Alogliptin attenuates diabetes-associated cognitive impairment in rats via HMGB1/RAGE/TLR4-NFκB pathway modulation

Abstract

Chronic hyperglycemia associated with diabetes mellitus (DM) induces systemic metabolic disturbances that progressively promote microvascular and macrovascular complications including the impairment of neuronal integrity and cognitive function. Accumulating evidence has supported that cognitive impairment and Type 2 Diabetes Mellitus (T2DM) share common pathological mechanisms. The current investigation explored potential benefits of alogliptin, a dipeptidyl peptidase IV (DPP-4) inhibitor, on diabetes induced cognitive impairment by revealing its role in attenuating neuroinflammatory pathways. T2DM was induced with a high-fat diet (HFD) for 8 weeks followed by a single low dose of streptozotocin (STZ, 30 mg/kg I.P). Rats of the treatment groups received alogliptin at different doses (20 mg/kg/day or 40 mg/kg/day) for 28 days. Memory function was assessed using the Morris Water Maze (MWM) and Y-maze tests. Blood samples were withdrawn at the end of the experiment, and brain tissue was dissected for biochemical, immunohistochemical, and histopathological examination. Alogliptin reduced diabetes-induced cognitive impairment evident in memory tasks, alleviated histological changes in the brain and attenuated oxidative stress by increasing SOD, CAT and GSH levels while reducing MDA levels. Alogliptin also decreased neuroinflammatory signaling via reducing HMGB1, RAGE, TLR4/ NF-κB which in turn decreased inflammatory cytokines TNF-α and IL-1β. Alogliptin also refined mTOR signaling pathway and improved neuronal health. According to these findings, alogliptin reduces neuroinflammation and alters mTOR action leading to the improvement of neurodegeneration and memory function.