Neuroprotective effects of Ligusticum wallichii in vascular dementia via AKT activation, oxidative stress and the Bcl-2/Bax/caspase-3 axis

BACKGROUND: Vascular dementia (VD) is a major cause of cognitive decline associated with cerebrovascular dysfunction, and effective therapeutic strategies remain limited. Ligusticum wallichii is a traditional medicinal herb with neuroprotective activity. METHODS: This study investigated the protective effects of L. wallichii against VD by combining network pharmacology with experimental validation. Active constituents and putative targets of L. wallichii were identified using the TCMSP database and SwissTargetPrediction platform, whereas VD-related genes were collected from GeneCards, DisGeNET and OMIM. Protein-protein interaction analysis, Gene Ontology annotation, KEGG pathway enrichment and molecular docking were used to prioritize targets and pathways. The extract used for animal studies was profiled by HPLC. A rat model of VD induced by permanent bilateral common carotid artery occlusion was used for in vivo validation. RESULTS: Seven database-derived compounds and 450 putative targets were identified, of which 177 overlapped with VD-related genes. Network analysis highlighted AKT1, TNF, EGFR, BCL2 and CASP3 as hub targets associated with oxidative stress- and apoptosis-related signalling. HPLC detected ferulic acid, senkyunolide H, senkyunolide I, senkyunolide A and Z-ligustilide in the extract. In vivo, L. wallichii reduced neurological deficit scores, improved spatial learning and memory, alleviated hippocampal neuronal injury, restored cholinergic balance and increased antioxidant indices. Western blotting showed restoration of AKT phosphorylation, increased Bcl-2 expression, reduced Bax and Caspase-3 expression, and recovery of the Bcl-2/Bax ratio after treatment. CONCLUSIONS: These findings associate the neuroprotective effects of L. wallichii in VD with AKT activation, attenuation of oxidative stress and inhibition of Bcl-2/Bax/Caspase-3-related apoptosis.