基于缝隙连接蛋白Cx43介导的星形胶质细胞保护作用探讨马钱苷抗抑郁作用机制

To resolve the present limitations of antidepressants, increasing researchers focus on traditional chinese medicines. Our previous study revealed that loganin, one main component of Cornus officinalis Sieb. et Zucc., reversed the depressive-like behaviors of mice and rats. However, the mechanism underlying antidepressant effects of loganin is unknown. Recent studies suggest that connexin43 (Cx43) is a potential target for depression therapy due to its protective effects on astrocytes, and loganin protects astrocyte against central nervous system injury. Therefore, we put forward the question that whether Cx43 associates with antidepressant effects of loganin. The effects of loganin on astrocyte and astrocytic gap junction will be explored in rats and primary astrocyte under stress. To confirm the role of Cx43 in loganin-induced antidepressant effects, we evaluate that whether Gap26, a selective inhibitor for Cx43, interferes with loganin-induced antidepressant effects. Moreover, inhibitors and activators of H3K9me3 and PKC will be used to identify the pathway associated with loganin-induced changes of Cx43. In conclusion, the present study will explain the mechanism underlying antidepressant effects of loganin, providing a potential treatment for depression.

临床治疗抑郁症的药物有效率低且副作用严重，亟待开发新型抗抑郁药物。本课题组证实药食同源中药山茱萸的主要成分马钱苷抗抑郁药效明确，但其抗抑郁作用机制尚未阐明。最新研究表明，缝隙连接蛋白Cx43是调控星形胶质细胞功能的关键分子，已成为治疗抑郁症的潜在靶点，而马钱苷对星形胶质细胞具有保护作用。由此，我们提出“马钱苷通过Cx43改善星形胶质细胞功能从而发挥抗抑郁作用”这一科学假说。我们将利用体内外应激模型，从动物行为学、细胞生物学及分子生物学等多方面研究马钱苷对星形胶质细胞数量、形态及缝隙连接功能的作用；通过Cx43模拟肽段Gap26阻断缝隙连接功能，观察马钱苷对星形胶质细胞的保护作用及抗抑郁药效是否受到干扰，确定Cx43对马钱苷发挥抗抑郁药效的作用；通过抑制或激活H3K9me3及PKC，确定马钱苷调控Cx43的关键环节；从而阐明马钱苷的抗抑郁作用机制，为研究新型抗抑郁药物提供新的思路。

临床现有的抗抑郁药物有效率低且副作用严重，亟待开发新型抗抑郁药物。本课题组前期证实药食同源中药山茱萸的主要成分马钱苷抗抑郁药效明确，但其抗抑郁作用机制尚未阐明。最新研究表明，缝隙连接蛋白Cx43是调控星形胶质细胞功能的关键分子，已成为治疗抑郁症的潜在靶点。本研究利用体内外应激模型，通过免疫荧光、CCK-8实验证明马钱苷增加星形胶质细胞生存率及星形胶质细胞的分支。进一步通过细胞生物学和分子生物学方法证明马钱苷改善星形胶质细胞缝隙连接结构、增加星形胶质细胞间缝隙连接通讯，马钱苷对星形胶质细胞缝隙连接功能的保护作用与促进Cx43的表达、增加细胞膜上Cx43的分布、抑制Cx43丝氨酸368位点磷酸化及Cx43降解相关。此外，我们使用Cx43模拟肽段Gap26阻断缝隙连接功能，通过行为药理学研究证明马钱苷改善缝隙连接功能损伤介导的大鼠抑郁样行为，确定马钱苷可通过Cx43发挥抗抑郁药效的作用。本课题为阐明马钱苷的抗抑郁作用机制，为研究新型抗抑郁药物提供新的思路。