Neuroprotective Agents in Glaucoma Therapy: Future Directions

Properties of Drugs Already used in Glaucoma

In experimental models, Brimonidine protects against many types of ocular injury, including ischemia, compression, and transient and chronic ocular hypertension. The exact mechanism(s) are not well defined,^[101] but include induction of FGF and BDNF synthesis,^[102,103] upregulation of antiapoptotic genes such as Bcl-2 and Bcl-XL,^[104] and inhibition of ischemia-induced glutamate release^[105] or perhaps NMDA receptor modulation.^[106] One recent episcleral vein-cauterized rat model of glaucoma found brimonidine reduced levels of glial fibrillary acidic protein and hence the level of reactive gliosis,^[107] while another found improved RGC survival at 12 weeks compared with controls.^[108]

Brimonidine has been studied specifically as a neuroprotectant in three small human clinical trials. Its use as prophylaxis in Leber hereditary optic neuropathy^[109] and rescue in anterior ischemic optic neuropathy^[110] failed to show any benefit. Results from the Low-Pressure Glaucoma Treatment Study (LoGTS),^[111] a multicenter double-masked randomized trial comparing long-term visual field stability in 160 patients with normal-tension glaucoma treated with brimonidine or timolol, are pending.

Betaxolol, a relatively selective β1-adrenergic antagonist, was neuroprotective in animal models – possibly by direct inhibition of voltage-gated calcium and sodium channels – preventing excitotoxic damage caused by glutamate-mediated currents.^[112,113] Betaxolol has also been attributed with upregulation of BDNF synthesis.^[114] Timolol, a nonselective β-adrenergic antagonist, was marginally neuroprotective from its ability to attenuate glutamate toxicity through binding voltage-gated sodium and calcium channels, but at a much lower affinity.^[113]

Dorzolamide, a topical carbonic anhydrase inhibitor, increases retinal artery flow velocities,^[115] reduces intracellular pH and prevents apoptosis.^[116] However, there are conflicting results, with no protection against animal models of inherited glaucoma and chronic ocular hypertension.^[117,118]

Efforts to identify a neuroprotective agent are ongoing globally. The task for researchers is to not only develop a neuroprotective compound with efficacy for human use, but also to determine new clinically measurable and validated end points to confirm compound efficacy. This requires collaboration between academia, industry and government agencies.

Cite this: Neuroprotective Agents in Glaucoma Therapy: Recent Developments and Future Directions - Medscape - Oct 01, 2010.

Table 1. Summary of causes of retinal ganglion cell injury and potential sites for neuroprotection.
Mechanism of RGC loss	Potential neuroprotective class	Examples
Neurotrophin deprivation	Exogenous neurotrophins Neurotrophin receptor agonists	BDNF, NGF TrkA receptor agonist, TrkB receptor agonist
Ischemia	Vasodilators Calcium-channel blockers	Ginkgo biloba, vitamin E Nifedipine, verapamil, diltiazem, nilvadipine
Mitochondrial dysfunction	Antioxidants Vasodilators	Coenzyme Q10, vitamin E, melatonin, ginkgo biloba
Excitotoxicity	NMDA antagonists Calcium-channel blockers	Memantine, riluzole, flupirtine, dextromethorphan Flunarizine, lomerizine
Oxidative stress	Antioxidants/free-radical scavengers Nitric oxide synthase inhibitors	Coenzyme Q10, vitamin E, melatonin, ginkgo biloba Aminoguanidine
Protein misfolding	Vaccines and other immune mediators Heat-shock proteins	Glatiramer acetate, amyloid β antibodies Geranylgeraylacterone
Glial cell modulation	Growth factors	TGF, CNTF
Apoptotic pathways	Caspase inhibitors Calpain inhibitors TNF-α inhibitors	GLC756

BDNF: Brain-derived neurotrophic factor; CNTF: Ciliary neurotrophic factor; NMDA: N-methyl-D-aspartate; RGC: Retinal ganglion cell.

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