基于“肾脑相济”理论探讨电针诱导脑海马内源性神经干细胞分化治疗围绝经期抑郁症的作用

Perimenopausal depression refers to a mental illness occured during the process of lossing the female reproductive function. According to traditional Chinese medicine, the discordance between Kidney and Brain is the major pathogenesis. According to modern medicine discovery, depression results from hippocampal damage and inhibition of proliferation and differentiation of neural stem cells (NSCs). The therapeutic effects on perimenopausal depression by electroacupuncture is significant. However, the mechanisms whereby it may influence the discordance between Kidney and Brain remains elusive. Here, a new idea of treating perimenopausal depression by electroacupuncture is proposed based on the theory of interdependence betweeen Kidney and Brain. We proposed here that electroacupuncture stimulates acupuncture points by nourishing Kidney and Brain, and causes up stimulation of signaling pathways involving CREB/BDNF to induce proliferation and differentiation of hippocampal endogenous NSCs, and to convert a hostile environment to one supportive of neural survival and mature. We also explored the mechanisms of regulation of NSCs by CREB/BDNF signaling pathway, and the therapeutic targets of electroacupuncture. These results will illuminate a new outlook of the relationship of "Kidney Brain" theory and the endogenous NSCs, we'll filter out a new treatment program of "regulation of proliferation and differentiation of NSCs by electroacupuncture" to gain the therapeutic effect of perimenopausal depression. These results will open up the new ways and ideas to the treatment of such kind of mental disease, also lay foundation for application of acupuncture and moxibustion in the field of stem cells.

围绝经期抑郁症是指女性生殖机能由盛转衰的过程中出现的一种精神疾病。中医认为"肾脑失济"为其主要病机。现代医学研究发现，海马损伤、NSCs增殖分化抑制是抑郁症发病的关键环节。针刺干预"肾脑失济"治疗围绝经期抑郁效果确切，但具体机制尚不清楚。本项目拟在前期工作基础上，采用"肾脑相济"中医理论指导下的电针策略，通过对补肾养脑穴位组合的刺激，激活CREB/BDNF信号通路，从而促进脑海马内源性NSCs增殖、定向分化为神经元，有效改善海马区内环境、促进分化后的神经元存活，治疗抑郁症；通过探索CREB/BDNF信号调控脑内源性NSCs的机制和电针刺激的干预靶点，揭示中医"肾脑相济"理论与内源性NSCs的关系，构建针灸作为干预因素，调控并促进脑内源性NSCs增殖、分化和改善脑内环境的新策略。项目的实施为中医针灸治疗类似情感性精神障碍疾病开辟新思路，也为针灸在干细胞领域的应用奠定基础。

本实验采用对成年雌性大鼠进行双侧卵巢摘除联合慢性不可预见应激来构建围绝经期抑郁症模型，研究电针对抑郁大鼠海马神经干细胞增殖、定向分化及凋亡的作用，并从CREB/BDNF通路角度探讨其机制。用随机数字表法将大鼠随机分为空白组、假手术组、模型组、西药组、电针组及KG-501组。造模成功后，选取大鼠的“肾俞”、“百会”以及“三阴交”穴进行电针治疗，采用旷场试验、糖水实验等进行行为学检测，治疗结束后，分体内及体外两部分研究。.体内部分：取材采用免疫组化检测海马组织相关区域神经干细胞增殖及分化情况，包括计数神经细胞等相关指标；用荧光免疫组化检测各组大鼠脑海马区Nestin等阳性细胞表达；氧化应激相关指标SOD等；ELISA法测定海马的5-HT等神经递质和激素的含量，海马区的炎症介质1L-6等含量，ELISA法检测神经细胞分化标记蛋白GFAP等，海马组织中CREB/BDNF通路相关蛋白等；用RT-PCR法及weatern-blot法检测其中部分相关指标。.体外细胞研究部分：电针治疗28d后，体外分离、培养海马神经元，用免疫荧光鉴定所得海马神经元。检测各组海马神经元的细胞活力、细胞周期及凋亡数量。检测海马神经元中CREB/BDNF通路CREB和BDNF的变化，并用CREB抑制剂KG-501抑制此通路，观察对神经元存活、形态和功能的影响。.结果显示成年雌性大鼠进行双侧卵巢摘除联合慢性不可预见应激构建围绝经期抑郁症模型很好地模拟了本病。电针治疗有效改变了大鼠行为学表现，在改善海马或皮层神经细胞形态、内环境、激素水平上有明显作用，能够在大鼠海马区神经细胞增殖、定向分化及凋亡方面有效调控。有力证实依据“肾脑相济”理论，电针“肾脑同治”对围绝经期抑郁症的疗效显著，其疗效机制可能与通过调控CREB/BDNF通路进而调控脑海马内源性NSCs增殖、定向分化及凋亡有关。.本项目研究成果主要以论文形式提供，共发表论文12篇，其中SCI收录1篇。出版著作4部。主办国内会议1次，参加国内外学术交流6次，其中大会报告2次。培养博士研究生3名，硕士研究生1人。

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