Shuang Ruonan, Tong Yue, Wang Xinge, Hou Dahai, Yang Huina, Xu Shijun, Chen Chang
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, PR China.
School of Elderly Care Services and Management, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, PR China.
J Ethnopharmacol. 2025 Jul 25;353(Pt A):120323. doi: 10.1016/j.jep.2025.120323.
Bupleurum chinense DC. (Chaihu) [Apiaceae], a traditional Chinese medicinal herb, is a well-recognized natural remedy known for its antidepressant properties. Narcissoside (NCS), a flavonoid compound primarily extracted from Bupleurum chinense, has been reported to exert neuroprotective effects.
To explore the potential antidepressant effect and mechanism of NCS against neuroinflammation and neurogenesis based on the TREM2/PI3K/Akt pathway.
Using the chronic unpredictable mild stress (CUMS) mouse chronic stress models, different doses of NCS were administered to intervene. Depression-related behavior was tested in mice treated with NCS using sucrose preference test (SPT), open field test (OFT), tail suspension test (TST), and forced swimming test (FST). Neuroinflammation was observed by ELISA and qRT-PCR. Immunohistochemistry, immunofluorescence, Golgi staining, and electrophysiological methods were used to observe the characteristics of neurogenesis. Analysis of the signaling pathway involving TREM2/PI3K/Akt using western blotting. Pharmacological inhibition of adult neurogenesis by Temozolomide (TMZ) and deletion of TREM2 expression by shRNA lentiviral particles was used to validate the antidepressant-like and neurogenetic effects of microglial TREM2 expression on NCS intervention in CUMS mice. The interaction between NCS and TREM2 was predicted by molecular docking and verified by MST technique.
NCS effectively improved depression-like behavior in mice. NCS reduced the release of pro-inflammatory factors, increased the production of new neurons, alleviated neuron injury, and promoted the dendrite maturation of new neurons in the hippocampus. Temozolomide, which inhibits adult neurogenesis in mice, impaired the antidepressant response of NCS. In addition, TREM2/PI3K/Akt signaling was enhanced after NCS intervention. A murine model subjected to CUMS and treated with NCS, a known flavonoid with novel antidepressant activity, exhibited alleviated depressive symptoms, along with restored neuron injury markers and improved neurogenesis. These effects were observed in depressed mice through modulation of the TREM2/PI3K/Akt signaling pathway. Knocking out TREM2 expression with shRNA lentiviral particles impaired the antidepressant response of NCS.
NCS plays an antidepressant role, and its mechanism depends on the inhibition of neuroinflammation, the enhancement of adult hippocampal neurogenesis, and the activation of TREM2/PI3K/Akt pathway.
柴胡（伞形科植物柴胡）是一种传统的中药材，是一种公认的具有抗抑郁特性的天然药物。水仙苷（NCS）是一种主要从柴胡中提取的黄酮类化合物，据报道具有神经保护作用。
基于TREM2/PI3K/Akt通路探讨水仙苷对神经炎症和神经发生的潜在抗抑郁作用及机制。
采用慢性不可预测温和应激（CUMS）小鼠慢性应激模型，给予不同剂量的水仙苷进行干预。采用蔗糖偏好试验（SPT）、旷场试验（OFT）、悬尾试验（TST）和强迫游泳试验（FST）对接受水仙苷治疗的小鼠进行抑郁相关行为测试。通过酶联免疫吸附测定（ELISA）和定量逆转录聚合酶链反应（qRT-PCR）观察神经炎症。采用免疫组织化学、免疫荧光、高尔基染色和电生理方法观察神经发生的特征。使用蛋白质免疫印迹法分析涉及TREM2/PI3K/Akt的信号通路。使用替莫唑胺（TMZ）对成年神经发生进行药理学抑制，并使用短发夹RNA慢病毒颗粒敲除TREM2表达，以验证小胶质细胞TREM2表达对CUMS小鼠水仙苷干预的抗抑郁样和神经发生作用。通过分子对接预测水仙苷与TREM2之间的相互作用，并通过 MST技术进行验证。
水仙苷有效改善了小鼠的抑郁样行为。水仙苷减少了促炎因子的释放，增加了新神经元的产生，减轻了神经元损伤，并促进了海马中新神经元的树突成熟。抑制小鼠成年神经发生的替莫唑胺损害了水仙苷的抗抑郁反应。此外，水仙苷干预后TREM2/PI3K/Akt信号增强。在接受CUMS处理并用水仙苷治疗的小鼠模型中，水仙苷是一种具有新型抗抑郁活性的已知黄酮类化合物，其抑郁症状减轻，同时神经元损伤标志物恢复，神经发生改善。通过调节TREM2/PI3K/Akt信号通路在抑郁小鼠中观察到了这些作用。用短发夹RNA慢病毒颗粒敲除TREM2表达损害了水仙苷的抗抑郁反应。
水仙苷发挥抗抑郁作用，其机制依赖于抑制神经炎症、增强成年海马神经发生以及激活TREM2/PI3K/Akt通路。
