Delayed matrix metalloproteinase inhibition reduces intracerebral hemorrhage after embolic stroke in rats

被引:48
作者
Copin, Jean-Christophe [1 ,2 ]
Merlani, Paolo [1 ]
Sugawara, Taku [3 ]
Chan, Pak H. [4 ,5 ,6 ]
Gasche, Yvan [1 ,2 ]
机构
[1] Univ Geneva, Ctr Med, Dept Anesthesiol Pharmacol & Intens Care, CH-1211 Geneva, Switzerland
[2] Univ Geneva, Geneva Neurosci Ctr, CH-1211 Geneva, Switzerland
[3] Akita Univ, Sch Med, Dept Neurosurg, Akita 0108543, Japan
[4] Stanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USA
[5] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA
[6] Stanford Univ, Sch Med, Program Neurosci, Stanford, CA 94305 USA
基金
瑞士国家科学基金会; 美国国家卫生研究院;
关键词
blood-brain barrier; ischemia; matrix metalloproteinase; tissue plasminogen activator; thrombolysis;
D O I
10.1016/j.expneurol.2008.05.022
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Hemorrhagic transformation (HT) and brain edema are life-threatening complications of recombinant tissue plasminogen activator (rt-PA)-induced reperfusion after ischemic stroke. The risk of HT limits the therapeutic window for reperfusion to 3 It after stroke onset. Pre-treatment with matrix metalloproteinase (MMP) inhibitors reduces HT and cerebral edema in experimental stroke. However, whether a delayed therapeutic intervention Would be beneficial is unknown, In this study, 215 male Sprague-Dawley rats were Subjected to embolic stroke and 75 rats were included in the final analysis. The animals were treated with the MMP inhibitor p-aminobenzoyl-gly-Pro-D-leu-D-ala-hydroxamate before or after 3 or 6 h of ischemia. Animals were monitored for reperfusion and received rt-PA 6 h after ischemia onset. The results at 24 h showed that MMP inhibition 3 It after ischemia significantly decreased the degree of brain edema (17% of hemispheric enlargement in the treated group versus 24% in controls, P=0.018), reduced the risk (OR=0.163; 95% CI: 0.029 to 0.953) and gravity (0.09 versus 0.19 mg of parenchymal hemoglobin, P=0.02) of intracerebral hemorrhage, and improved neurological outcome (20% of the treated animals had a slight deficit: all of the controls had a bad outcome, P < 0.05). Delaying MMP inhibition to 6 h after ischemia restricted the beneficial role of the treatment to a reduction in the risk of parenchymal hemorrhage (OR=0.242: 95% CI: 0.060 to 0.989). Our results confirm the involvement of MMPs in HT and Support the possibility of extending the therapeutic Window for thrombolysis in stroke by administering a broad-spectrum MMP inhibitor after the onset of ischemia. (C) 2008 Elsevier Inc. All rights reserved.
引用
收藏
页码:196 / 201
页数:6
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