17β-Estradiol attenuates blood-brain barrier disruption induced by cerebral ischemia-reperfusion injury in female
17β-Estradiol attenuates blood-brain barrier disruption induced by cerebral ischemia-reperfusion injury in female
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DOI：
10.1016/j.brainres.2005.08.048
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发表时间：
2005-10-26
期刊：
影响因子：
2.9
通讯作者：
Yang, SH
中科院分区：
文献类型：
--
作者：
Liu, R;Wen, Y;Yang, SH
基质金属蛋白酶（matrix metalloproteinases，MMPs）介导的血脑屏障（blood-brain barrier，BBB）的破坏是脑缺血的重要环节。虽然雌激素的神经保护作用已经在缺血性中风模型中得到很好的证实，但雌激素对血脑屏障完整性的影响仍有待阐明。在本研究中，我们确定了17 β-雌二醇（E2）对短暂局灶性脑缺血引起的血脑屏障破坏的影响及其对MMP 2和MMP 9活化的影响。结扎双侧大脑中动脉（MCA）1h，再灌注，造成大鼠短暂性脑缺血。在MCA闭塞前2小时给予E2（100 μ g/kg）或溶媒。通过荧光检测外渗的伊文思蓝来确定血脑屏障的完整性。在单独的实验中，通过免疫印迹和MMPs活性测定来确定E2对MMP 2和MMP 9表达和活化的影响。再灌注后4 h，E2治疗分别阻止了缺血皮质和皮质下超过50%和30%的BBB破坏。MMP 2和MMP 9表达在再灌注后2 h升高，4 h达高峰，E2治疗后明显降低。E2处理还减弱了缺血再灌注损伤引起的MMPs活性的增加。结论：雌激素可通过抑制MMP 2和MMP 9的活化，减轻短暂性脑缺血引起的血脑屏障破坏。我们的结果表明雌激素作为针对缺血性中风的多靶向保护剂对中枢神经系统的细胞和血管成分具有重要作用。(c)2005 Elsevier B. V.保留所有权利。
Disruption of blood-brain barrier (BBB), mediated through matrix metalloproteinases (MMPs), is a critical event during cerebral ischemia. While neuroprotective effects of estrogens have been well established in ischemic stroke models, the effects of estrogens on BBB integrity remain to be elucidated. In the present study, we determined effects of 17 beta-estradiol (E2) on BBB disruption induced by transient focal cerebral ischemia and its effects on MMP2 and MMP9 activation. Transient cerebral ischemia was induced by middle cerebral artery (MCA) occlusion for 1 h followed by reperfusion in ovariectomized rats. E2 (100 mu g/kg) or vehicle was administered 2 h before MCA occlusion. BBB integrity was determined by fluorescent detection of extravasated Evans blue. In separate experiments, effect of E2 on MMP2 and MMP9 expression and activation was determined by immunoblot and MMPs activity assay. E2 treatment prevented more than 50% and 30% of BBB disruption in the ischemic cortex and subcortex at 4 h after reperfusion, respectively. MMP2 and MMP9 expression was elevated at 2 h and peaked at 4 h after reperfusion in the ischemic cortex, which was markedly reduced by E2 treatment. E2 treatment also attenuated the increase of MMPs activity induced by ischemia-reperfusion injury. In conclusion, estrogens could attenuate BBB disruption induced by transient cerebral ischemia, by inhibition of MMP2 and MMP9 activation. Our results suggest an important role of estrogens as multiple targeting protectants against ischemic stroke on cellular as well as vascular components of central nervous system. (c) 2005 Elsevier B.V. All rights reserved.