Type 2 diabetes mellitus (T2DM) is a widely distributed dysmetabolic condition increasingly linked to neurocognitive decline, neuroinflammation, oxidative stress, and neuronal apoptosis. Chronic hyperglycemia and insulin resistance disrupt homeostasis in the central nervous system, contributing to neurodegenerative processes. This study evaluated the effects of semaglutide (SMG), a glucagon-like peptide-1 receptor agonist, on T2DM-associated neurobehavioral and biochemical alterations using a rat model. T2DM was induced by nicotinamide-streptozotocin, followed by oral administration of SMG at a dose of 1.44 mg/kg for one month. Cognitive function was evaluated using the elevated plus maze (EPM) and novel object recognition (NOR) paradigms. Fasting blood glucose and body weight were monitored throughout the experiment. Neuroinflammatory markers (COX-2, TNF-α, and IL-6), oxidative stress biomarkers (MDA, GSH, and catalase), and apoptosis-associated proteins (Caspase-3, Bax, and Bcl-2) were measured in brain tissue homogenates using ELISA. Diabetic rats exhibited marked cognitive deficits, hyperglycemia, increased neuroinflammatory markers, and altered apoptosis-related biomarkers, with reduced Bcl-2 expression. Treatment with SMG significantly improved learning and memory performance, fasting blood glucose, and body weight. At the molecular level, SMG treatment was associated with lower levels of MDA, TNF-α, Bax, IL-6, COX-2, and Caspase-3, together with higher levels of Bcl-2, catalase, and GSH compared with untreated diabetic rats. Overall, oral SMG treatment was associated with improved cognitive performance and metabolic control, accompanied by attenuation of diabetes-associated neuroinflammatory, oxidative stress, and apoptosis-related alterations in brain tissue. However, the present study was not designed to distinguish direct neuroprotective effects from changes secondary to improved metabolic control. Further studies are required to clarify the underlying mechanisms and determine the translational relevance of these findings.
