Liu Yang, Wan Yue, Fang Yongkang, Yao Ensheng, Xu Shabei, Ning Qin, Zhang Guibing, Wang Wei, Huang Xiaojiang, Xie Minjie
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
Department of Neurology, The Third People's Hospital of Hubei Province, Wuhan, 430030, China.
J Mol Neurosci. 2016 Feb;58(2):254-65. doi: 10.1007/s12031-015-0670-y. Epub 2015 Nov 6.
Multiple players are involved in the highly complex pathophysiologic responses after stroke. Therefore, therapeutic approaches that target multiple cellular elements of the neurovascular unit in the damage cascade hold considerable promise for the treatment of stroke. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active eicosanoids called epoxyeicosatrienoic acids (EETs), which are further converted by soluble epoxide hydrolase (sEH) to less bioactive diols. EETs have been shown to exert direct cytoprotective effects upon several individual components of the neurovascular unit under simulated ischemic conditions in vitro. However, the cellular mechanism underlying EET-mediated neuroprotective effects after ischemia remains to be clarified. In this study, we investigated the effects of 14,15-EET and 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), a selective inhibitor of sEH, on multiple elements of neurovascular unit of the rat brain after middle cerebral artery occlusion-induced focal ischemia. The results showed that exogenous administration of 14,15-EET or AUDA could suppress astrogliosis and glial scar formation, inhibit microglia activation and inflammatory response, promote angiogenesis, attenuate neuronal apoptosis and infarct volume, and further promote the behavioral function recovery after focal ischemia. The results suggest that epoxyeicosanoid signaling is a promising multi-mechanism therapeutic target for the treatment of stroke.
多个参与者参与了中风后高度复杂的病理生理反应。因此，针对损伤级联反应中神经血管单元多个细胞成分的治疗方法在中风治疗方面具有很大的前景。细胞色素P450（CYP）环氧合酶将花生四烯酸代谢为具有生物活性的类二十烷酸，称为环氧二十碳三烯酸（EETs），EETs会被可溶性环氧化物水解酶（sEH）进一步转化为生物活性较低的二醇。在体外模拟缺血条件下，EETs已被证明对神经血管单元的几个单独成分具有直接的细胞保护作用。然而，缺血后EET介导的神经保护作用的细胞机制仍有待阐明。在本研究中，我们研究了14,15-EET和sEH的选择性抑制剂12-（3-金刚烷-1-基-脲基）十二烷酸（AUDA）对大脑中动脉闭塞诱导的局灶性缺血后大鼠脑内神经血管单元多个成分的影响。结果表明，外源性给予14,15-EET或AUDA可抑制星形胶质细胞增生和胶质瘢痕形成，抑制小胶质细胞活化和炎症反应，促进血管生成，减轻神经元凋亡和梗死体积，并进一步促进局灶性缺血后的行为功能恢复。结果表明，环氧二十碳三烯酸信号通路是一种有前景的多机制中风治疗靶点。
