丹酚酸B抗抑郁作用的神经免疫机制研究

Major depressive disorder (MDD) is one of the most frequently occurring mental disorders. Traditional Chinese medicine (TCM) has its own remarkable characteristics and advantages in the treatment of MDD, although the mechanism is not clear. Recent researches indicated that the neuroinflammatory responses and subsequent neurogenesis reduction were the important pathological basis of MDD. Salvianolic acid (SalB), which was defined as facilitating blood circulation and removing blood stasis according to TCM theory, was shown the anti-inflammation and neuroprotective effects. Based on our previous study and followed by the theory of eliminating stasis to promote regeneration, our hypothesis is that SalB has therapeutic effects of antidepressant through regulating miacrglial activation, inhibiting neuroinflammation and promoting neurogenesis. We intends to carry out the following research: (1) The effects of SalB on behaviors of chronic mild stress-treated mice will be assessed by sucrose preference test, forced swimming test and tail suspension test to evaluate the antidepressant potentials of SalB. (2) The morphology, surface markers and secretion of cytokines of microglia will be detected to reveal the mechanism of SalB on neuroinflammatory suppression by regulating microglial activation. (3) The effect of SalB on neurogenesis will be estimated by in vivo and in vitro experiments, and the role of classical or alternative activated microglia on neurogenesis are analyzed to bring to insight of antidepressant effects of SalB. In this project proposal, we will focus on the effects of SalB on the phenotypes of the microglia, to investigate the novel antidepressant therapy by blocking neuroinflammatory response and promoting neurogenesis, to explore the scientific basis for the TCM conception of “eliminating stasis to promote regeneration”, and to provide new research ideas for treatment of MDD.

抑郁症是一种常见的精神障碍，中医药在治疗抑郁症方面具有自身特色和优势。近年研究揭示中枢炎症及其引起的神经发生减少是抑郁症的重要病理基础；丹酚酸B具有抗炎和神经保护作用。依据课题组前期工作基础，遵循祛瘀生新理论，本项目首次提出“丹酚酸B通过调节小胶质细胞激活途径，抑制中枢炎症、促进神经发生从而发挥抗抑郁作用”的工作假说。拟开展以下研究：（1）采用抑郁模型小鼠，以糖水偏好、强迫游泳等行为学指标探索丹酚酸B的抗抑郁作用；（2）以分子生物学、免疫化学等技术分析小胶质细胞的激活途径，揭示丹酚酸B抑制中枢炎症的细胞基础；（3）通过体内外实验检测丹酚酸B对神经发生的影响，以探究神经发生与小胶质细胞表型的相关性以及丹酚酸B抗抑郁作用的实现途径。本项目以丹酚酸B为研究对象，聚焦于小胶质细胞表型，探索抑制中枢炎症、促进神经发生的抗抑郁新策略，为阐释祛瘀生新的现代科学内涵提供依据，为抑郁症治疗提供新的研究思路。

抑郁症是一种常见的精神障碍，中医药在治疗抑郁症方面具有自身特色和优势。近年研究揭示中枢炎症及其引起的神经发生减少是抑郁症的重要病理基础，而丹酚酸B具有抗炎和神经保护作用，我们以“丹酚酸B通过调节小胶质细胞激活途径，抑制中枢炎症、促进神经发生从而发挥抗抑郁作用”为假说完成了以下研究：（1）证实了丹酚酸B调节抑制中枢炎症反应是其活血化瘀的重要药理学基础，丹酚酸B能够治疗CMS模型小鼠的抑郁症状。经过3周的慢性温和刺激后，CMS小鼠在一系列行为学测试中表现出典型抑郁表型。诸如，糖水偏爱降低，强迫游泳和悬尾实验中的绝望行为的增加等；（2）证实了丹酚酸B通过干预小胶质细胞激活途径具有抗抑郁效应,丹酚酸B治疗后的抑郁小鼠其海马和皮层的促炎性细胞因子IL-1β 和TNF-α 均明显的比对照组小鼠表达的更少。相对应的，IL-10 和TGF-β 这两种抗炎性因子的表达则增加；（3）通过体内外实验检测丹酚酸B对神经发生的影响，探究神经发生与小胶质细胞表型的相关性以及丹酚酸B抗抑郁作用的实现途径。丹酚酸B治疗后的抑郁小鼠，其皮层海马中小胶质细胞的表型标记物的鉴定表明，其中M1型表型的小胶质细胞向M2表型变化的数量明显的多于对照组的抑郁小鼠。在体外培养的小胶质细胞能够被外源的LPS激活成M1表型，而丹酚酸B的可以抑制这种M1的激活同时引起M2表型的激活。研究证实了丹酚酸B通过调节小胶质细胞激活途径，抑制中枢炎症、促进神经发生从而发挥抗抑郁作用， 进一步探讨了“从瘀治郁”的细胞和分子基础，阐释“祛瘀生新”的现代科学内涵。我们在根据“从瘀治郁”提出治疗抑郁症的“祛瘀生新”视角，其基础是丹参的活血化瘀作用是丹酚酸B调节和抑制了中枢系统的炎症反应。而这种调节作用，是通过干预小胶质细胞的激活途径来实现的，进一步阐释了“祛瘀生新”的科学内涵。