Mechanistic study on Kai Xin San's regulation of DARPP-32 phosphorylation in anti-depressant effects based on multi-omics.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: The classical prescription Kai Xin San (KXS) has a long history of clinical use and proven efficacy in treating depression. However, its active components and mechanisms of action require further elucidation. AIM OF THE STUDY: In this study, the pharmacological substance and mechanism of action of the anti-depressant effect of KXS will be investigated. MATERIALS AND METHODS: Wistar-Kyoto (WKY) rat served as a disease model. In this study, the depression-like degree was assessed by behavioral testing, and the efficacy of KXS in reducing disease was assessed using pathological staining, ELISA. Furthermore, UPLC-Q-TOF-MS, network pharmacology and proteomics were used to predict the pharmacological substance and potential targets of KXS in the treatment of depression. Subsequently, methods such as western blotting and immunohistochemistry were used for verification. RESULTS: KXS is effective in the treatment of depression, which is associated with chemical constituents such as polyporenic acid C, tumulosic acid, oleanolic acid, etc. Moreover, DARPP-32 is a potential key target. KXS regulates DARPP-32 expression and phosphorylation of Thr34 and Thr75 sites, thereby enhancing the downstream effect of AC/cAMP/PKA signalling and promoting BDNF expression through the DARPP-32/PP1/CREB axis. CONCLUSION: KXS has multi-component characteristics in the treatment of depression. KXS improves the level of BDNF and other factors related to treatment of depression by regulating the expression of DARPP-32 and phosphorylation of its site, then feeding back to cAMP signalling pathway, thereby improving depression-like behavior and preventing the progression of depression.