Progesterone and allopregnanolone attenuate blood-brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases.
Progesterone and allopregnanolone attenuate blood-brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases.
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DOI：
10.1016/j.expneurol.2010.08.023
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发表时间：
2010-11
影响因子：
5.3
通讯作者：
Stein, Donald G.
中科院分区：
文献类型：
--
作者：
Ishrat, Tauheed;Sayeed, Iqbal;Atif, Fahim;Hua, Fang;Stein, Donald G.
关键词：
中风后血脑屏障(BBB)的破坏与金属蛋白酶(MMPs)的上调和炎症有关。本研究旨在探讨孕酮(Prog)及其神经活性代谢物别孕酮(Allo)对永久性大脑中动脉闭塞(PMCAO)后血脑屏障完整性的影响。采用电凝法制作大鼠pMCAO模型，分别于结扎后1h腹腔注射Prog(8 mg/kg)、Allo(8 mg/kg)或赋形剂，再于术后6、24、48h皮下注射Prog(8 mg/kg)，用Western印迹、免疫组织化学和明胶酶谱检测大鼠pMCAO后72h的基质金属蛋白酶的活性和表达。免疫印迹法检测缺血后72h脑组织中Occludin 1、Claudin5、肿瘤坏死因子-α(TN-α)、白介素6(IL-6)的表达。72 h后用Evans蓝渗出法测定血脑屏障通透性，甲酚紫法测定脑梗塞面积。缺血损伤显著增加MMP9、MMP2、α和IL-6的表达，降低occludin 1和claudin5的水平。随之而来的是梗塞面积增大(对侧大脑半球百分比)和伊文思蓝渗入脑内，表明血脑屏障受损。Prog和Allo通过减少MMPs和炎症反应，并通过阻止occludin 1和claudin5的降解来减轻pMCAO后血脑屏障的破坏和梗塞范围。我们的结论是，Prog和Allo可以帮助保护pMCAO后的血脑屏障破坏。
Blood-brain barrier (BBB) breakdown after stroke is linked to the up-regulation of metalloproteinases (MMPs) and inflammation. This study examines the effects of progesterone (PROG) and its neuroactive metabolite allopregnanolone (ALLO) on BBB integrity following permanent middle cerebral artery occlusion (pMCAO). Rats underwent pMCAO by electro-coagulation and received intraperitoneal injections of PROG (8 mg/kg), ALLO (8 mg/kg) or vehicle at 1 h post-occlusion and then subcutaneous injections (8 mg/kg) at 6, 24, and 48 h. MMP activation and expression were analyzed by Western blot, immunohistochemistry and gelatin zymography 72 h post-pMCAO. Occludin1, claudin5, tumor necrosis factor-alpha (TNF-α) and Interleukin-6 (IL-6) were analyzed at 72 h post-pMCAO with Western blots. BBB permeability was measured by Evans blue extravasation and infarct size was evaluated by cresyl violet at 72 h after pMCAO. Ischemic injury significantly (p<0.05) increased the expression of MMP-9, MMP-2, TNF-α and IL-6, and reduced the level of occludin1 and claudin5. These changes were followed by increased infarct size (% contralateral hemisphere) and Evans blue extravasation into the brain indicating compromise of the BBB. PROG and ALLO attenuated BBB disruption and infarct size following pMCAO by reducing MMPs and the inflammatory response and by preventing the degradation of occludin1 and claudin5. We conclude that PROG and ALLO can help to protect BBB disruption following pMCAO.
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影响因子：
2.9
作者：
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通讯作者：
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DOI：
10.1073/pnas.0808698106
发表时间：
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影响因子：
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