Bupleurum Chinense Dc.-Scutellaria Baicalensis Georgi Exerts Antidepressant Action by Improving Synaptic Plasticity Through Gsk3β/Β-Catenin Signaling

Abstract

Changes in neuroplasticity are closely associated with depression. Chronic stress causes neuronal structural disorders and impairs synaptic plasticity, leading to the onset and development of depression. Bupleurum chinense DC.-Scutellaria baicalensis Georgi (BS), as a classic drug pair in TCM, is effective in the clinical treatment of depression. However, its potential mechanism has not been elucidated yet. Our study aimed to investigate how BS improves hippocampal synaptic plasticity and reduces depression-like behavior in CORT mice. We first applied network pharmacology to predict the molecular targets and pathways of action of BS in depression, utilized CORT mice to study the therapeutic effects of BS, and explored the role played by GSK3β in hippocampal neuronal synaptic plasticity and the effects of BS in a mouse model by lentiviral transfection technique. The results of network analysis revealed the important targets and the mechanism of action in modulating synapses. The experiments in vivo confirmed that silencing GSK3β and BS both improved the synaptic integrity of hippocampal neurons and attenuated depressive-like behaviors in CORT mice, and that the antidepressant effect of BS in regulating hippocampal synaptic plasticity was counteracted when silencing GSK3β. The mice showed a significant pleasure deficit and behavioral despair, with no obvious increase in the number of neurons in hippocampal area, dendritic complexity and dendritic spine number, and at the same time, the expression of GSK3β/β-catenin pathway-related proteins were suppressed. In summary, the present study demonstrated that BS can improve neuronal synaptic integrity and alleviate depression via GSK3β/β-catenin pathway.

Note:
Funding declaration: This work was supported by the National Natural Science Foundation of China (No. 82204641), the National Natural Science Foundation of China Youth Program Funding Matching Project of Nanjing University of Chinese Medicine (No. XPT82204641), the Project of Administration of Traditional Chinese Medicine of Jiangsu Province (QN202104), the NATCM’s Project of High level Construction of Key TCM Disciplines and the Open Project of Chinese Materia Medica First Class Discipline of Nanjing University of Chinese Medicine (No. ZYXYL2024-016).

Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval: All animal experimental procedures were approved by the Animal Ethical Committee of Nanjing University of Chinese Medicine (202409A088) and were performed strictly in accordance with the the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, revised in 1996).

Keywords: Bupleurum chinense DC.-Scutellaria baicalensis Georgi, Depression, GSK3β/β-catenin, Synaptic plasticity, Network Pharmacology