State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, PR China.
State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, PR China; Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, PR China.
J Ethnopharmacol. 2024 Jan 30;319(Pt 3):117289. doi: 10.1016/j.jep.2023.117289. Epub 2023 Oct 14.
Radix Bupleuri, also named "Chaihu" in Chinese, is a substance derived from the dry roots of Bupleurum chinense DC. [Apiaceae] and Bupleurum scorzonerifolium Willd. [Apiaceae]. Radix Bupleuri was initially recorded as a medicinal herb in Shen Nong Ben Cao Jing, the earliest monograph concerning traditional Chinese medicine (TCM). Ever since, Radix Bupleuri has been broadly used to alleviate exterior syndrome, disperse heat, modulate the liver-qi, and elevate yang-qi in TCM. Radix Bupleuri has also been utilized as an important component in Xiaoyaosan, a classical formula for relieving depression, which was originated from the famous Chinese medical book called "Tai Ping Hui Min He Ji Ju Fang" in Song Dynasty. Currently, many valuable pharmacological effects of Radix Bupleuri have been explored, such as antidepressant, neuroprotective activities, antiinflammation, anticancer, immunoregulation, etc. Former studies have illustrated that Saikosaponin A (SSa), one of the primary active components of Radix Bupleuri, possesses potential antidepressant properties. However, the underlying mechanisms still remain unknown.
We used a chronic social defeat stress (CSDS) mouse model to explore the ameliorative effects and potential mechanisms of SSa in depressive disorder in vivo.
The CSDS mouse model was established and mice underwent behavioral studies using assays such as the social interaction test (SIT), sucrose preference test (SPT), forced-swim test (FST), tail suspension test (TST), and open field test (OFT). Western blotting, immunofluorescence, and Golgi staining were performed to investigate signaling pathway activity, and alterations in synaptic spines in the hippocampus. To model the anticipated interaction between SSa and Tet1, molecular docking and microscale thermophoresis (MST) techniques were employed. Finally, sh-RNA Tet1 was employed for validation via lentiviral transfection in CSDS mice to confirm the requirement of Tet1 for SSA efficacy.
SSa dramatically reduced depressed symptoms, boosted the expression of Tet1, Notch, DLL3, and BDNF, encouraged hippocampus development, and enhanced the dendritic spine density of hippocampal neurons. In contrast, Tet1 knockdown in CSDS mice dampened the beneficial effects of SSa on depressive symptoms.
Therefore, our results suggest that SSa significantly activates the Tet1/Notch/DLL3 signaling pathways and promotes hippocampal neurogenesis to exert antidepressant effects in the CSDS mouse model in vivo. The present results also provide new insight into the importance of the Tet1/DLL3/Notch pathways as potential targets for novel antidepressant development.
柴胡，在中国被称为“柴胡”，是一种从柴胡或北柴胡的干燥根中提取的物质。[伞形科]。柴胡最初被记录在《神农本草经》中，这是最早的一本关于中药（TCM）的专著。从那时起，柴胡就被广泛用于中医解表散热、调肝理气、升阳。柴胡也是逍遥散的重要组成部分，逍遥散是一种源自宋代著名医书《太平惠民和剂局方》的治疗抑郁症的经典方剂。目前，柴胡的许多有价值的药理作用已经被探索出来，如抗抑郁、神经保护作用、抗炎、抗癌、免疫调节等。先前的研究表明，柴胡皂苷 A（SSa）作为柴胡的主要活性成分之一，具有潜在的抗抑郁作用。然而，其潜在机制仍不清楚。
我们使用慢性社交挫败应激（CSDS）小鼠模型在体内研究 SSa 对抑郁障碍的改善作用及其潜在机制。
建立 CSDS 小鼠模型，采用社会交往测试（SIT）、蔗糖偏好测试（SPT）、强迫游泳测试（FST）、悬尾测试（TST）和旷场测试（OFT）等行为学测试方法对小鼠进行测试。采用 Western blot、免疫荧光和高尔基染色法研究信号通路活性及海马突触小棘的变化。采用分子对接和微量热泳动（MST）技术模拟 SSa 与 Tet1 的预期相互作用。最后，采用慢病毒转染 CSDS 小鼠进行 sh-RNA Tet1 验证，以确认 Tet1 对 SSA 疗效的要求。
SSa 显著减轻抑郁症状，上调 Tet1、Notch、DLL3 和 BDNF 的表达，促进海马发育，增加海马神经元树突棘密度。相反，CSDS 小鼠中 Tet1 的敲低减弱了 SSa 对抑郁症状的有益作用。
因此，我们的结果表明，SSa 可显著激活 Tet1/Notch/DLL3 信号通路，促进海马神经发生，从而在体内 CSDS 小鼠模型中发挥抗抑郁作用。本研究结果还为 Tet1/DLL3/Notch 通路作为新型抗抑郁药物开发的潜在靶点提供了新的见解。
