Chaihu Shugan San Exerts Antidepressant Effects by Regulating Glucocorticoid Metabolism in CUMS Rats and Network Pharmacology Provides Complementary Mechanistic Insights

Traditional Chinese medicine Chaihu Shugan San (CSGS)
is a classic
Chinese herb prescription for improving depression, but its specific
molecular mechanism has not been fully clarified. This study integrates
network pharmacology and experimental validation to investigate CSGS’s
antidepressant effects, focusing on its impact on GC metabolism and
related pathways. In this research, the antidepressant mechanism of
CSGS in relation to the depression model induced by chronic unpredictable
mild stress will be discussed. High-performance liquid tandem mass
spectrometry was applied for the verification of the grown metabolites’
economic vitality in rat plasma and the prefrontal cortex. The revelation
of behavioral test results showed that the administration of CSGS
improved depression symptoms significantly at the end of the administration
period, which was 8 weeks. Network pharmacology was used to assist
in verifying and improving the mechanism by which the active ingredients
of CSGS affect the glucocorticoid metabolic pathway to exert antidepressant
effects. CSGS significantly improved glucocorticoid (GC) metabolism
by reducing corticosterone (CORT) levels and increasing dehydrocorticosterone
(11-DHCORT) and the 11-DHCORT/CORT ratio in plasma and PFC. It regulated
GC metabolism in the liver and PFC by downregulating GC synthase (11β-HSD1)
and upregulating GC metabolic enzymes (11β-HSD2). Additionally,
CSGS restored GC signaling by upregulating GR and HSP-90α, downregulating
FKBP51 and HSP-70, and alleviating inflammation by inhibiting NF-κB
P65 and HAT expression. These effects, particularly in the liver and
PFC, were stronger than those with fluoxetine. Network pharmacology
revealed that CSGS targets multiple pathways including PI3K-Akt, FoxO,
HIF-1, and mTOR. These results indicate that CSGS can improve the
depressive state of rats by regulating glucocorticoid metabolism and
other related pathways as well as downstream signaling proteins.