Glaucoma: role of neuroprotective agents

Achyut N. Pandey, Parul Singh, Ameeta Kaul, P. D. Sharma


Glaucoma is an optic neuropathy, considered as the second leading cause of blindness worldwide. Glaucoma is characterized by selective death of retinal ganglion cells (RGC) and a progressive loss of vision. Elevated intraocular pressure (IOP) is one of the most important risk factors for developing glaucoma and hence we mainly focus on lowering IOP to arrest the progression of glaucoma. However, many patients continue to demonstrate a clinically downhill course despite the control of initially raised IOP. In fact, some patients develop what is called normal tension glaucoma, not associated to an increased IOP. This emphasizes that several pressure-independent mechanisms are responsible for the development and progression of glaucomatous neuropathy and that high IOP and vascular insufficiency in the optic nerve head are only risk factors for the development of glaucoma, and are not the only target for the treatment of glaucoma. The reason is that the process of RGC death is thought to be biphasic, and the primary injury is followed by a slower secondary degeneration related to a noxious environment surrounding the apoptotic cells. This environment is characterized by changes in the extra-cellular ionic concentrations, increased amounts of free radicals, neurotrophins (NT) depletion and increased glutamate-induced excitotoxicity due to high extra-cellular glutamate levels, which binds to N-methyl-D-aspartate (NMDA) receptors leading to an abnormally high intracellular Ca2+ concentration. Neuroprotection is a process that attempts to preserve the remaining cells that are still vulnerable to damage, and the main aim of neuroprotective therapy is to employ pharmacologic or other means to attenuate the hostility of the environment surrounding the degenerating cells, or to supply the cells with the tools to deal with this aggression, providing resilience to the insult. Several agents have been reported neuroprotective in glaucoma, both in clinical assays, such as Ca2+ channel blockers, and in experimental studies, such as betaxolol, brimonidine, NMDA antagonists, nitric oxide synthase inhibitors, NT and Ginkgo biloba extract. Most neuroprotective agents for glaucoma have proved beneficial effects over RGC, not showing effects over IOP. However, when analyzing classically used medications for glaucoma, it becomes difficult to understand if its effect over the progression of glaucoma is due to neuroprotective pathways or by means of lowering IOP. The ideal anti-glaucoma drug would be one that when applied topically, reduces IOP, but also probes to reach the retina in appropriate amounts, and activates specific receptors in the retina to attenuate RGC death. In this review, we will examine currently advocated neuroprotective drug-based strategies in the potential management of glaucoma.


Apoptosis, Cytoprotection, Gene therapy, Neuroprotective agents, Therapeutic use, Retinal ganglion cells

Full Text:



Ederer F, Gaasterland DE, Sullivan EK, AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 1. Study design and methods and baseline characteristics of study patients. Control Clin Trials. 1994;15(4):299-325.

The advanced glaucoma intervention study, 6: Effect of cataract on visual field and visual acuity. The AGIS Investigators. Arch Ophthalmol. 2000;118(12):1639-52.

Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol. 1998;126(4):487-97.

Sommer A. Collaborative normal-tension glaucoma study. Am J Ophthalmol. 1999;128(6):776-7.

Lichter PR, Musch DC, Gillespie BW, Guire KE, Janz NK, Wren PA, et al. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology. 2001;108(11):1943-53.

Heijl A, Leske MC, Bengtsson B, Hyman L, Hussein M. Reduction of intraocular pressure and glaucoma progression: Results from the early manifest glaucoma trial. Arch Ophthalmol. 2002;120:1268-79.

McKinnon SJ. Glaucoma, apoptosis, and neuroprotection. Curr Opin Ophthalmol. 1997;8(2):28-37.

Quigley HA, McKinnon SJ, Zack DJ, Pease ME, Kerrigan-Baumrind LA, Kerrigan DF, et al. Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats. Invest Ophthalmol Vis Sci. 2000;41(11):3460-6.

Pease ME, McKinnon SJ, Quigley HA, Kerrigan-Baumrind LA, Zack DJ. Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma. Invest Ophthalmol Vis Sci. 2000;41(3):764-74.

