Baicalin alleviates pathological changes in Alzheimer's disease comorbid with type 2 diabetes: Targeting metabolic dysregulation and neuroinflammation.

Derived from the plant Scutellaria baicalensis Georgi, baicalin is a naturally occurring flavonoid, has demonstrated anti-inflammatory, neuroprotective, hypoglycemic, and lipid-lowering properties. While its effects on Alzheimer's disease (AD) or type 2 diabetes mellitus (T2DM) have been studied individually, its therapeutic role in AD comorbid with T2DM remains unclear. This study aims to explore the potential therapeutic mechanisms associated with baicalin through a rat model featuring AD combined with T2DM. A dual-pathology rat model was developed using a streptozotocin (STZ) and a high-fat dietary regimen injections to induce T2DM, followed by intracerebroventricular STZ to induce AD pathology. Behavioral tests, biochemical assays, histological analyses, qPCR, and Western blotting were used to evaluate baicalin's effects. Untargeted metabolomics was applied to profile metabolic alterations, while network pharmacology and molecular docking were integrated to predict key targets and pathways. Finally, cellular thermal shift assay (CETSA) was conducted to validate the direct binding of baicalin to core proteins. Baicalin significantly improved cognitive performance, ameliorated glucose and lipid metabolism, and suppressed neuroinflammation in AD-T2DM rats. Metabolomics identified disruptions in energy metabolism, amino acid metabolism, and purine metabolism pathways. Network pharmacology analysis revealed ALDH2, NOS2, GOT1, GPT, and XDH as key targets associated with these metabolic disturbances. Molecular docking demonstrated strong binding affinities between baicalin and the identified targets. qPCR confirmed the regulation of ALDH2 and NOS2 gene expression by baicalin, and CETSA experiments further validated the thermal stabilization of these proteins, supporting direct interactions in vivo. Baicalin exerts therapeutic effects by targeting ALDH2 and NOS2 to modulate arginine and proline metabolism and regulate key metabolites such as GABA and L-arginine. This mechanism improves neuronal function and insulin sensitivity, highlighting baicalin as a promising multi-target treatment for AD with T2DM.