Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage.
Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage.
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DOI：
10.1038/jcbfm.2008.120
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发表时间：
2009-02
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蛛网膜下腔出血（SAH）由于血管痉挛和炎症引起继发性脑损伤。在这里，我们研究了轻中度SAH的大鼠模型，旨在尽量减少缺血/缺氧，以检查磺酰脲受体1（SUR 1）在SAH诱导的炎症反应中的作用。编码SUR 1的Abcc 8和SUR 1蛋白的mRNA在SAH邻近的皮质中大量上调，其中肿瘤坏死因子-α（TNFα）和核因子（NF）κB信号传导显著。体外实验证实TNFα可刺激Abcc 8的转录。为了研究SAH后SUR 1表达的功能后果，我们研究了强效选择性SUR 1抑制剂格列本脲的作用。我们检查了屏障通透性（免疫球蛋白G，IgG外渗），及其相关的紧密连接蛋白，封闭蛋白1（ZO-1）的定位。SAH导致屏障通透性大幅增加，破坏ZO-1的正常连接定位，格列本脲显著降低这两种作用。此外，SAH引起炎症标志物（包括TNFα和NFκB）和细胞损伤或细胞死亡标志物（包括IgG内吞作用和caspase-3激活）大幅增加，格列本脲可显著降低这些影响。我们的结论是，通过格列本脲阻断SUR 1可以改善SAH后导致皮质功能障碍的炎症相关的几种病理效应。
Subarachnoid hemorrhage (SAH) causes secondary brain injury due to vasospasm and inflammation. Here, we studied a rat model of mild-to-moderate SAH intended to minimize ischemia/hypoxia to examine the role of sulfonylurea receptor 1 (SUR1) in the inflammatory response induced by SAH. mRNA for Abcc8, which encodes SUR1, and SUR1 protein were abundantly upregulated in cortex adjacent to SAH, where tumor-necrosis factor-α (TNFα) and nuclear factor (NF)κB signaling were prominent. In vitro experiments confirmed that Abcc8 transcription is stimulated by TNFα. To investigate the functional consequences of SUR1 expression after SAH, we studied the effect of the potent, selective SUR1 inhibitor, glibenclamide. We examined barrier permeability (immunoglobulin G, IgG extravasation), and its correlate, the localization of the tight junction protein, zona occludens 1 (ZO-1). SAH caused a large increase in barrier permeability and disrupted the normal junctional localization of ZO-1, with glibenclamide significantly reducing both effects. In addition, SAH caused large increases in markers of inflammation, including TNFα and NFκB, and markers of cell injury or cell death, including IgG endocytosis and caspase-3 activation, with glibenclamide significantly reducing these effects. We conclude that block of SUR1 by glibenclamide may ameliorate several pathologic effects associated with inflammation that lead to cortical dysfunction after SAH.
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