Neuroprotective Agents in Glaucoma

Abstract

Glaucoma is the leading cause of irreversible blindness worldwide. The disease is driven not only by elevated intraocular pressure but also by a set of IOP-independent mechanisms that include glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, neurotrophic deprivation, vascular dysregulation, and neuroinflammation, each of which independently destroys retinal ganglion cells. Neuroprotective strategies targeting each of these pathways are discussed in the thesis, including NMDA receptor antagonists, antioxidants, neurotrophic factor gene therapy, and stem cell transplantation. The most instructive case study is memantine, which showed compelling results in primate models but failed two large phase III trials, suggesting that single-target approaches are not enough against a multifactorial disease and preclinical success does not guarantee clinical translation. Nicotinamide is the most promising near-term agent, with a landmark Science paper showing it dramatically reduced glaucomatous damage in aged mice and Phase II trials now underway. Calcium channel blockers also showed meaningful visual field preservation in a 3-year RCT in normal-tension glaucoma. Insensitivity of visual field endpoints, lack of validated early biomarkers of RGC damage, and poor translatability of animal models are major barriers to clinical progress. The thesis concludes that meaningful clinical neuroprotection will likely require combination strategies that simultaneously target multiple pathological mechanisms in conjunction with more sensitive structural endpoints such as OCT-based RNFL measurements and new biomarkers such as serum BDNF and plasma neurofilament light chain.