Attenuation of transient focal cerebral ischemic injury in transgenic mice expressing a mutant ICE inhibitory protein
Attenuation of transient focal cerebral ischemic injury in transgenic mice expressing a mutant ICE inhibitory protein
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DOI：
10.1097/00004647-199704000-00002
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发表时间：
1997-04-01
影响因子：
6.3
通讯作者：
Moskowitz, MA
中科院分区：
文献类型：
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作者：
Hara, H;Fink, K;Moskowitz, MA
我们利用表达白介素1β转换酶(ICE)显性负突变(C285G)的转基因小鼠建立短暂性局灶性脑缺血模型，以探讨ICE在缺血性脑损伤中的作用。转基因突变ICE小鼠(n=11)和野生型小鼠(n=9)行大脑中动脉闭塞3h，再灌注24h。脑梗塞和脑肿胀分别减少44%和46%。神经功能缺陷也显著减少。当测量再灌注后1小时时，局部脑血流量、血压、核心体温和心率在不同组之间没有差异。在排斥融合后30分钟，在缺血野生型脑中观察到的免疫反应性IL-1β水平在突变株中降低了77%，表明突变体中Proll-1β的切割受到抑制。再灌流后6h和2 4h，突变型DNA断裂明显减少。因此，内源性表达ICE抑制物可抵抗脑缺血和脑肿胀。我们的结果表明，下调ICE的表达可能为脑缺血提供一个有用的治疗靶点。
We used transgenic mice expressing a dominant negative mutation of interleukin-1 beta converting enzyme (ICE) (C285G) in a model of transient focal ischemia in order to investigate the role of ICE in ischemic brain damage. Transgenic mutant ICE mice (n = 11) and wild-type littermates (n = 9) were subjected to 3 h of middle cerebral artery occlusion followed by 24 h of reperfusion. Cerebral infarcts and brain swelling were reduced by 44% and 46%, respectively. Neurological deficits were also significantly reduced. Regional CBF, blood pressure, core temperature, and heart rate did not differ between groups when measured for up to 1 h after reperfusion. Increases in immunoreactive IL-1 beta levels, observed in ischemic wild-type brain at 30 min after repel-fusion, were 77% lower in the mutant strain, indicating that proLL-1 beta cleavage is inhibited in the mutants. DNA fragmentation was reduced in the mutants 6 and 24 h after reperfusion. Hence, endogenous expression of an ICE inhibitor confers resistance to cerebral ischemia and brain swelling. Our results indicate that downregulation of ICE expression might provide a useful therapeutic target in cerebral ischemia.