melatonin in the eye: Implications for glaucoma
Per O. Lundmark, S.R. Pandi-Perumal, V. Srinivasan, D.P. Cardinali, R.E. Rosenstein
Experimental Eye Research. 2007; 84(6): 1021
[VIEW] | [DOI]
35 Effect of 2-(6-cyano-1-hexyn-1-yl)adenosine on ocular blood flow in rabbits
Konno T, Uchibori T, Nagai A, et al.
LIFE SCIENCES. 2007; 80 (12): 1115-1122
[Pubmed]
36 Neuroprotective and Intraocular pressure-lowering effects of (-)Delta 9-tetrahydrocannabinol in a rat model of glaucoma
Crandall J, Matragoon S, Khalifa YM, et al.
OPHTHALMIC RESEARCH. 2007; 39 (2): 69-75
[Pubmed]
37 Chondroitin sulfate-derived disaccharide protects retinal cells from elevated intraocular pressure in aged and immunocompromised rats
Bakalash S, Rolls A, Lider O, et al.
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE. 2007; 48 (3): 1181-1190
[Pubmed]
38 Retinal ganglion cell protection by 17-beta-estradiol in a mouse model of inherited glaucoma
Zhou XH, Li F, Ge J, et al.
DEVELOPMENTAL NEUROBIOLOGY. 2007; 67 (5): 603-616
[Pubmed]
39 Effect of ocular hypertension on retinal nitridergic pathway activity
Belforte, N., Moreno, M.C., Cymeryng, C., Bordone, M., Keller Sarmiento, M.I., Rosenstein, R.E.
Investigative Ophthalmology and Visual Science. 2007; 48(5): 2127-2133
[Pubmed]
40 Immune factors and glaucoma
Ma, J.-Z., He, X.-G.
International Journal of Ophthalmology. 2007; 7(5): 1379-1383
[Pubmed]
41 Retinal ganglion cell protection by 17-ß-estradiol in a mouse model of inherited glaucoma
Xiaohong Zhou,Feng Li,Jian Ge,Steven R. Sarkisian,Hiroshi Tomita,Alexander Zaharia,James Chodosh,Wei Cao
Developmental Neurobiology. 2007; 67(5): 603
[Pubmed] | [DOI]
42 Glaucoma is a neuronal disease
J Caprioli
Eye. 2007; 21: S6
[Pubmed] | [DOI]
43 Effect of 2-(6-cyano-1-hexyn-1-yl)adenosine on ocular blood flow in rabbits
Takashi Konno,Takehiro Uchibori,Akihiko Nagai,Kentaro Kogi,Norimichi Nakahata
Life Sciences. 2007; 80(12): 1115
[Pubmed] | [DOI]
44 Morphological and functional changes in experimental ocular hypertension and role of neuroprotective drugs
Garcia-Campos J, Villena A, Diaz F, et al.
HISTOLOGY AND HISTOPATHOLOGY. 2007; 22 (10-12): 1399-1411
[Pubmed]
45 Effect of acathopanax senticosus on the level of glutamate and NO on the retina in high ocular pressure models
Gao, D.-W., Shao, L., Yang, Y.
International Journal of Ophthalmology. 2006; 6(6): 1294-1296
[Pubmed]
46 Estrogen has a neuroprotective effect on axotomized RGCs through ERK signal transduction pathway
Toru Nakazawa,Hidetoshi Takahashi,Masahiko Shimura
Brain Research. 2006; 1093(1): 141
[Pubmed] | [DOI]
47 Retinal growth hormone in perinatal and adult rats
Harvey S, Baudet ML, Sanders EJ
JOURNAL OF MOLECULAR NEUROSCIENCE. 2006; 28 (3): 257-264
[Pubmed]
48 Assessment of neuroprotective effects of glutamate modulation on glaucoma-related retinal ganglion cell apoptosis in vivo
Guo L, Salt TE, Maass A, Luong V, Moss SE, Fitzke FW, Cordeiro MF
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE. 2006; 47 (2): 626-633
[Pubmed]
49 Adenosine A2A receptor mediated protective effect of 2-(6cyano-1-hexyn-1-yl) adenosine on retinal ischaemia/reperfusion damage in rats
Konno T, Sato A, Uchibori T, et al.
