人参皂苷Rg1通过调控星形胶质细胞网络缝隙连接细胞间通讯功能发挥抗抑郁作用的机理研究

Although the clinical efficacy of first-line antidepressants acceptable, there are many side effects. We have demonstrated that ginsenosides Rg1 produced definite antidepressant-like effects with minor side effects. Furthermore, ginsenosides Rg1 ameliorated sleep disorders, cognitive dysfuntion, and sexual dysfunction associated with depression. However, its mechanism of antidepressant action has not been fully elucidated. Astrocyte gap junctional intercellular communication (GJIC) function in the prefrontal cortex is closely related to the occurrence of depression and antidepressant effects of drugs. Rg1 improved the GJIC function and its protective effects on corticosterone-induced injury were reversed by pharmacological gap junction blockade. Therefore, this project is planned to study the animals, cellular and molecular mechanism of Rg1 regulating the GJIC function and the relationship between this and its antidepressant-like effects, using the blockers, analog peptide, RNAi and gene knockout via behavioral pharmacology, cell biology, molecular biology, proteomics and electrophysiology. We manage to answer whether the regulation of GJIC function is crucial for the antidepressant-like effects of Rg1. Together, this study may provide scientific evidence supporting Rg1 to become a novel potential antidepressant and may also facilitate the development of other traditional Chinese medicines for treatment of depression.

尽管临床一线抗抑郁药疗效尚可，但存在不良反应多等诸多缺憾。前期证实，人参皂苷Rg1不但抗抑郁作用确切，而且具有毒副作用小且能改善伴随的睡眠障碍、认知障碍和性功能障碍等独特优势，但其抗抑郁作用机制尚未完全阐明。前期还发现前额皮质区星形胶质细胞缝隙连接细胞间通讯（GJIC）功能与抑郁症发生和药物抗抑郁作用密切相关，而Rg1能改善GJIC功能，且Rg1抗皮质酮损伤的作用可被缝隙连接阻断剂所抑制。因此本项目拟在此基础上，采用阻断剂、模拟肽段、RNAi、基因敲除等多种干预手段，通过行为药理学、细胞生物学、分子生物学、蛋白质组学和电生理学等多种研究方法，从动物、细胞和分子多水平研究Rg1调控GJIC功能的机制以及该作用与其抗抑郁的关系，力争回答调控GJIC功能是否是Rg1发挥抗抑郁作用的关键环节及其精细调控机理，为将Rg1开发为新型安全的抗抑郁中药提供实验依据，也为中药抗抑郁作用机制研究提供有益借鉴。

尽管临床一线抗抑郁药疗效尚可，但存在不良反应多等诸多缺憾。前期证实，人参皂苷Rg1不但抗抑郁作用确切，而且具有毒副作用小且能改善伴随的睡眠障碍、认知障碍和性功能障碍等独特优势，但其抗抑郁作用机制尚未完全阐明。前期还发现前额皮质区星形胶质细胞缝隙连接细胞间通讯（GJIC）功能与抑郁症发生和药物抗抑郁作用密切相关，而Rg1能改善GJIC功能。因此本项目在前期工作基础上，采用缝隙连接阻断剂和缝隙连接蛋白Cx43模拟肽段等干预手段，通过行为药理学、细胞生物学、分子生物学等多种研究方法，从动物、细胞和分子多水平研究Rg1调控GJIC功能的机制以及该作用与其抗抑郁的关系。通过研究我们发现，Rg1抗皮质酮损伤的作用可被缝隙连接阻断剂所抑制，而且在缝隙连接功能或Cx43蛋白功能被抑制的情况下，Rg1的抗抑郁效应无法发挥出来，表明Rg1的抗抑郁效应是依赖于星形胶质细胞间缝隙连接功能以及缝隙连接蛋白Cx43的，并且蛋白酶体途径是这一作用机制的重要通路。这些研究为将Rg1开发为新型安全的抗抑郁中药提供了实验依据，也为中药抗抑郁作用机制研究提供了有益借鉴。