Machado Livia S, Kozak Anna, Ergul Adviye, Hess David C, Borlongan Cesario V, Fagan Susan C
Program in Clinical and Experimental Therapeutics, Clinical Pharmacy Department, College of Pharmacy, University of Georgia, Augusta, GA, USA.
BMC Neurosci. 2006 Jul 17;7:56. doi: 10.1186/1471-2202-7-56.
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 mug/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.
在大鼠实验性缺血性卒中后，脑内基质金属蛋白酶2和9（MMP - 2和MMP - 9）水平升高。这两种蛋白酶参与基底膜的降解以及缺血后血脑屏障稳定性的丧失，且与缺血性卒中的溶栓治疗有关。米诺环素是一种亲脂性四环素，在多种脑损伤模型中具有神经保护作用。米诺环素可抑制炎症、细胞凋亡和细胞外基质降解。在本研究中，我们调查了在Wistar大鼠短暂性闭塞模型中，延迟给予米诺环素是否能抑制由缺血激活的脑MMPs。
在闭塞3小时和存活21小时后，与对侧半球相比，缺血组织中的MMP - 2和MMP - 9均升高（MMP - 9，p < 0.0001）。每天两次腹腔注射浓度为45 mg/kg的米诺环素（首次剂量在再灌注开始后立即给予）可显著降低缺血升高的MMP - 2和MMP - 9的明胶酶活性（p < 0.0003）。治疗还降低了这两种酶的蛋白浓度（MMP - 9，p < 0.038；MMP - 2，p < 0.018）。米诺环素在低至0.1μg/ml的浓度下与重组MMP - 2和MMP - 9进行体外孵育会损害酶活性，且MMP - 9在较低米诺环素浓度下更敏感（p < 0.05）。
米诺环素可抑制实验性卒中后由缺血激活的明胶蛋白酶的酶活性，且在低剂量时可能对MMP - 9具有选择性。米诺环素是急性治疗缺血性卒中的一种潜在新型治疗药物。
