Neuroprotective effects of GLP‐1 receptor agonists and their potential in retinal diseases

Abstract

Aims/Purpose: Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone naturally released in response to a meal and therapeutically used in the treatment of diabetes. GLP‐1 receptor agonists, including semaglutide (SEM), have shown to promote neuronal survival in animal models of stroke, Alzheimer's and Parkinson's disease including retinal diseases such as age‐related macular degeneration (AMD), diabetic retinopathy, retinal ischemia, glaucoma and retinitis pigmentosa. The purpose of this study is to identify a neuroprotective effect of SEM.Methods: Retinal explants were treated with 50 nM SEM and incubated for 30 min, 4, 8 and 24 h. Tissue survival was measured through colorimetric lactate dehydrogenase (LDH) viability assays. Specific RGC survival was determined through immunohistochemical (IHC) staining. Energy metabolism was assessed through stable isotope labeling (13C) and gas chromatography–mass spectrometry (GC–MS). Mitochondrial function was assessed using Seahorse analysis.Results: Ex vivo treatment with 50 nM SEM increased retinal tissue survival by 55.9% compared to control. IHC and Seahorse analyses revealed no significant differences between control and treatment with SEM in retinal explants and wholemounts. Minor effects on glucose metabolism were observed, in general showing improved metabolism in retinal explants. Significantly increased 13C labeling was observed in the TCA cycle intermediates citrate and α‐Ketoglutarate (KG) after 30 min incubation with 50 nM SEM (Citrate; Control: 10.8% vs. SEM: 23.93% and α‐KG; Control: 9.45% vs. SEM: 19.25%, presented as molecular carbon labeling).Conclusions: The present study reveals that treatment with semaglutide has no toxic effect on retinal tissue and potentially has a neuroprotective effect. However, further studies are needed to fully understand the therapeutic potential of GLP‐1 receptor agonists in retinal diseases.