Betulinic acid protects against cerebral ischemia-reperfusion injury in mice by reducing oxidative and nitrosative stress
Betulinic acid protects against cerebral ischemia-reperfusion injury in mice by reducing oxidative and nitrosative stress
复制标题
桦木酸通过减少氧化和亚硝化应激来保护小鼠免受脑缺血再灌注损伤。
DOI：
10.1016/j.niox.2011.01.007
复制
发表时间：
2011-04-30
影响因子：
3.9
通讯作者：
Li, Huige
中科院分区：
文献类型：
--
作者：
Lu, Qing;Xia, Ning;Li, Huige
脑缺血再灌注后活性氧和活性氮的产生增加是神经元损伤的主要原因。在高胆固醇血症载脂蛋白E基因敲除（ApoE-KO）小鼠中，大脑中动脉（MCA）闭塞2 h，再灌注22 h，导致缺血半球中NADPH氧化酶亚基（NOX 2，NOX 4和p22 phox）和一氧化氮合酶亚型（神经元型nNOS和诱导型iNOS）的表达增强。这与3-硝基酪氨酸水平升高有关，3-硝基酪氨酸是过氧亚硝酸盐介导的氧化蛋白质修饰的指标。在MCA闭塞之前用桦木酸预处理（50 mg/kg/天，通过管饲持续7天）防止缺血再灌注诱导的NOX 2、nNOS和iNOS的上调。同时，桦木酸降低了3-硝基酪氨酸的水平。此外，桦木酸治疗增强了非缺血半球内皮eNOS的表达。最后，桦木酸减少了梗死体积，改善了小鼠中风模型的神经功能缺损。结论桦木酸对小鼠脑缺血再灌注损伤具有保护作用。这可能是由于氧化应激（通过下调NOX 2）和亚硝化应激（通过减少nNOS和iNOS）的减少，以及血流的增强（通过上调eNOS）。(C)2011 Elsevier Inc. All rights reserved.
Increased production of reactive oxygen and nitrogen species following cerebral ischemia-reperfusion is a major cause for neuronal injury. In hypercholesterolemic apolipoprotein E knockout (ApoE-KO) mice, 2 h of middle cerebral artery (MCA) occlusion followed by 22 h of reperfusion led to an enhanced expression of NADPH oxidase subunits (NOX2, NOX4 and p22phox) and isoforms of nitric oxide synthase (neuronal nNOS and inducible iNOS) in the ischemic hemisphere compared with the non-ischemic contralateral hemisphere. This was associated with elevated levels of 3-nitrotyrosine, an indicator of peroxynitrite-mediated oxidative protein modification. Pre-treatment with betulinic acid (50 mg/kg/day for 7 days via gavage) prior MCA occlusion prevented the ischemia reperfusion-induced upregulation of NOX2, nNOS and iNOS. In parallel, betulinic acid reduced the levels of 3-nitrotyrosine. In addition, treatment with betulinic acid enhanced the expression of endothelial eNOS in the non-ischemic hemispheres. Finally, betulinic acid reduced infarct volume and ameliorated the neurological deficit in this mouse stroke model. In conclusion, betulinic acid protects against cerebral ischemia-reperfusion injury in mice. This is likely to result from a reduction of oxidative stress (by downregulation of NOX2) and nitrosative stress (by reduction of nNOS and iNOS), and an enhancement of blood flow (by upregulation of eNOS). (C) 2011 Elsevier Inc. All rights reserved.