The 5-HT1A receptor antagonist WAY-100635 maleate promotes retinal ganglion cell differentiation and protects the retino-visual circuits

BACKGROUND: Growing evidence implicates early metabolic dysfunctions in retinal ganglion cells (RGCs) as a contributor to both high- and normal-tension glaucoma, yet no approved therapy directly protects RGCs to preserve vision. We aimed at identifying a safe, druggable neuroprotective strategy that restores RGC metabolic homeostasis for glaucoma therapy. METHODS: Using a live-cell mitochondrial screen in human embryonic stem cell-derived retinal ganglion cells (H7; female donor), we identified the clinically tested 5-HT1A antagonist WAY-100635 (WAY) as a neuroprotective agent. Mechanisms are probed by pharmacologic competition with agonist 8-OH-DPAT, cAMP assays, and PGC-1α dependent mitochondrial-biogenesis tests. RGC metabolism and survival are assessed by Seahorse and apoptosis assays. In vivo efficacy is evaluated in acute optic-nerve crush (ONC) and microbead-induced ocular-hypertension glaucoma models using histology, brain MRI, visual-acuity, contrast sensitivity testing, and flash VEPs to quantify cortical responses in wild-type C57BL/6 J male mice. Statistics used two-tailed Student's t-tests or ANOVA, as appropriate. RESULTS: hRGCs, it restores mitochondrial fitness, attenuates excitotoxicity, and shifts metabolism toward aerobic glycolysis, while in progenitors, WAY enhances cristae maturation, oxidative phosphorylation, accelerating RGC specification. Systemic dosing in ONC mice preserves RGC somata, retinal function (PhNR), and optic-pathway integrity. WAY-treated glaucoma mice show preserved visual acuity and fVEP propagation to cortex, halting glaucoma progression. CONCLUSIONS: A clinically tested 5-HT1A antagonist WAY restores RGC metabolic homeostasis and preserves visual-pathway function across acute and chronic injury models, without detected systemic toxicity, supporting development of a neuroprotective candidate for glaucoma and potentially for other mitochondrial optic neuropathies.