Brain regional and cellular localization of gelatinase activity in rat that have undergone transient middle cerebral artery occlusion
Brain regional and cellular localization of gelatinase activity in rat that have undergone transient middle cerebral artery occlusion
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DOI：
10.1016/j.neuroscience.2007.12.030
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发表时间：
2008-03-03
期刊：
影响因子：
3.3
通讯作者：
Bagetta, G.
中科院分区：
文献类型：
--
作者：
Amantea, D.;Corasaniti, M. T.;Bagetta, G.
基质金属蛋白酶（MMPs）参与了缺血性卒中的病理生理过程。特别地，明胶酶MMP-2和MMP-9促进血脑屏障的破坏和缺血性损伤后的出血性转化。除了细胞外基质降解外，MMPs还可以通过尚未完全理解的机制直接调节神经元细胞死亡。在这里，我们描述了激活的MMP-2和MMP-9在大脑中动脉闭塞（MCAo）2小时，然后再灌注不同时间（15分钟，2小时，6小时和22小时）的大鼠脑中的时空分布。通过原位酶谱分析，我们观察到明胶酶在缺血核心区和缺血半暗区分别在再灌注开始后15 min和2 h被激活，原位酶谱信号与NeuN阳性细胞广泛共定位，从而表明蛋白水解主要发生在神经元中。明胶溶解活性主要在细胞核中检测到，仅在损伤后的后期阶段在胞质溶胶中少量出现;我们没有检测到细胞外基质中明胶溶解的变化。最后，我们报告了N-[（2 R）-2-（羟氨基羰基-甲基）-L-甲基戊酰基]-L-色氨酸甲酰胺（GM 6001）对MMPs的药理学抑制显著减少了由短暂MCAo诱导的脑梗死体积。综上所述，我们的数据强调了明胶酶在再灌注早期阶段的关键作用，并进一步扩展了以前的观察记录这些酶在脑缺血的病理生理学中的有害作用。(C)2008年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Matrix metalloproteinases (MMPs) have been implicated in the pathophysiology of ischemic stroke. In particular, the gelatinases MMP-2 and MMP-9 contribute to disruption of the blood-brain barrier and hemorrhagic transformation following ischemic injury. In addition to extracellular matrix degradation, MMPs may directly regulate neuronal cell death through mechanisms that are not completely understood. Here we describe the spatio-temporal distribution of activated MMP-2 and MMP-9 in the brain of rats subjected to 2 h middle cerebral artery occlusion (MCAo) followed by different periods of reperfusion (15 min, 2 h, 6 h and 22 h). By in situ zymography we have observed that gelatinases become activated 15 min and 2 h after the beginning of reperfusion in the ischemic core and penumbra, respectively.In situ zymography signal broadly co-localized with NeuN-positive cells, thus suggesting that proteolysis mainly occurs in neurons. Gelatinolytic activity was mainly detected in cell nuclei, marginally appearing in the cytosol only at later stages following the insult; we did not detect variations in gelatinolysis in the extracellular matrix. Finally, we report that pharmacological inhibition of MMPs by N-[(2R)-2-(hydroxamidocarbonyl-methyl)-L-methylpenthanoyi]-L-tryptophan methylamide (GM6001) significantly reduces brain infarct volume induced by transient MCAo. Taken together our data underscore the crucial role of gelatinases during the early stages of reperfusion and further extend previous observations documenting the detrimental role of these enzymes in the pathophysiology of brain ischemia. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.