Asahi M, Asahi K, Jung J C, del Zoppo G J, Fini M E, Lo E H
Department of Neurology, Massachusetts General Hospital, and Harvard Medical School, Charlestown 02129, USA.
J Cereb Blood Flow Metab. 2000 Dec;20(12):1681-9. doi: 10.1097/00004647-200012000-00007.
It has been shown recently that matrix metalloproteinases (MMPs) are elevated after cerebral ischemia. In the current study, we investigated the pathophysiologic role for MMP-9 (gelatinase B, EC.3.4.24.35) in a mouse model of permanent focal cerebral ischemia, using a combination of genetic and pharmacologic approaches. Zymography and Western blot analysis demonstrated that MMP-9 protein levels were rapidly up-regulated in brain after ischemic onset. Reverse transcription polymerase chain reaction showed increased transcription of MMP-9. There were no differences in systemic hemodynamic parameters and gross cerebrovascular anatomy between wild type mice and mutant mice with a targeted knockout of the MMP-9 gene. After induction of focal ischemia, similar reductions in cerebral blood flow were obtained. In the MMP-9 knockout mice, ischemic lesion volumes were significantly reduced compared with wild type littermates in male and female mice. In normal wild type mice, the broad spectrum MMP inhibitor BB-94 (batimastat) also significantly reduced ischemic lesion size. However, BB-94 had no detectable protective effect when administered to MMP-9 knockout mice subjected to focal cerebral ischemia. These data demonstrate that MMP-9 plays a deleterious role in the development of brain injury after focal ischemia.
最近研究表明，脑缺血后基质金属蛋白酶（MMPs）水平会升高。在本研究中，我们采用基因和药理学相结合的方法，研究了MMP-9（明胶酶B，EC.3.4.24.35）在永久性局灶性脑缺血小鼠模型中的病理生理作用。酶谱分析和蛋白质印迹分析表明，缺血发作后大脑中MMP-9蛋白水平迅速上调。逆转录聚合酶链反应显示MMP-9转录增加。MMP-9基因靶向敲除的突变小鼠与野生型小鼠之间，全身血流动力学参数和大体脑血管解剖结构并无差异。局灶性缺血诱导后，二者脑血流量的减少情况相似。在雄性和雌性小鼠中，与野生型同窝小鼠相比，MMP-9基因敲除小鼠的缺血性损伤体积显著减小。在正常野生型小鼠中，广谱MMP抑制剂BB-94（batimastat）也能显著减小缺血性损伤大小。然而，给局灶性脑缺血的MMP-9基因敲除小鼠施用BB-94时，未检测到其具有保护作用。这些数据表明，MMP-9在局灶性缺血后脑损伤的发展中起有害作用。
