Unraveling the antidepressant mechanisms of JiaWeiSiNiSan: Insights from network pharmacology and experimental validation.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Depression is a prevalent mental health disorder with significant global impact. JiaWeiSiNiSan (JWSNS) has been employed for centuries in traditional Chinese medicine as a classical herbal formula for treating depression. However, the precise mechanisms underlying its therapeutic effects remain unclear. AIM OF THE STUDY: This study aims to elucidate the active components and molecular mechanisms of JWSNS as an antidepressant using network pharmacology and experimental validation both in vivo and in vitro. MATERIALS AND METHODS: Ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry was employed to analyze an aqueous extract, drug-containing serum, and cerebrospinal fluid (CSF) components of JWSNS. The investigation further examines the primary antidepressant components, prospective therapeutic targets, and potential pharmacological mechanisms of the brain-entering components of JWSNS through network pharmacology. This hypothesis was subsequently validated through experiments on chronic unpredictable mild stress (CUMS)mice and lipopolysaccharide-induced cellular assay. RESULTS: The analysis revealed 189 compounds in the aqueous extract of JWSNS, with 27 detected in serum and 23 in cerebrospinal fluid. The intersection analysis revealed 68 overlapped targets between JWSNS-containing CSF and depression, predominantly enriched in the serotonergic synapse, dopaminergic synapse, tyrosine metabolism, and tryptophan (Trp) metabolism signaling pathways. This study has demonstrated that the protein-protein interaction network of common targets includes key genes such as AKT1, TNF, MAOA, MAOB, and SLC6A4. JWSNS administration ameliorates depressive-like behaviors, disruptions in the IDO1-Try-Kyn pathway, elevated pro-inflammatory cytokines, neuronal loss, and microglial activation in the hippocampus and medial prefrontal cortex of CUMS mice. Furthermore, in vivo and in vitro studies have demonstrated that JWSNS results in an enhancement of CD200-CD200R and CX3CL1-CX3CR1 axes. CONCLUSIONS: This study demonstrated that JWSNS exhibits antidepressant-like effects in CUMS-exposed mice by ameliorating Trp metabolism disorders and reducing IDO1 activity, thereby modifying microglia-neuron communication and safeguarding hippocampal neurons.