基于mTOR-PPARγ信号轴调控的小胶质细胞活化表型探究川续断皂苷Ⅵ的抗抑郁作用机制

中药续断具有补肝肾、续筋骨、安胎之功效，主要活性成分川续断皂苷Ⅵ已被发现具有显著的抗抑郁活性，但其分子机制尚未揭示。研究表明，抑郁症与小胶质细胞介导的神经炎症相关。既往非抑郁症领域的研究已证实川续断皂苷Ⅵ通过激活PI3K/AKT/mTOR信号轴发挥神经保护功能，亦可通过抑制小胶质细胞的促炎性激活来缓解神经炎症。最新研究发现PPARγ信号途径是调节小胶质细胞活化表型及抑郁症治疗的重要靶点。我们前期研究发现川续断皂苷Ⅵ的抗抑郁作用与小胶质细胞的表型调控相关。因此我们提出假说：川续断皂苷Ⅵ通过mTOR-PPARγ信号轴来调控小胶质细胞表型，修复神经损伤，从而发挥抗抑郁作用。本项目拟在川续断皂苷Ⅵ干预的抑郁模型动物中，特异性清除M2型小胶质细胞，并多位点阻断mTOR-PPARγ信号轴，深入探讨川续断皂苷Ⅵ的神经保护及抗抑郁机制。为川续断皂苷Ⅵ在防治抑郁症的药理作用机制研究方面提供实验和理论依据。

The traditional Chinese medicine Dipsaci Radix has the effects of tonifying liver and kidney, grafting bones and muscles, and calming fetus. Asperosaponin Ⅵ is the main active ingredients of Dipsaci Radix, which has been found has obvious antidepressant activity. But the molecular mechanism of asperosaponin Ⅵ antidepressant effect have not been revealed. Research has shown that depression is associated with microglia-mediated neuroinflammation. Previous research in non-depression areas has been shown that asperosaponin Ⅵ perform neuro-protective function by activating PI3K/AKT/mTOR signal. Asperosaponin Ⅵ also inhibits promote inflammatory activation of microglia to relieve neuroinflammation. Recent studies have found that PPARγ signaling pathway is an important target to regulate microglia activation phenotype and antidepressant. Our previous study found that the antidepressant effect of asperosaponin Ⅵ was associated with the phenotypic regulation of microglia. So we hypothesized that asperosaponin Ⅵ regulates the microglial phenotype by activating mTOR-PPARγ signal axis, to repair nerve damage, thus play a role of antidepressant. This project intends to ablate specifically the M2-type microglia and block the multiple sites of mTOR-PPARγ signal axis in asperosaponin Ⅵ intervention depression animal model, to explore the molecular mechanism of neuroprotective and antidepressant of asperosaponin Ⅵ. The study provides experimental and theoretical basis for pharmacological mechanisms research of asperosaponin Ⅵ in prevention and control of depression.