Ebselen Reduces Cytochrome c Release From Mitochondria and Subsequent DNA Fragmentation After Transient Focal Cerebral Ischemia in Mice
Ebselen Reduces Cytochrome c Release From Mitochondria and Subsequent DNA Fragmentation After Transient Focal Cerebral Ischemia in Mice
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DOI：
10.1161/01.str.32.8.1906
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发表时间：
2001-08
期刊：
影响因子：
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通讯作者：
S. Namura;Izumi Nagata;S. Takami;H. Masayasu;H. Kikuchi
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文献类型：
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作者：
S. Namura;Izumi Nagata;S. Takami;H. Masayasu;H. Kikuchi
背景和目的-硒有机化合物依布硒啉具有抗氧化和抗炎特性。虽然依布硒啉已被证明可以保护大脑免受中风，但目前还不清楚依布硒啉是如何提供神经保护的。在本研究中，作者检测了依布硒啉是否抑制小鼠短暂局灶性脑缺血引起的神经元凋亡。细胞色素c的释放和DNA片段，这两者都是细胞凋亡的生化标志物，进行了比较之间的车辆和依布硒处理的小鼠。方法：在氟烷麻醉下，通过短暂性大脑中动脉闭塞30分钟诱导ICR小鼠脑缺血。依布硒啉（Ebselen，10 mg/kg）于缺血前30 min和再灌注后12 h口服2次。通过Western印迹分析，我们检测了线粒体细胞色素c的释放。为了评估脑损伤，对脑切片进行末端脱氧核苷酸转移酶介导的DNA缺口末端标记（TUNEL）和尼氏染色。通过在缺血后21天计数神经元核（NeuN）免疫阳性细胞来确定依布硒啉的延长的神经保护功效。结果：缺血后3 ~ 24小时，细胞色素c在缺血侧半球释放.依布硒啉处理减少了细胞色素c在12和24小时的释放。此外，依布硒啉减少缺血后3天TUNEL法测定的DNA片段和脑损伤体积。此外，ebselen增加缺血后21天NeuN免疫阳性细胞的数量。结论：这些结果表明依布硒啉通过抑制细胞色素c的释放来减弱缺血性神经元的凋亡。依布硒啉可能是一种潜在的脑卒中治疗药物。
Background and Purpose— The seleno-organic compound ebselen has both antioxidant and anti-inflammatory properties. Although ebselen has been shown to protect the brain against stroke, it is unclear how ebselen provides neuroprotection. In the present study the authors examined whether ebselen inhibits neuronal apoptosis resulting from transient focal cerebral ischemia in mice. The cytochrome c release and DNA fragmentation, both of which are biochemical markers of apoptosis, were compared between vehicle- and ebselen-treated mice. Methods— Cerebral ischemia was induced by transient middle cerebral artery occlusion for 30 minutes in ICR mice under halothane anesthesia. Ebselen (10 mg/kg) was given orally twice, 30 minutes before ischemia and 12 hours after reperfusion. By Western blot analysis, we examined release of mitochondrial cytochrome c. To evaluate brain damage, the brain sections were treated for terminal deoxynucleotidyl transferase–mediated DNA nick-end labeling (TUNEL) and Nissl staining. Prolonged neuroprotective efficacy of ebselen was determined by counting neuronal nuclei (NeuN) immunopositive cells at 21 days after ischemia. Results— Cytochrome c release was detected in the ischemic hemisphere at 3 to 24 hours after ischemia. Ebselen treatment diminished the cytochrome c release at 12 and 24 hours. In addition, ebselen decreased both DNA fragmentation determined by TUNEL and brain damage volume at 3 days after ischemia. Furthermore, ebselen increased the number of NeuN immunopositive cells at 21 days after ischemia. Conclusions— These results indicate that ebselen attenuates ischemic neuronal apoptosis by inhibiting cytochrome c release. Ebselen may be a potential compound in stroke therapy.