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

## TL;DR

Semaglutide protects retinal ganglion cells from degeneration caused by rotenone by improving glucose metabolism, suggesting a potential treatment for glaucoma.

## Contribution

This study demonstrates that semaglutide, a GLP-1RA, protects retinal ganglion cells from rotenone-induced damage through enhanced glucose metabolism.

## Key findings

- SEM pretreatment prevented rotenone-induced retinal ganglion cell loss in mice.
- SEM enhanced glucose metabolism in retinal ganglion cells, suggesting improved metabolic flexibility.
- SEM may offer neuroprotection in glaucoma by counteracting mitochondrial dysfunction.

## Abstract

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.

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.

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.

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.