Pathophysiology and treatment for the acute phase of ischemic cerebrovascular disease

过氧亚硝酸盐已被证明是负责硝化在体内，而髓过氧化物酶（MPO）也可以催化蛋白质硝化在高NO2-水平的存在下。MPO介导的酶失活或脂质过氧化的最新报告表明MPO在各种病理条件下的作用。作为本项目的第一项研究，我们测量了MPO缺陷型或野生型小鼠局灶性脑缺血再灌注2小时后的硝基酪氨酸形成和梗死体积，以阐明MPO在缺血性脑损伤中的作用。再灌注后24小时，MPO缺陷型小鼠中的梗死体积显著大于野生型小鼠中的梗死体积（81±20 mm 3对52±13 mm 3; p<0.01），并且MPO缺陷型小鼠中梗死区域中的硝基酪氨酸水平显示出高于野生型小鼠的趋势（13.4±6.1对9.8±4.4 μg/mg; p=0.13）。再灌注后14小时，MPO缺陷小鼠的硝基酪氨酸水平显着高于对照小鼠。 ...更多信息 在野生型小鼠中的at（3.3±2.9对1.4±0.4 μg/mg; p<0.05）。我们的结论是，MPO的缺乏增加了缺血性神经元损伤在体内，MPO介导的途径是不负责的硝化反应在脑缺血再灌注。此外，溶栓的好处已被广泛关注的讨论，但很少有人关注再灌注损伤。本项目的第二项研究的目的是评估大鼠永久性和短暂性局灶性缺血之间硝基酪氨酸形成和梗死体积的差异。永久性（n=14）或短暂性（n=12）局灶性缺血诱导永久性或2小时闭塞大脑中动脉，分别与永久性结扎双侧颈总动脉在Sprague-Dawley大鼠。在两种模型中，在开始闭塞后24小时处死所有动物。短暂性局灶性脑缺血组梗死灶周围区和梗死核心区硝基酪氨酸的比值明显高于永久性局灶性脑缺血组（P<0.01）。短暂性脑缺血时皮质的体积明显大于永久性脑缺血时（p<0.05），脑肿胀明显扩大。这些结果可能是由于再灌注引起的超氧化物和一氧化氮的产生增加所致，并提示在治疗急性缺血性脑损伤时有必要给予神经保护药物以及溶栓药物。少

Peroxynitrite has been shown to be responsible for nitration in vivo, while myeloperoxidase (MPO) can also catalyze protein nitration in the presence of high NO2- levels. Recent reports of MPO-mediated enzyme inactivation or lipid peroxidation have suggested a role of MPO in various pathological conditions. As the first study in this project, we measured nitrotyrosine formation and infarct volume in MPO-deficient or wild-type mice subjected to 2-hour focal cerebral ischemia-reperfusion, to clarify the role of MPO in ischemia brain injury. Twenty-four hours after reperfusion, infarct volume in MPO-deficient mice was significantly larger than that in the wild- type mice (81±20 mm3 vs. 52±13 mm3; p<0.01), and nitrotyrosine levels in the infarct region showed a tendency to be higher in the MPO-deficient mice than in the wild-type mice (13.4±6.1 vs. 9.8±4.4 μg/mg; p=0.13). At 14 hours after reperfusion, the nitrotyrosine level was significantly higher in MPO-deficient mice, compared with th … More at in the wild-type mice (3.3±2.9 vs. 1.4±0.4 μg/mg; p<0.05). We conclude that the absence of MPO increases ischemic neuronal damage in vivo, and the MPO-mediated pathway is not responsible for the nitration reaction in cerebral ischemia-reperfusion.Furthermore, widespread interest in the benefit of thrombolysis has been discussed, but little attention has been paid to reperfusion injury. The purpose of the second study in this project is to evaluate the difference in nitrotyrosine formation and infarct volume between permanent and transient focal ischemia in rats. Permanent (n=14) or transient (n=12) focal ischemia was induced by permanent or 2-hour occlusion of the middle cerebral artery, respectively, with the permanent ligation of the bilateral common carotid arteries in Sprague-Dawley rats. All animals were killed at 24-hour after the start of occlusion in both models. The ratio of nitrotyrosine in the pen-infarct and core-of-infarct regions in transient focal ischemia was significantly higher than in permanent focal ischemia (p<0.01). Infarct volume in cortex, in neither caudoputamen nor whole brain, was significantly larger in transient ischemia than in permanent ischemia (p<0.05), with significant expansion of brain swelling. These results may be caused by the higher production of superoxide and nitric oxide owing to reperfusion, and suggest the necessity to administer neuroprotective drugs as well as thrombolytic agents in the treatment of acute ischemic cerebral damage. Less