Mechanism of Jiawei Xionggui decoction in improving hypercholesterolemia-related cognitive impairment based on bioinformatics and experimental validation

AimTo investigate the therapeutic effects of Jiawei Xionggui decoction (JWXG) on hypercholesterolemia-related cognitive impairment (HRCI)using an integrated approach combining bioinformatics and animal experiments and the underlying mechanisms.MethodsThe blood-absorbed components of JWXG were identified by high-resolution mass spectrometry. Network pharmacology, molecular docking, and molecular dynamics simulations were employed to predict core targets of these components against HRCI. Transcriptomic data from brain tissues of high-cholesterol diet(HCD)model mice in public databases were analyzed to identify differentially expressed genes. An HRCI mouse model was established using a high-cholesterol diet and treated with JWXG aqueous extract via gavage. Serum cholesterol levels were measured using assay kits, cognitive function was assessed with the Morris water maze, neural pathological damage was evaluated by HE staining, key protein expression was detected via Western blot, and neuronal apoptosis was examined by TUNEL staining.ResultsThe main blood-absorbed components of JWXG included baicalein, baicalin, catalpol, chrysin, wogonin, and ferulic acid. KEGG and GO enrichment analyses of core targets revealed a focus on the apoptosis pathway. Molecular docking and dynamics simulations demonstrated strong binding affinities of baicalin and catalpol to Bax and Bcl-2. Transcriptomic data indicated high expression of the Bax gene in the brain tissues of HCD mice. Animal experiments showed that JWXG significantly reduced serum cholesterol levels, improved learning and memory abilities, and alleviated hippocampal neuropathological damage in HRCI mice. JWXG also markedly increased the Bcl-2/Bax protein ratio and decreased the number of TUNELpositive cells in the cortex of HRCI mice.ConclusionJWXG exerts neuroprotective effects and ameliorates HRCI by antagonizing neuronal apoptosis.