Explore the Mechanism of Xiaoyaosan for Treatment of Bipolar Disorder Based on Network Pharmacology, Experimental Validation and Molecular Docking.

AIM OF THE STUDY: Xiaoyaosan (XYS) has significant anti-inflammatory effects and is widely used for treating depression. However, the multitarget mechanism of XYS in the treatment of bipolar disorder (BD) remains unexplored. In this study, network pharmacology, molecular docking, and experimental validation were integrated to elucidate the mechanisms of XYS and its therapeutic efficacy in BD. METHODS: First, network pharmacology was employed to elucidate the anti-BD mechanism of XYS. Second, the therapeutic effects of XYS against BD were investigated in a BD mouse model induced by Ank3 gene knockdown combined with chronic social defeat stress (CSDS). Finally, the targets from these predictions were validated in a series of experiments and molecular docking. RESULTS: First, on the basis of network pharmacology, 120 predicted intersection targets between the targets of XYS and BD-related targets were identified. The key core targets of the anti-BD activity of XYS were STAT3, AKT1, IL-6, and MAPK3. Thus, inflammation pathways might play a critical role in the anti-BD effects of XYS. Second, XYS clearly inhibited BD activity, which was manifested by a significant alleviation of manic hyperactivity behavior and a significant improvement in depressive hyperactivity behavior in BD model mice. Additionally, the up-regulation of STAT3, AKT1, IL-6, and MAPK3 was improved by XYS intervention in a BD mouse model. Moreover, molecular docking results also revealed that XYS showed strong stable binding to key core targets from network pharmacological predictions. CONCLUSIONS: XYS can markedly improve BD through modulation of the expression of the key multitargets STAT3, AKT1, IL-6, and MAPK3 in inflammation pathways. These novel findings elucidate the anti-BD mechanism of XYS from the perspective of multiple targets and pathways.