Synergistic Effect of Hesperidin, Acarbose, and Exercise Combination on Neuroinflammation and Neurochemical Alterations in Diabetic Encephalopathy Rat Model

ABSTRACT Diabetes mellitus (DM) encephalopathy is a condition that affects the nervous system in diabetic patients. This study is designed to assess the regulatory effect of hesperidin (HSP, 25 mg/mL) with exercise (EX) on neurobehavioral, neurochemicals (acetylcholinesterase [AChE], butyrylcholinesterase [BChE], angiotensin‐I converting enzyme [ACE], Arginase, ATPase, 5‐nucleotidase, adenosine deaminase [ADA], lactate dehydrogenase [LDH] enzymes, antioxidants [SOD and GSH]) and oxidative stress (TBARS, ROS) and inflammatory (Tumor necrosis factor‐α [TNF‐α] and Interleukin‐10 [IL‐10]) makers in diabetic rats treated with acarbose (ACA, 25 mg/mL). Freshly prepared Streptozotocin (STZ) was administered to 64 rats, excluding the control rats via the intraperitoneal route to induce diabetes mellitus (DM). Concurrently, a confirmatory test was conducted using fasting blood glucose levels (FBGL). The results revealed a significant increase in percentage alteration (55%–90%) within the treatment group compared to the untreated group, which showed an alteration of > 40%. There was a reduction in TNF‐α, AChE, BChE, ACE, arginase, ATPase, 5′‐nucleotidase, ADA, and LDH activities, and TBARS and ROS levels relative to the control group. Meanwhile, an increase in IL‐10 and antioxidants (SOD and GSH) were recorded in the treated DM rats. Groups treated with HSP, ACA, and EX separately ameliorated cognitive indices and mitigated encephalopathy, coupled with inflammatory cytokines. However, the treatment with a combination of ACA + HSP + EX has the best improvement when linking DM to inflammation. The combined administration of acarbose, hesperidin, and exercise produced the most pronounced improvement in neuroinflammatory and biochemical parameters, supporting the potential of this tri‐modal approach as a therapeutic strategy for DM encephalopathy.