Caspase-9 inhibition after focal cerebral ischemia improves outcome following reversible focal ischemia
Caspase-9 inhibition after focal cerebral ischemia improves outcome following reversible focal ischemia
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DOI：
10.1023/a:1019921904378
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发表时间：
2002-09-01
影响因子：
3.6
通讯作者：
Ratcheson, RA
中科院分区：
文献类型：
--
作者：
Mouw, G;Zechel, JL;Ratcheson, RA
脑缺血启动了一种称为细胞凋亡的细胞死亡程序。这些促死亡事件的早期步骤是从线粒体释放细胞色素c和激活caspase-9。本报告的目的是确定给予caspase-9特异性抑制剂Z-Leu-Glu(Ome)-His-Asp(Ome)-FMK.TFA(Z-Lehd-FMK)是否能减轻脑缺血后的细胞凋亡和由此引起的脑损伤。成年Wistar大鼠大脑中动脉暂时闭塞(MCAO)3h，再灌注2 4h。脑室内注射4.8杯Z-Lehd-FMK，灌流后15min。与对照组(n=12)相比，实验组(n=12)给予caspase-9抑制剂Z-Lehd-FMK后，总梗塞体积减少49%(p<；0.05)，神经预后改善63%(p<；0.01)。对接受缺血再灌注的动物进行的蛋白质印迹分析显示，caspase-9的活性形式出现。抑制caspase-9是细胞色素依赖性细胞凋亡的顶端caspase-9，是减轻局灶性脑缺血后神经损伤的有效干预措施。
Cerebral ischemia initiates a program of cell death known as apoptosis. Early steps in these death promoting events are the release of cytochrome c from the mitochondria and activation of caspase-9. The purpose of this report is to determine if the administration of a specific caspase-9 inhibitor, Z-Leu-Glu(Ome)-His-Asp(Ome)-FMK.TFA (Z-LEHD-FMK) would attenuate apoptosis and the resultant brain injury after ischemia. Adult Wistar rats underwent 3 h of temporary middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. An intraventricular injection of 4.8 mug of Z-LEHD-FMK was given 15-min postreperfusion. Administration of the caspase-9 inhibitor, Z-LEHD-FMK, to the experimental group (n = 12) reduced total infarction volume by 49% (p < 0.05) and improved neurological outcome by 63% (p < 0.01) as compared to the control group (n = 12). Western blot analysis of animals that underwent ischemia-reperfusion showed the appearance of the active form of caspase-9. Inhibition of caspase-9, the apical caspase in cytochrome-c-dependent apoptosis, is an effective intervention to attenuate neurological injury after focal ischemia.