多模态影像整合细胞间通讯信息解析补阳还五汤迭加丰富环境刺激对神经机能联系不能的调控作用

Diaschisis refers to delayed neuron injury and inhibition of nerve conduction due to hypo-perfusion and hypo-metabolism in remote infarction after cerebral ischemic stroke. Diaschisis is an important cause of unsatisfactory effect of stroke rehabilitation. Research confirms that enriched environment is an effective, low-risk and low-cost rehabilitation which can improve neuroplasticity. A significant result of the previous national science fund project is that Buyang Huanwu decoction combined with enriched environment can activate molecular switch of brain repair and alleviate the injury of remote infarction regions after cerebral ischemic stroke. The project will build the evaluation system of micro PET/CT united micro MRI which can visualize and quantify anatomic connectivity and functional change of remote infarction regions after cerebral ischemic stroke and provide objective evidence of relieving diaschisis treated by the Buyang Huanwu decoction combined with enriched environment. Furthermore, the molecular mechanism of regulating diaschisis will be probed from gap junction mediated intercellular communication. Multi-dimension analysis will be used to probe into the regulating effect on diaschisis by Buyang Huanwu decoction combined with enriched environment from integral brain function information and gene and protein relative to intercellular communication. The aim of the project is to provide strong theoretical support of Chinese herbs treatment combined with stimulation of enriched environment promoting rehabilitation of cerebral function.

缺血性脑卒中后，梗死灶远隔脑区出现低灌注、低代谢、迟发性神经元死亡和神经传导抑制，即神经机能联系不能，是卒中康复效果不理想的重要原因。研究证实多个干预因子的环境（丰富环境）可提高神经可塑性，是有效、低风险、低成本的康复手段。补阳还五汤迭加丰富环境刺激可调控远隔脑区神经再生分子开关，减轻脑缺血后远隔损害是前一项国家自然基金获得的重要结果。在此基础上，本项目拟构建micro PET/CT联合micro MRI评价体系，对脑缺血大鼠远隔脑区解剖连通性和功能改变进行可视化和定量化，为补阳还五汤迭加丰富环境刺激解除神经机能联系不能提供影像学证据，并进一步从缝隙连接介导的细胞间通讯探讨其调控神经机能联系不能的分子机制。将多模态神经影像信息整合细胞间通讯信息，多维度解析补阳还五汤迭加丰富环境刺激对神经机能联系不能的调控作用。该研究工作将为中药治疗和丰富环境有机结合促进脑功能整体康复提供强有力的理论支持。

本项目围绕“发挥丰富环境刺激激发潜能优势，配合益气活血中药调节脏腑气血促进脑卒中康复”的研究构想。针对卒中后神经可塑性变化特点，构建补阳还五汤迭加丰富环境刺激促进脑卒中康复模式。突破传统药理学研究手段难以直接探究神经机能联系不能的瓶颈问题，创新地将micro MRI解剖成像、功能成像与micro PET/CT分子成像结合，实现可视化和定量化分析脑缺血大鼠远隔脑区组织结构及血流动力学、细胞生化代谢、能量代谢等脑功能变化。研究已明确补阳还五汤迭加丰富环境可改善脑缺血大鼠远隔脑区血流灌注、能量代谢，促进组织微结构损伤后的重塑，对神经机能联系不能产生积极的干预作用。在此基础上，以星形胶质细胞缝隙连接通讯及GSK-3介导的神经血管胶质单元修复信号为核心，将远隔脑区解剖连通性、功能改变与细胞水平的基因、蛋白表达相结合，解析补阳还五汤迭加丰富环境干预远隔脑区损伤的神经机制。研究发现，补阳还五汤迭加丰富环境可上调磷酸化GSK-3α/βSer21/9表达，启动β-Catenin/GSK-3/TCF-4、PI3K/AKT/GSK-3/Caspase-3及Netrin/Slit/GSK-3/Rho GTPases多条信号通路刺激内源性修复，干预神经机能联系不能。并可改善中枢微环境，一方面抑制星形胶质细胞过度活化，调控星形胶质细胞缝隙连接蛋白CX43表达，适时阻断星形胶质细胞缝隙连接，减轻远隔脑区损害；另一方面上调神经生长因子、神经营养因子，下调轴突生长抑制信号等作用，增强神经可塑性，干预神经机能联系不能。本项目研究为益气活血中药和丰富环境刺激有机结合促进脑卒中康复提供强有力的理论支持，体现了中医药独特理论、治疗优势与现代康复医学的优势互补，藉此为制定脑卒中康复策略提供新思路。