基于缺血性中风“从络论治”理论的复方当归注射液调控神经血管单元功能的研究

The pathogenesis of ischemic stroke is complex and clinical treatment is difficult. As an important basicstructure of maintaining the homeostasis of brain micro-environment, neurovascular unit (NVU) provides a new target for clinical treatment of stroke. According to the Chinese medicine, stoke falls into the category of collateral disease and its core therapeutic principle is the rule of collateral. Brain microvascular endothelial cell (BMVEC) is a basic part of brain collateral. Thus the study on the effect and mechanism of medicine using BMVEC as its breakthrough point conforms to the guiding ideology of rule of collateral. The component compatibility of Compound angelica injection(CAI) can promote blood circulation and remove obstruction in channels. Preliminary research shows that CAI has definite protective effect on ischemic apoplexy model, and its protection is extremely likely to be associated with the function by improving the BMVEC. Based on the rule of collateral, using regulating the microvascular function and maintaining the homeostasis of brain micro-environment (NVU) as its entry point, our investigations are suggested to elucidate the molecular mechanism of CAI on the regulation function of BMVEC and on intervention of the effector cell in NVU in vitro and in vivo, which will provide theoretical basis for the combination of traditional Chinese and western medicine on the research of the prevention of stroke by using multi-link and multi-target Chinese herbal compound, and is expected to further enrich modern molecular biology of the collateral disease theory.

缺血性脑中风（卒中）发病机制复杂，临床治疗困难，作为维持脑内微环境稳态的重要基本结构，神经血管单元为临床治疗卒中提供了新的靶点。中医认为卒中属于“络病”范畴，核心治则即“从络论治”。脑微血管内皮细胞是脑络的基本组成部分，以脑微血管内皮细胞为契入点研究药物的作用效应及机制符合“从络论治”的指导思想。复方当归注射液配伍组分具有活血通络作用，前期研究基础显示复方当归注射液对缺血性中风模型有确切的保护作用，并且其保护作用极有可能与改善脑微血管内皮细胞的功能有关。立足于“从络论治”，本课题拟以调控微血管功能、维持脑内微环境的稳态（神经血管单元）为切入点，从在体和离体角度分别研究复方当归注射液对微血管内皮细胞功能的调控作用及在此基础上对神经血管单元中效应细胞功能的干预，为中药复方多环节、多靶点调控防治脑卒中的中西医结合研究提供理论基础，也有望进一步丰富络病理论的现代分子生物学内涵。

神经血管单元作为维持脑内微环境稳态的重要基本结构，为临床治疗卒中提供了新的靶点。本课题从在体和离体角度分别研究复方当归注射液对缺血性中风的保护作用、对微血管内皮细胞功能的调控作用及在此基础上对神经血管单元中效应细胞功能的干预。在整体动物水平，构建大鼠大脑中动脉栓塞模型，通过行为学和形态学，明确复方当归注射液对中风的保护作用，对血脑屏障密切相关的基质金属蛋白酶的表达有明显影响，并初步显示对炎症相关通路JAK2/STAT3通路的干预。在离体水平，复方当归注射液对原代培养的脑微血管内皮细胞在拟缺血条件下有保护作用，提高细胞活性，降低氧化应激及炎症因子的表达。药物干预后的内皮细胞条件培养液能明显保护拟缺血损伤后的神经元和小胶质细胞的活性；这种保护效应与活化神经元PI3K/AKT信号通路与抑制小胶质细胞JAK2-STAT3信号通路有一定相关性。本课题的研究为中药复方多环节、多靶点调控防治缺血性中风的中西医结合研究提供了理论基础。