Semaglutide Protects Retinal Ganglion Cells Against Rotenone-Induced Degeneration via Improved Glucose Metabolism.

Purpose: Glaucoma is a multifactorial disease, where metabolic and mitochondrial dysfunction may play a major role in the progressive loss of retinal ganglion cells that characterize the disease. Currently, treatment strategies consist of IOP-lowering approaches with no available neuroprotective agent. In epidemiological studies and models of glaucoma, GLP-1 receptor agonists (GLP-1RAs) reduce the risk of glaucoma and provide protection against the loss of retinal ganglion cells. Methods: In this study, we explored the potential of semaglutide (SEM), a known GLP-1RA, to protect retinal ganglion cells from rotenone-induced metabolic dysfunction. We pretreated C57BL/6 mice subcutaneously with either SEM (5 mg/kg) or saline solution for one week. After one week, the mice received intravitreal injections of rotenone (10 mM) or dimethylsulfoxide (1%) and were euthanized 24 hours later. Results: We demonstrated that rotenone caused a significant loss of retinal ganglion cells, which was prevented by SEM pretreatment. Metabolic analyses revealed that SEM enhanced glucose metabolism, which suggested the enhancement of glucose homeostasis/alternative pathways possibly supporting metabolic flexibility of retinal ganglion cells. Conclusions: SEM may help preserve retinal ganglion cells under conditions of mitochondrial Complex I inhibition, suggesting a potential therapeutic role in glaucoma management; however, further studies are required to confirm metabolic changes observed in this study.