黄芪抑制柠檬酸载体阻断外周巨噬细胞炎性反应以及对抗缺血性脑卒中的机制研究

Pharmacological studies show that Astragalus membranaceus protect the integrity of blood-brain barrier and prevent ischemic stroke. Saponins and flavonoids are the main active ingredients of Astragalus membranaceus, but the ability to cross the blood-brain barrier is weak, suggesting the possibility that these active ingredients of Astragalus membranaceus protect central nervous tissue through peripheral intervention. This project is designed to investigate whether and how active ingredients of Astragalus membranaceus protect the brain from ischemic damage by suppression of peripheral macrophage activation through metabolism reprogram in the context of inhibited citrate carrier. The contents included in the protect are as follows: ① To prepare Astragalus membranaceus monomer compounds for screening candiate targeting citrate carrier in macrophages; ② To elucidate the molecular mechanism by which f Astragalus membranaceus macrophage activation along the signaling pathway of citrate carrier/ itaconate/ succinate dehydrogenase; ③To establish the functional interaction between peripheral macrophage inactivation and neuroprotection by of Astragalus membranaceus; ④ To reproduce the protective effects of Astragalus membranaceus in animal model for a full evaluation. This study aims to find a potential molecular mechanism by which Astragalus membranaceus suppresses macrophage activation to combat neural inflammatory response from the aspect of metabolic regulation, contributing to providing new insights for the design of novel therapeutical strategy in the management of encephalopathy with traditional Chinese medicine.

黄芪具有保护血脑屏障完整性以及对抗缺血性脑卒中损害的作用。皂苷类和黄酮类化合物是黄芪的主要活性成分，但其透过血脑屏障的能力较低，提示黄芪活性成分通过外周干预保护中枢神经组织的潜在作用。本课题拟从抑制外周巨噬细胞柠檬酸载体转运为切入点，探讨黄芪活性成分通过调控外周巨噬细胞代谢重塑保护缺血性脑卒中的作用机制，拟开展如下实验：① 黄芪单体化合物的制备及靶向筛选阻断柠檬酸载体蛋白的黄芪活性成分；② 研究黄芪活性成分通过柠檬酸载体/衣康酸/琥珀酸脱氢酶信号通路阻断巨噬细胞炎性反应的作用机制；③ 研究黄芪活性成分通过外周调控保护中枢神经细胞的作用；④ 整体动物模型验证黄芪活性成分通过外周调节对抗缺血性脑卒中的作用。本研究从代谢角度探讨黄芪活性成分保护脑组织稳态的新路径，为中药外周干预治疗脑病新策略的制定提供新见解。

黄芪甲苷是中药黄芪的主要活性成分，对缺血/再灌注损伤、脑卒中以及神经系统退行性疾病具有显著的改善作用。但其透过血脑屏障的能力较低，提示黄芪甲苷通过外周干预保护中枢神经系统的潜在作用。本研究以阻断柠檬酸载体（CIC）对线粒体柠檬酸转运为切入点，探讨了黄芪甲苷通过调控外周巨噬细胞代谢重塑改善缺血性脑卒中损伤的作用机制。① 阐明了阻断外周巨噬细胞柠檬酸转运抑制巨噬细胞炎性活化，改善缺血性脑损伤的作用机制。② 发现了黄芪甲苷抑制外周炎症型巨噬细胞浸润，减轻缺血性脑卒中的药理作用。③ 探讨了黄芪甲苷与CIC结合阻断柠檬酸转运，减弱组蛋白H3K27乙酰化水平抑制HIF-1α对Irg1的转录调控，修复TCA循环；并阻断HIF-1α对GABA转氨酶的转录调控减少琥珀酸蓄积，保护线粒体功能，进而抑制巨噬细胞炎性活化的作用机制。本研究从细胞代谢角度探讨黄芪活性成分保护脑组织稳态的新路径，为中药外周干预治疗脑病新策略的制定提供新见解。已在Cell Reports期刊发表SCI论文1篇，并协助培养硕士研究生1名。