Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents
Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents
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DOI：
10.1161/01.str.0000244808.17972.55
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发表时间：
2006-11-01
期刊：
影响因子：
8.3
通讯作者：
Tomimoto, Hidekazu
中科院分区：
文献类型：
--
作者：
Nakaji, Kayoko;Ihara, Masafumi;Tomimoto, Hidekazu
背景与目的：脑血管白质（WM）病变可导致老年人认知功能障碍和运动功能障碍。血脑屏障（BBB）的破坏被认为是导致这些WM病变的关键早期事件。先前的研究表明，在大鼠慢性脑灌注不足模型中，基质金属蛋白酶-2 （MMP-2）参与131313破坏和MMP-2的上调。在本研究中，我们询问MMP-2是否参与慢性脑灌注不足后血脑屏障的破坏和随后的WM病变。方法：我们比较了使用或不使用MMP抑制剂的大鼠慢性脑灌注不足后白质病变的严重程度。然后，我们也在野生型和mmp -2缺失小鼠中诱导慢性脑灌注不足。结果：相对选择性MMP-2抑制剂AG3340处理后，慢性脑灌注不足后WM病变的严重程度明显减轻，激活的星形胶质细胞和小胶质细胞数量也明显低于对照。基因敲除MMP-2也降低了WM病变的严重程度和小鼠系统中激活的星形胶质细胞和小胶质细胞的数量。在这两种啮齿动物中，通过IgM染色和Evans蓝色外渗试验评估，当MMP-2活性减弱时，血脑屏障功能的破坏程度较轻。结论-这些发现表明，MMP-2在慢性脑灌注不足后血脑屏障破坏、胶质细胞活化和WM病变中起关键作用，并提示MMP-2抑制剂作为脑血管WM病变治疗工具的潜在价值。
Background and Purpose-Cerebrovascular white matter (WM) lesions contribute to cognitive impairment and motor dysfunction in the elderly. A disruption of the blood-brain barrier (BBB) is believed to be a critical early event leading to these WM lesions. Previous studies have suggested the involvement of matrix metalloproteinase-2 (MMP-2) in 131313 disruptions and the upregulation of MMP-2 after chronic cerebral hypoperfusion in a rat model. In the present study, we asked whether MMP-2 is involved in the BBB disruption and the subsequent WM lesions after chronic cerebral hypoperfusion.Methods-We compared the severity of white matter lesions in rats after chronic cerebral hypoperfusion with or without an MMP inhibitor. Then, we also induced the chronic cerebral hypoperfusion in wild-type and MMP-2-null mice.Results-In the rats treated with a relatively selective MMP-2 inhibitor, AG3340, the WM lesions after chronic cerebral hypoperfusion were significantly less severe, and the number of activated astroglia and microglia were also significantly lower as compared with the vehicle-treated rats. Gene knockout of MMP-2 also reduced the severity of the WM lesions and the number of activated astroglia and microglia in a mice system. In both rodents, the disruption of BBB function, as assessed by IgM staining and the Evans blue extravasation test, was less severe when MMP-2 activity was attenuated.Conclusions-These findinas indicate that MMP-2 plays a critical role in the BBB disruption, glial cell activation, and WM lesions after chronic cerebral hypoperfusion and suggest the potential value of MMP-2 inhibitors as a therapeutic tool in cerebrovascular WM lesions.