Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke.
Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke.
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DOI：
10.1186/1471-2202-7-56
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发表时间：
2006-07-17
期刊：
影响因子：
2.4
通讯作者：
Fagan SC
中科院分区：
文献类型：
--
作者：
Machado LS;Kozak A;Ergul A;Hess DC;Borlongan CV;Fagan SC
大鼠实验性缺血性脑卒中后脑内基质金属蛋白酶2和9（MMP-2和MMP-9）表达增加。这两种蛋白酶与缺血后发生的基底层降解和血脑屏障稳定性丧失有关，并且与缺血性卒中中的溶栓治疗有关。米诺环素是一种亲脂性四环素，在几种脑损伤模型中具有神经保护作用。米诺环素抑制炎症、细胞凋亡和细胞外基质降解。在这项研究中，我们调查是否延迟米诺环素抑制脑MMPs激活缺血模型暂时闭塞在Wistar大鼠。在闭塞3小时和存活21小时后，与对侧半球相比，MMP-2和MMP-9在缺血组织中均升高（对于MMP-9，p < 0.0001）。腹膜内米诺环素以45 mg/kg浓度每天两次（在再灌注开始后立即第一次剂量）显著降低缺血升高的MMP-2和MMP-9的明胶分解活性（p < 0.0003）。处理还降低了两种酶的蛋白质浓度（对于MMP-9，p < 0.038;对于MMP-2，p < 0.018）。在体外孵育浓度低至0.1 μg/ml的米诺环素与重组MMP-2和MMP-9的酶活性受损，MMP-9在较低的米诺环素浓度下更敏感（p < 0.05）。米诺环素抑制实验性中风后缺血激活的明胶蛋白酶的酶活性，并且在低剂量下可能对MMP-9具有选择性。米诺环素是一种潜在的治疗缺血性脑卒中的新药物。
Matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) are increased in the brain after experimental ischemic stroke in rats. These two proteases are involved with the degradation of the basal lamina and loss of stability of the blood brain barrier that occurs after ischemia and that is associated with thrombolytic therapy in ischemic stroke. Minocycline is a lipophilic tetracycline and is neuroprotective in several models of brain injury. Minocycline inhibits inflammation, apoptosis and extracellular matrix degradation. In this study we investigated whether delayed minocycline inhibits brain MMPs activated by ischemia in a model of temporary occlusion in Wistar rats. Both MMP-2 and MMP-9 were elevated in the ischemic tissue as compared to the contra-lateral hemisphere after 3 hours occlusion and 21 hours survival (p < 0.0001 for MMP-9). Intraperitoneal minocycline at 45 mg/kg concentration twice a day (first dose immediately after the onset of reperfusion) significantly reduced gelatinolytic activity of ischemia-elevated MMP-2 and MMP-9 (p < 0.0003). Treatment also reduced protein concentration of both enzymes (p < 0.038 for MMP-9 and p < 0.018 for MMP-2). In vitro incubation of minocycline in concentrations as low as 0.1 μg/ml with recombinant MMP-2 and MMP-9 impaired enzymatic activity and MMP-9 was more sensitive at lower minocycline concentrations (p < 0.05). Minocycline inhibits enzymatic activity of gelatin proteases activated by ischemia after experimental stroke and is likely to be selective for MMP-9 at low doses. Minocycline is a potential new therapeutic agent to acute treatment of ischemic stroke.
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DOI：
10.1097/00004647-199906000-00005
发表时间：
1999-06-01
影响因子：
6.3
作者：
Heo, JH;Lucero, J;del Zoppo, GJ
通讯作者：
del Zoppo, GJ
影响因子：
8.3
作者：
BEDERSON, JB;PITTS, LH;BARTKOWSKI, H
通讯作者：
BARTKOWSKI, H
影响因子：
8.3
作者：
HAMANN, GF;OKADA, Y;DELZOPPO, GJ
通讯作者：
DELZOPPO, GJ
影响因子：
8.3
作者：
Lo, EH;Broderick, JP;Moskowitz, MA
通讯作者：
Moskowitz, MA
影响因子：
8.3
作者：
Pfefferkorn, T;Rosenberg, GA
通讯作者：
Rosenberg, GA