BRITISH JOURNAL OF OPHTHALMOLOGY. 2006; 90 (7): 900-905
[Pubmed]
50 Estrogen has a neuroprotective effect on axotomized RGCs through ERK signal transduction pathway
Nakazawa T, Takahashi H, Shimura M
BRAIN RESEARCH. 2006; 1093(1): 141-149
[Pubmed]
51 Neuroprotective effect of latanoprost on rat retinal ganglion cells
Kudo H, Nakazawa T, Shimura M, Hidetoshi Takahashi, Nobuo Fuse, Kenji Kashiwagi, Makoto Tamai
GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY. 2006; 244 (8): 1003-1009
[Pubmed]
52 Inhibitive effect of genistein on interleukin-8 expression in cultured human retinal pigment epithelial cells
Li H, Pan JS, Wang B
METHODS AND FINDINGS IN EXPERIMENTAL AND CLINICAL PHARMACOLOGY. 2006; 28 (5): 295-299
[Pubmed]
53 Effect of glaucoma on the retinal glutamate/glutamine cycle activity
Moreno MC, Sande P, Marcos HA, de Zavalia N, Sarmiento MIK, Rosenstein RE
FASEB JOURNAL. 2005; 19 (7): MAY
[Pubmed]
54 Nanotechnology approaches for the regeneration and neuroprotection of the central nervous system
Gabriel A. Silva
Surgical Neurology. 2005; 63(4): 301
[Pubmed] | [DOI]
55 Pharmacological consequences of oxidative stress in ocular tissues
Sunny E. Ohia,Catherine A. Opere,Angela M. LeDay
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 2005; 579(1-2): 22
[Pubmed] | [DOI]
56 Small neuroscience: The nanostructure of the central nervous system and emerging nanotechnology applications
Silva GA
CURRENT NANOSCIENCE. 2005; 1 (3): 225-236
[Pubmed]
57 Accuracy assessment and implementation of an electromagnetically-tracked endoscopic orbital navigation system
Sztipanovits, D.R., Galloway, R., Mawn, L.A.
Progress in Biomedical Optics and Imaging - Proceedings of SPIE. 2005; 5744(II ): 648-660
[Pubmed]
58 Nanotechnology approaches for the regeneration and neuroprotection of the central nervous system
Silva GA
SURGICAL NEUROLOGY. 2005; 63 (4): 301-306
[Pubmed]
59 Pharmacological consequences of oxidative stress in ocular tissues
Ohia SE, Opere CA, LeDay AM
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS. 2005; 579 (1-2): 22-36
[Pubmed]
60 Pigment epithelium-derived factor is a substrate for matrix metalloproteinase type 2 and type 9: Implications for downregulation in hypoxia
Notari L, Miller A, Martinez A, Amaral J, Ju MH, Robinson G, Smith LEH, Becerra SP
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE. 2005; 46 (8): 2736-2747
[Pubmed]
61 New therapies for glaucoma: are they all up to the task?
Yorio T, Dibas A
EXPERT OPINION ON THERAPEUTIC PATENTS. 2004; 14 (12): 1743-1762
[Pubmed]
62 Change of retinal ganglion cells in the ocular hyertension model rat
Ito, T., Ohguro, H., Ohguro, I., Mamiya, K., Ishikawa, F., Metoki, T., Yamazaki, H., et al
Hirosaki Medical Journal. 2004; 56(1): 15-20
[Pubmed]
63 Retinal Oxidative Stress Induced by High Intraocular Pressure
María Cecilia Moreno,Julieta Campanelli,Pablo Sande,Daniel A. Sáenz,María Inés Keller Sarmiento,Ruth E. Rosenstein
Free Radical Biology and Medicine. 2004; 37(6): 803
[Pubmed] | [DOI]
64 New therapies for glaucoma: are they all up to the task?
Thomas Yorio,Adnan Dibas
Expert Opinion on Therapeutic Patents. 2004; 14(12): 1743
[Pubmed] | [DOI]
65 Retinal oxidative stress induced by high intraocular pressure
Moreno, M.C., Campanelli, J., Sande, P., Sáenz, D.A., Keller Sarmiento, M.I., Rosenstein, R.E.
FREE RADICAL BIOLOGY AND MEDICINE. 2004; 37 (6): 803-812
[Pubmed]
66 Perspective of neuroprotective treatment for glaucomatous optic neuropathy
Nakamura, M.
Japanese Journal of Clinical Ophthalmology. 2004; 58(6): 887-891
[Pubmed]



 

Top
Print this article  Email this article
Previous article Next article
Online since 12th February '04
© 2004 - Journal of Postgraduate Medicine
Official Publication of the Staff Society of the Seth GS Medical College and KEM Hospital, Mumbai, India
Published by Wolters Kluwer - Medknow