OBJECTIVE To investigate the mechanism of action of Chaihu Shugan San (CSS) and its absorbed components, Meranzin hydrate (MH) and ferulic acid (FA), on atherosclerosis (AS) and depression.

METHODS An AS combined with depression model was established in ApoE^-/- mice, which were randomly divided into the blank group, model group, CSS group, MH group, and FA group. AS progression was evaluated through lipid profile analysis (TC, TG, LDL-C, HDL-C), aortic plaque analysis (Oil Red O staining), and cardiac function assessment. Behavioral tests, including the open field test, light/dark box test, tail suspension test, and forced swim test, were conducted to evaluate depressive-like behaviors. Hippocampal neuronal morphology changes were observed through Golgi staining. Serum inflammatory cytokines (TNF-α, IL-1β, IL-6), neurotransmitters (5-HT, BDNF), and vascular adhesion molecules (VCAM-1) were measured. 16S rRNA sequencing was used to analyze the gut microbiome composition.

RESULTS Compared to the model group, the CSS, MH, and FA treatment groups showed improvements in several areas. First, significant reduction in AS lesions, lower blood lipid levels, and enhanced cardiovascular function were observed (P < 0.01, P < 0.001). Second, depressive-like behaviors were improved, with stronger activity and less immobility time. Damage to neuronal dendritic spines was also repaired (P < 0.05, P < 0.01, P < 0.001). Additionally, serum levels of inflammatory cytokines, neurotransmitters, and vascular adhesion molecules were reversed (P < 0.05, P < 0.01, P < 0.001). Finally, gut microbiome α and β diversity were regulated, and beneficial bacteria abundance was increased.

CONCLUSION CSS exhibits the best effects in treating both AS and depression. The two absorption components, MH and FA, together contribute to the anti-AS and anti-depression effects. At the same concentration, MH shows better anti-AS and anti-depression effects than FA.