Glaucoma Neuroprotection Review Highlights Nicotinamide, GLP-1RAs, and Advanced Translational Strategies

Glaucoma remains a leading cause of irreversible blindness, characterized by progressive retinal ganglion cell (RGC) loss. Current standard-of-care primarily focuses on reducing intraocular pressure (IOP), which, while effective, often fails to halt disease progression in many patients, indicating a critical need for IOP-independent neuroprotective strategies. Previous attempts, such as with memantine, faced challenges in trial design and endpoint sensitivity, underscoring a significant translational gap in bringing neuroprotective therapies from preclinical promise to clinical reality. This review addresses this gap by surveying emerging targets and strategies.

This comprehensive review synthesized findings from preclinical research and emerging clinical efforts to identify promising drug targets and therapeutic candidates for glaucoma neuroprotection. The authors critically analyzed strategies beyond intraocular pressure reduction, focusing on mechanisms like glutamate excitotoxicity, neurotrophic factor deprivation, and mitochondrial dysfunction. They also evaluated novel approaches to bridge the translational gap, including the integration of new, more sensitive endpoints, AI-guided endpoint selection, novel biomarkers, and precision medicine frameworks, to accelerate the development of clinically validated treatments.

Preclinical research has identified several promising neuroprotective targets for glaucoma, including mechanisms related to glutamate excitotoxicity, neurotrophic factor deprivation, and mitochondrial dysfunction. Nicotinamide has emerged as a leading candidate, demonstrating robust RGC protection by supporting NAD levels and bioenergetics. Current clinical efforts are expanding into metabolic repurposing, with agents like metformin and semaglutide showing promise. Sustained-delivery systems for neurotrophic factors, such as ciliary neurotrophic factor implants, and functional enhancers like citicoline, are also under investigation. > To bridge the translational gap, the field is integrating new, higher-sensitivity endpoints, including advanced assessment of photopic negative response, alongside AI-guided endpoint selection using graph attention neural networks. Novel biomarkers, such as the detection of apoptotic retinal cells and neurofilament light chain in aqueous humor, are being explored. Furthermore, precision medicine frameworks, incorporating polygenic risk scores and multi-omics analysis, are being developed to tailor future treatments.