Investigating the potential neuroprotective effect of semaglutide in the mouse retina

AbstractPurpose: To investigate the potential locally mediated neuroprotective effect of the glucagon‐like peptide 1 receptor agonist, semaglutide, in the mouse retina, including an assessment of the underlying mechanisms of action.Methods: The study was conducted using surgically isolated retinas from female C57BL/6jRj mice as ex vivo model system. Retinas were exposed to different concentrations (10–100 nM) of semaglutide for different exposure durations (2–48 h). Retinal explant viability was assessed employing the lactate dehydrogenase release assay. The number of retinal ganglion cells (RGCs) was quantified employing immunohistochemistry. The acute and intermediate effect of semaglutide on the ex vivo retinal glucose metabolism under euglycemic conditions was assessed through metabolic mapping employing [U‐13C]glucose, followed by relative analyte quantification employing gas chromatography–mass spectrometry. The influence of semaglutide on the retinal mitochondrial function was assessed by employing the Seahorse assay on isolated retinal mitochondria.Results: Semaglutide exerted no effect on the retinal explant or RGC viability. Semaglutide may acutely potentiate the retinal ex vivo glucose metabolism/mitochondrial function indicated by statistically significant glucose hypermetabolism (increased 13C‐enrichment) of certain tricarboxylic acid intermediates (citrate and α‐ketoglutarate) relative to the control. Results on the effect of semaglutide on the mitochondrial function/oxygen consumption rate are not yet available.Conclusions: Under the experimental conditions, semaglutide did not influence the retinal explant or RGC‐specific viability. Semaglutide may acutely potentiate the retinal ex vivo glucose metabolism by enhancing the mitochondrial function. Additional studies are needed for clarification.