Topical and systemic administration of FDA-approved GLP-1R Agonists rescue retinal ganglion cells in hypertensive glaucoma

Abstract

Purpose : The centrally-acting GLP-1R agonist NLY01 reduces microglial/macrophage activation and rescues retinal ganglion cells (RGCs) in a mouse model of hypertensive glaucoma (PMID33147455). Clinically-available GLP-1R agonists are also associated with a reduced risk for glaucoma in diabetic patients (PMID34413054). In this study, we examined whether FDA-approved GLP1R agonists, administered either topically or systemically, prevent RGC loss and decrease neuroinflammation in an mouse model of hypertensive glaucoma.

Methods : Three-month old C57BL/6J mice were injected with either microbeads or BSS. IOP was measured weekly and remained elevated in bead-injected eyes for 7 weeks. GLP-1R agonists were initiated within 3 days of ocular injection and administered either twice daily topical (lixisenatide 20µg/kg/day or liragutide 400µg/kg/day) or twice weekly subcutaneous (liraglutide 400µg/kg/day or NLY01 5mg/kg/injection). At the end of 7 weeks, retina flatmounts were immunolabeled for RBPMS and Iba1 to quantify RGC and myeloid cell density, respectively. Quantitative PCR assessed pro-inflammatory cytokine expression in cellular populations enriched for either macrophage/microglia or astrocytes. Microelectrode array recording of dark and light-adapted retinas functioned to characterize RGC function. RGC axons were quantified using optic nerve cross sections.

Results : Compared to bead-injected eyes treated with topical liraglutide, RGC density was 24% lower in bead-injected untreated eyes (p=0.0048). Similarly, topical lixisenatide was associated with 29% RGC rescue following IOP elevation (p=0.0096). Subcutaneous liraglutide and NLY01 injections resulted in complete RGC rescue after IOP elevation. While myeloid cellular density trended up following microbead injections, differences were not significant and remained comparable before and after treatment with topical and systemic agents. Pro-inflammatory cytokine expression, RGC function, and axon quantifications are pending.

Conclusions : Topically and systemically administered GLP-1R agonists improved RGC survival following IOP elevation. The number of activated myeloid cells in the retina were not significantly affected by GLP-1R agonist treatment in this experiment.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.