Molecular and Cellular Mechanisms of Neuroprotection in Glaucoma Pathogenesis: From Experimental Models to Clinical Translation

Glaucoma is a progressive neurodegenerative disease characterized by the loss of retinal ganglion cells (RGCs) and optic nerve degeneration, ultimately leading to irreversible vision loss. While intraocular pressure (IOP) reduction remains the primary clinical strategy, accumulating evidence indicates that IOP-independent mechanisms significantly contribute to disease progression, highlighting the need for effective neuroprotective approaches. At the molecular level, oxidative stress, mitochondrial dysfunction, glutamate excitotoxicity, impaired axonal transport, and chronic neuroinflammation have been identified as key contributors to RGC apoptosis. Cellular stress pathways involving Bcl-2 family proteins, MAPK signaling, and activation of glial cells mediate these degenerative processes, while endogenous neurotrophic signaling, particularly via BDNF and CNTF, plays a critical role in RGC survival. Experimental models using optic nerve crush, induced ocular hypertension, and genetic mouse models have enabled in-depth characterization of these mechanisms and facilitated the evaluation of candidate neuroprotective agents. Promising interventions include small molecule antioxidants, mitochondrial stabilizers, NMDA receptor antagonists, and gene therapy approaches aimed at enhancing neurotrophic support or silencing apoptotic pathways. Clinical translation, however, faces several hurdles, including variability in disease phenotypes, limited biomarkers of early neurodegeneration, and challenges in delivering therapeutics to target retinal neurons. Novel imaging modalities and fluid biomarkers, such as neurofilament light chain and glial markers, are being explored to enable earlier detection and stratification of patients likely to benefit from neuroprotective treatment. The integration of molecular insights into personalized treatment paradigms may ultimately transform glaucoma management from pressure-centered to neuron-centered care, preserving vision through targeted protection of retinal neurons.