Pearson HE, Thompson TP. Atrophy and degeneration of ganglion cells in central retina following loss of postsynaptic target neurons in the dorsal lateral geniculate nucleus of the adult cat. Exp Neurol. 1993;119(1):113-9.

Lipton SA, Nicotera P. Calcium, free radicals and excitotoxins in neuronal apoptosis. Cell Calcium. 1998;23(2-3):165-71.

Leung CK, Lindsey JD, Crowston JG, Lijia C, Chiang S, Weinreb RN. Longitudinal profile of retinal ganglion cell damage after optic nerve crush with blue-light confocal scanning laser ophthalmoscopy. Invest Ophthalmol Vis Sci. 2008;49(11):4898-902.

Adams JM, Cory S. The Bcl-2 protein family: Arbiters of cell survival. Science. 1998;281(5381):1322-6.

Levin LA, Weinreb RN, Di Polo A. A Pocket Guide of Neuroprotection in Glaucoma. New York: Ethis Communications; 2007.

Das A, Garner DP, Del Re AM, Woodward JJ, Kumar DM, Agarwal N, et al. Calpeptin provides functional neuroprotection to rat retinal ganglion cells following Ca2+ influx. Brain Res. 2006;1084(1):146-57.

Naskar R, Dreyer EB. New horizons in neuroprotection. Surv Ophthlamol. 2001;45 Suppl 3:S250-6.

Boveris A, Chance B. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J. 1973;134(3):707-16.

Yildirim O, Ates NA, Ercan B, Muslu N, Unlü A, Tamer L, et al. Role of oxidative stress enzymes in open-angle glaucoma. Eye (Lond). 2005;19(5):580-3.

Nurcombe V, Bennett MR. Embryonic chick retinal ganglion cells identified “in vitro”. Their survival is dependent on a factor from the optic tectum. Exp Brain Res. 1981;44(3):249-58.

Barkana Y, Belkin M. Neuroprotection in ophthalmology: A review. Brain Res Bull. 2004;62(6):447-53.

Nouri-Mahdavi K, Hoffman D, Coleman AL, Liu G, Li G, Gaasterland D, et al. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology. 2004;111(9):1627-35.

Asrani S, Zeimer R, Wilensky J, Gieser D, Vitale S, Lindenmuth K. Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J Glaucoma. 2000;9(2):134-42.

Vorwerk CK, Lipton SA, Zurakowski D, Hyman BT, Sabel BA, Dreyer EB. Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine. Invest Ophthalmol Vis Sci. 1996;37(8):1618-24.

Chaudhary P, Ahmed F, Sharma SC. MK801-a neuroprotectant in rat hypertensive eyes. Brain Res. 1998;792(1):154-8.

Russo R, Cavaliere F, Berliocchi L, Nucci C, Gliozzi M, Mazzei C, et al. Modulation of pro-survival and death-associated pathways under retinal ischemia/reperfusion: Effects of NMDA receptor blockade. J Neurochem. 2008;107(5):1347-57.

Seif el Nasr M, Peruche B, Rossberg C, Mennel HD, Krieglstein J. Neuroprotective effect of memantine demonstrated in vivo and in vitro. Eur J Pharmacol. 1990;185(1):19-24.

Ritch R. Natural compounds: Evidence for a protective role in eye disease. Can J Ophthalmol. 2007;42(3):425-38.

Lam TT, Fu J, Hrynewycz M, Tso MO. The effect of aurintricarboxylic acid, an endonuclease inhibitor, on ischemia/reperfusion damage in rat retina. J Ocul Pharmacol Ther. 1995;11(3):253-9.

Tsai DC, Hsu WM, Chou CK, Chen SJ, Peng CH, Chi CW, et al. Significant variation of the elevated nitric oxide levels in aqueous humor from patients with different types of glaucoma. Ophthalmologica. 2002;216(5):346-50.

Neufeld AH, Hernandez MR, Gonzalez M. Nitric oxide synthase in the human glaucomatous optic nerve head. Arch Ophthalmol. 1997;115(4):497-503.