1,25(OH)2D3通过脑内小胶质细胞IL-6通路参与卒中后抑郁的机制研究

Studies have found that the incidence of post-stroke depression (PSD) is high, which may lead to poor prognosis of the patients. Therefore, exploring the mechanisms of PSD is of great importance. Vitamin D (VD) is an important immunomodulatory factor and its receptor (VDR) is widely distributed in the hippocampus and other regions, which is closely related to emotion and cognition. VDR regulates the expression of IL-6 in the microglia in the brain, and the lack of VD is closely related to depression. VD is generally absent among the old, especially patients with stroke. Our research found that VD deficiency is an independent risk factor for PSD, and VD level is negatively correlated with IL-6. Therefore, we hypothesized that the deficiency of VD may increase the expression of IL-6 in the microglia, resulting in a decrease in the level of 5-HT and BDNF in the hippocampus，which may lead to PSD. We want to clarify the causal relationship between VD deficiency and PSDas well as protective effect of Vitamin D supplement by a prospective cohort study and animal experiments. Rats models in this study include IL-6 gene knock-out or over-expressed rats. We aim to explore whether VD deficiency induces PSD via IL-6 in terms of animal behavior, cellular and molecular level, which may provide new ideas for the pathogenesis of PSD and the treatment of PSD.

卒中后抑郁(PSD)发生率高、预后差，研究其发生机制十分重要。维生素D (VD)是重要的免疫调节因子，其受体(VDR)广泛分布于海马等区域，与情绪和认知关系密切，VDR调节脑内小胶质细胞IL-6的表达，VD缺乏与抑郁关系密切。我国中老年人尤其卒中病人VD普遍缺乏，我们的研究发现VD缺乏是卒中后抑郁的独立危险因素，VD水平与IL-6呈负相关。由此，我们提出假设：VD缺乏上调脑内小胶质细胞上IL-6表达，造成海马5-HT、BDNF水平下降导致PSD。本课题拟从临床队列研究和动物实验验证VD缺乏与PSD的因果关系及补充VD的保护作用；并从整体动物、细胞和分子水平利用IL-6脑内基因特异性敲除或过表达大鼠模型，探讨IL-6是否为VD缺乏导致PSD的主要分子机制。本研究将为PSD提供发病新视点和防治新策略。

卒中后抑郁（PSD）发病率高，严重影响卒中患者的神经功能康复以及卒中的复发，有更差的预后。本项目组多年来从事PSD的相关研究，发现维生素D (VD)缺乏与PSD显著相关，在临床前瞻性队列研究中发现PSD、VD缺乏与IL-6、BDNF都存在相关关系，但确切的因果关系和神经生物学机制仍不清楚。VD作为一种重要的免疫调节因子，在中枢神经系统炎症反应中起重要作用，与PSD的发生有密切关系。本研究通过前瞻性临床队列和动物实验验证了VD缺乏可导致PSD，并探讨了VD缺乏引起PSD的神经生物学机制。结果发现：（1）临床队列和动物实验均表明VD缺乏会增加患者PSD的发生率，增加大鼠卒中后抑郁样行为，在动物实验中还发现，VD缺乏大鼠卒中后补充VD可以减少大鼠抑郁样行为；（2）临床队列研究发现IL-6、BDNF在VD缺乏和PSD间起到中介作用，VD缺乏可上调IL-6等促炎因子水平，降低BDNF水平并诱发PSD；（3）在动物实验中，在大鼠体内过表达IL-6可以增加下游STAT3，Cas-3以及一系列炎症因子的表达，抑制5HTRA1表达并加重大鼠卒中后抑郁样行为，拮抗IL-6则可以抑制炎症与凋亡相关因子表达，增加5HTRA1表达并降低抑郁样行为；（4）IL-6拮抗剂可以抑制VD缺乏诱导的大鼠卒中后海马区小胶质细胞IL-6表达，从而抑制STAT3和Cas3的表达，增加5HTRA1表达并降低大鼠抑郁样行为。.以上结果提示，VD缺乏主要通过海马区IL-6上调介导PSD发生。即个体在VD缺乏的情况下若发生卒中，脑内有更严重的炎症免疫反应，IL-6等炎症因子明显上调，导致BDNF、5-HT下调，海马神经元功能损害和细胞凋亡，导致PSD发生。本项目研究结果为防治PSD提供新的思路：我国中老年人普遍存在VD缺乏，要注意预防；对于VD缺乏的卒中患者可及时补充VD预防PSD发生；此外，应用IL-6拮抗剂可能对PSD有防治价值。