Relative Importance of Proteinase-Activated Receptor-1 Versus Matrix Metalloproteinases in Intracerebral Hemorrhage-Mediated Neurotoxicity in Mice
Relative Importance of Proteinase-Activated Receptor-1 Versus Matrix Metalloproteinases in Intracerebral Hemorrhage-Mediated Neurotoxicity in Mice
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DOI：
10.1161/strokeaha.108.540393
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发表时间：
2009-06-01
期刊：
影响因子：
8.3
通讯作者：
Yong, V. Wee
中科院分区：
文献类型：
--
作者：
Xue, Mengzhou;Hollenberg, Morley D.;Yong, V. Wee
背景与目的——为了减少脑出血时的出血和中枢神经系统组织的损伤，凝血酶的凝血作用至关重要。然而，凝血酶本身可以杀死脑出血中的神经元，基质金属蛋白酶 (MMP) 也可以杀死神经元，在这种情况下，基质金属蛋白酶 (MMP) 也会升高，部分原因是凝血酶介导的 MMP 激活。因此，了解和阻断凝血酶的神经毒性作用而不抑制其治疗效果非常重要。在这项研究中，我们研究了蛋白酶激活受体1（一种凝血酶受体）和MMP在凝血酶或血液引起的脑损伤中的相对作用。方法-对小鼠进行立体定向脑内注射盐水、凝血酶和自体血液，有或没有水蛭素（一种凝血酶抑制剂）或GM6001（一种MMP抑制剂）。二十四小时后，获得组织切片来评估脑损伤的面积和死亡神经元的程度。将野生型小鼠的数据与蛋白酶激活受体 1 缺失小鼠获得的结果进行比较。结果 - 在血液引起的脑实质损伤中，水蛭素和 GM6001 均显着减少损伤至相当程度 (>40%)，这表明凝血酶和 MMP 均具有神经毒性。在蛋白酶激活受体1缺失小鼠中，与野生型动物相比，血液引起的脑损伤减少了22.6%；相比之下，GM6001使血液引起的脑损伤减少了48.3%。结论——脑出血中血液的神经毒性涉及蛋白酶激活受体1和MMP激活，其中后者在导致死亡方面更为突出。 （中风。2009；40：2199-2204。）
Background and Purpose-To reduce bleeding and damage to central nervous system tissue in intracerebral hemorrhage, the coagulant effect of thrombin is essential. However, thrombin itself can kill neurons in intracerebral hemorrhage as can the matrix metalloproteinases (MMPs), which are also elevated in this condition, in part due to thrombin-mediated activation of MMPs. It is thus important to understand and block the neurotoxic effects of thrombin without inhibiting its therapeutic outcomes. In this study, we have investigated the relative roles of proteinase activated receptor-1, a thrombin receptor, and MMPs in brain injury induced by thrombin or blood.Methods-Mice were subjected to stereotactic intracerebral injections of saline, thrombin, and autologous blood, with or without hirudin, a thrombin inhibitor, or GM6001, an MMP inhibitor. Twenty-four hours later, tissue sections were obtained to evaluate the area of brain damage and extent of dying neurons. Data from wild-type mice were compared with results obtained with proteinase activated receptor-1 null mice.Results-In blood-induced damage to the brain parenchyma, both hirudin and GM6001 significantly reduced injury to a comparable extent (>40%) implicating both thrombin and MMPs in neurotoxicity. In proteinase activated receptor-1 null mice, blood-induced brain damage was reduced by 22.6% relative to wild-type animals; by comparison, the blood-induced brain damage was reduced by 48.3% using GM6001.Conclusions-The neurotoxicity of blood in intracerebral hemorrhage involves both proteinase activated receptor-1 and MMP activation, with the latter appearing more prominent in causing death. (Stroke. 2009; 40: 2199-2204.)