Kai-Xin-San regulates synaptic plasticity through calcium signaling to alleviate symptoms of depression-like behavioral disorders in mice.

Background: Kai-Xin-San, a classical Chinese medicine prescription, has been widely applied in the clinical therapy for depression, but its pharmacological mechanism remains to be further explored. Based on network pharmacology, molecular docking and animal experiments, the research is performed to exploit pharmacological mechanism of Kai-Xin-San for treating depression. Methods: Obtain chemical components and potential targets of Kai-Xin-San through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, Encyclopedia of Traditional Chinese Medicine and Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine databases, and then screen the active ingredients of each herb in accordance with absorption, distribution, metabolism, and excretion. The GenCards, Online Mendelian Inheritance in Man, Therapeutic Target database and DrugBank databases were used to obtain the major targets of depression, and the STRING platform was used to construct the protein-protein interaction network and explore the potential protein functional modules in the network. The targets were subjected to Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis by STRING database and Metascape database. The interaction network of "Kai-Xin-San active components-depression-targetspathways" was constructed by Cytoscape, and molecular docking verification was performed by Auto Dock tools. Finally, animal experiments were carried out for further verification. The chronic restraint stress depression model was established and mice were randomly divided into 4 groups: control group, chronic restraint stress group, fluoxetine group and Kai-Xin-San group. Behavioral tests were used to evaluate the depressive phenotype of mice. The expression of CaMKII-, synaptophysin, poststroke depression-95, and CACNA1C were all detected using a western blot. Results: Network analysis shows that Kai-Xin-San may mainly regulate calcium signaling pathway to exert antidepressant effects. A majority of the targets and components have good binding activity, according to the molecular docking studies. In the current study, behavioral tests showed that Kai-Xin-San could effectively alleviate depression-like behaviors in mice compared with the chronic restraint stress group, which effect was comparable to fluoxetine. Meanwhile, compared with the chronic restraint stress group, protein levels of CACNA1C, CaMKII-a, synaptophysin and poststroke depression-95 were significantly increased (P < 0.05). Conclusion: The research initially identifies the multi-component, multi-target, and multi-path mechanism of Kai-Xin-San in the treatment of depression. Kai-Xin-San may improve synaptic plasticity through calcium signaling pathway to exert antidepressant effects. [ABSTRACT FROM AUTHOR]