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目的观察选择性一氧化氮合酶抑制剂氨基胍(AG)保护大鼠缺血性脑损伤的可能机制。方法采用线栓法复制大鼠大脑中动脉梗塞模型,缺血后2,6或12 h开始给予AG(100 m.gkg-1,ip,每天2次,给药3 d)治疗。测定脑梗死体积,脑线粒体肿胀度和呼吸链的完整性,脑线粒体内NO和丙二醛(MDA)含量,总ATP酶、超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)活性;培养大鼠神经元细胞,观察AG(10,20和100μmo.lL-1)对神经元细胞形态、活力及乳酸脱氢酶(LDH)释放和NO含量的影响。结果AG显著降低脑缺血后脑梗死体积,改善缺血后神经元超微结构变化,减轻脑线粒体肿胀度和呼吸链损伤;降低NO和MDA含量,增加总ATP酶、SOD和GSH-Px活性。AG使体外培养的缺血神经细胞损伤程度明显减轻,NO含量降低,LDH释放减少,细胞活力增加。结论AG可能通过抑制氧自由基生成,增加线粒体抗氧化作用,改善线粒体能量代谢和保护线粒体形态与功能的完整而对大鼠脑缺血损伤产生保护作用。
Objective To investigate the possible mechanism of aminoguanidine (AG), a selective inhibitor of nitric oxide synthase, in protection of ischemic brain injury in rats. Methods The rat model of middle cerebral artery occlusion was established by thread occlusion. AG (100 m.gkg -1, ip, twice a day for 3 days) was given at 2, 6 or 12 hours after ischemia. The volume of cerebral infarction, the degree of mitochondria swelling and the integrity of the respiratory chain, the content of NO and malondialdehyde (MDA), the content of total ATPase, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Cultured rat neurons were cultured and the effects of AG (10, 20 and 100μmo.lL-1) on neuronal morphology, vitality and lactate dehydrogenase (LDH) release and NO content were observed. Results AG significantly decreased the volume of cerebral infarction after cerebral ischemia, ameliorated the ultrastructural changes of neurons after ischemia, mitigated the mitochondrial swelling and respiratory chain injury, reduced the contents of NO and MDA and increased the activities of total ATPase, SOD and GSH-Px. AG significantly reduced the extent of ischemia-induced neuronal injury in vitro, decreased NO content, decreased LDH release, and increased cell viability. Conclusion AG may protect rat against cerebral ischemia by inhibiting the production of oxygen free radicals, increasing mitochondrial antioxidant activity, improving mitochondrial energy metabolism and protecting the integrity of mitochondrial morphology and function.