具有神经保护和降低体温双重功效抗脑缺血再灌注损伤药物先导化合物的发现研究

脑卒中是近年来全球致残人数排名第一、致死人数排名第二的急性脑血管疾病，其中缺血性脑卒中（Ischemic Stroke，IS）占全部脑卒中发病病例的80%。经过溶栓药物或手术治疗疏通血管后发生的缺血再灌注损伤是造成IS患者脑组织损伤的重要病理机制。自由基清除剂依达拉奉等药物被用于减轻IS患者的神经病变，但临床目前仍严重缺乏有效的脑缺血再灌注损伤治疗药物。研发针对IS急性期疾病发展关键病理环节的神经保护剂是当前热点研究领域。我们前期研究发现28-O-咖啡酰基白桦脂醇对大鼠脑缺血再灌注损伤模型具有显著的神经保护活性，可抑制神经元死亡和胶质细胞炎症反应，并具有降低体温这一对减轻IS神经损伤有益的作用。本项目拟在已有工作基础上，发现基于28-O-咖啡酰基白桦脂醇结构的具有更好神经保护和降低体温功效的抗IS缺血再灌注损伤神经保护剂先导化合物，并通过设计合成分子探针分析其与神经保护活性相关的结合蛋白。

Cerabral stroke is an acute cerebrovascular disease that causes the largest number of disabled people and ranks the second most fatal disease in the world in recent years, and ischemic stroke (IS) accounts for 80% of all cerebral stroke cases. Ischemia-reperfusion injury after thrombolytic therapy or surgical treatment is an important pathological mechanism for the damage of brain tissue in IS patients. Edaravone, a free radical scavenger, and several other drugs have been used to reduce neuropathy in patients with IS, but there is still a severe lack of effective therapeutic agents for cerebral ischemia-reperfusion injury. The pharmaceutical development of neuroprotective agents focused on the key pathological injuries in acute phase of IS is a hot research area at present. Our previous investigation revealed that 28-O-caffeoyl betulin possesses significant neuroprotective activity against cerebral ischemia-reperfusion injury in rat model by inhibition of both neuronal death and inflammatory reaction of glial cells, and has also the beneficial efficacy of hypothermia against IS neurological damage. Based on the previous findings and the structure of 28-O-caffeoyl betulin, this project intends to explore leading compound with potent dual efficacies of neuroprotection and hypothermia for the treatment of cerebral ischemia-reperfusion injury, and to explore the binding proteins relevant to the neuroprotective activity by designing and synthesizing biotin-labeled molecular probes.