The effects and mechanisms of Chai Shao Jie Yu Granules on chronic unpredictable mild stress (CUMS)-induced depressive rats based on network pharmacology

Ethnopharmacological relevance: Chai Shao Jie Yu Granules (CSJY) is a renowned and time-honored formula employed in clinical practice for the management of various conditions, notably depression. Depression, a prevalent psychiatric disorder, poses challenges with limited effective treatment options. Traditional herbal medicines have garnered increasing attention in the realm of combating depression, being perceived as safer alternatives to pharmacotherapy.

Aim of the study: To explore the effects and mechanisms of CSJY in chronic unpredictable mild stress (CUMS)-induced depression.

Materials and methods: Rat models of CUMS-induced depression were established, and the rats were randomly allocated into six groups: Control, CUMS, CUMS + Paroxetine (PX), CUMS + CSJY-L, CUMS + CSJY-M, and CUMS + CSJY-H. Throughout the study, the rats' body weight was monitored. Depression-related behaviors were assessed using the sucrose preference test (SPT) and open field test (OFT). High-performance liquid chromatography-mass spectrometry (HPLC-MS) measured monoamine neurotransmitters in the rat cortex and hippocampus. We measured adrenocorticotropic hormone (ACTH), corticosterone (CORT), and corticotropin-release hormone (CRH) levels in rat serum. Additionally, network pharmacology was employed to predict relevant molecular targets and potential mechanisms, followed by in vivo validation. Western blot analysis was conducted to evaluate the protein levels of 5-hydroxytryptamine/serotonin receptor 1A (5-HT1A) and Glutamate (Glu)-related proteins, such as p-GluA1, GluA1, p-GluN1, GluN1, p-GluN2A and GluN2A in the hippocampus.

Results: In behavioral assessments, CUMS rats exhibited depressive behaviors, which were ameliorated by CSJY or PX treatment. Moreover, CSJY or PX treatment increased serotonin (5-HT) levels. It reduced the kynurenine/tryptophan (KYN/TRP) and gamma-aminobutyric acid/glutamate (GABA/Glu) in the hippocampus and cortex, as well as reduced serum levels of ACTH, CORT and CRH. Furthermore, CSJY or PX administration enhanced the decreased expression of p-GluN1/GluN1 while upregulating 5-HT1A and p-GluA1/GluA1 levels in the CUMS group.

Conclusion: CSJY demonstrated the ability to alleviate depressive behaviors in CUMS-induced depression rats, potentially through the inhibition of the hypothalamic-pituitary-adrenal (HPA) axis, modulation of monoamine neurotransmitters, and glutamatergic neurons. These findings suggest that CSJY could serve as a promising treatment option for depression.