The GLP-1 receptor agonist Exendin-4 modulates hippocampal NMDA-receptor signalling in aged rats and improves cognitive impairment in diabetic elderly patients

Glucagon-like peptide-1 agonists (GLP-1A) are revolutionary drugs for the treatment of type 2 diabetes mellitus. Exendin-4 is an incretin agonist which shares 53% of GLP-1 amino-acid sequence and beyond its efficacy as antidiabetic, several studies demonstrated a neuroprotective effect in brain damage. NMDA receptor (NMDAR) is involved in memory formation processes and cognitive dysfunction. Herein, we wanted to explore whether Exendin-4 directly affected NMDA-R signal transduction pathway. We also evaluated clinical efficacy in ameliorating cognitive dysfunction. 18-months old Wistar rats were challenged for 30 days with intraperitoneal Exendin-4 or salt solution injection. Notably, in hippocampus Exendin-4 downregulated the gene expression of NMDA-R2A and 2B subunits, while significantly increased the NMDA-R2B phosphorylation. The clinical analysis of diabetic old patients revealed a significant improvement of cognitive dysfunction as demonstrated by the considerable increase in Mini Mental State Examination over time. Moreover, this improvement was not related to the glycaemic control. In conclusion, the GLP-1 agonist Exendin-4 ameliorated the cognitive performance of diabetic elderly patients and one suggested mechanism relies in the modulation of NDMAR-mediated glutamatergic signaling.