Semaglutide ameliorates diabetes-associated cognitive dysfunction in mouse model of type 2 diabetes

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with cognitive dysfunction, which significantly impacts the quality of life. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has shown potential neuroprotective effects. This study investigates the efficacy of semaglutide in ameliorating cognitive dysfunction in a mouse model of T2DM. METHODS: Male C57BL/6J mice were fed a high-fat diet for four weeks and received a single intraperitoneal injection of streptozotocin (150 mg/kg) to induce T2DM. All mice were divided into four groups: control, diabetes control (T2DM), semaglutide treatment (semaglutide, 0.1 mg/kg) and dapagliflozin treatment (dapagliflozin 1 mg/kg). Cognitive function was assessed using the Morris water maze (MWM) test. Histomorphological analysis of hippocampal tissues was performed using H&E and Nissl staining. Immunofluorescence was used to assess LRP1 expression and apoptosis. Biochemical analyses measured oxidative stress markers (SOD, MDA) and inflammatory cytokines (IL-1β, IL-6, TNF-α, CRP). RESULTS: Semaglutide treatment significantly reduced blood glucose levels in diabetic mice. In the MWM test, semaglutide-treated mice showed reduced escape latencies, indicating improved spatial learning and memory. Histomorphological analysis revealed preserved neuronal structure in the hippocampus with reduced neuronal damage and apoptosis in the semaglutide-treated group. Immunofluorescence showed increased LRP1 expression and decreased apoptosis. Biochemical analyses indicated that semaglutide reduced oxidative stress and inflammatory markers, further supporting its neuroprotective effects. CONCLUSIONS: Semaglutide effectively ameliorates cognitive dysfunction in T2DM mice, likely through mechanisms involving the reduction of oxidative stress, inflammation, and neuronal apoptosis. These findings suggest that semaglutide has potential as a therapeutic agent for managing diabetes-associated cognitive decline. Further research, including long-term studies and clinical trials, is necessary to validate these findings and explore the broader applicability of semaglutide in treating cognitive impairments in diabetic patients.