Baihe Zhimu Decoction ameliorates anxious depression via PI3K/AKT/mTOR pathway‐mediated neuroprotection and inhibition of hippocampal neuronal apoptosis

Abstract

Abstract Background Anxious depression involves severe emotional dysregulation with a high risk of relapse and suicide. Although the classical Traditional Chinese Medicine formula Baihe Zhimu Decoction (BZD) is widely used for affective disorders, its underlying mechanisms remain poorly understood. Methods In this study, the chemical constituents of BZD were first identified using UPLC‐Q‐TOF‐MS/MS, followed by a maximum‐dose safety evaluation. The therapeutic effects of BZD were then investigated in an anxious‐depression mouse model induced by chronic restraint stress (CRS) combined with corticosterone (CORT) administration. Behavioral assessments, including the open field test (OFT), elevated plus maze (EPM), sucrose preference test (SPT), and forced swim test (FST), were performed, together with histopathological examination of hippocampal tissues. Network pharmacology was employed to analyze the relationships between active compounds and potential targets and to predict related signaling pathways. Subsequently, western blot analysis, immunofluorescence staining, Hoechst staining, and flow cytometry, combined with pathway‐specific inhibitors, were used to examine the involvement of the signaling pathway in hippocampal tissues and primary hippocampal neurons. Results Forty‐one constituents were identified in BZD. In vivo results showed that BZD significantly alleviated hippocampal pathological injury and improved anxiety‐ and depression‐like behaviors in stressed mice. Network pharmacology analysis identified 19 active compounds and 622 potential targets, highlighting the PI3K/AKT/mTOR signaling pathway. Mechanistically, BZD activated this pathway and protected against neuronal injury, while these effects were attenuated by the PI3K inhibitor LY294002. Conclusions BZD exerts potent neuroprotective and therapeutic effects against anxious depression, primarily driven by activating the PI3K/AKT/mTOR pathway and preserving hippocampal neuronal integrity.