Isoflurane preconditioning inhibits the effects of tissue-type plasminogen activator on brain endothelial cell in an in vitro model of ischemic stroke.
Isoflurane preconditioning inhibits the effects of tissue-type plasminogen activator on brain endothelial cell in an in vitro model of ischemic stroke.
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DOI：
10.7150/ijms.18037
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发表时间：
2017
影响因子：
3.6
通讯作者：
Koo BN
中科院分区：
文献类型：
--
作者：
Cheon SY;Kim SY;Kam EH;Lee JH;Kim JM;Kim EJ;Kim TW;Koo BN
组织型纤溶酶原激活剂（tPA）是治疗缺血性卒中的唯一方法。然而，tPA可引起颅内出血，这是缺血性脑卒中患者接受tPA治疗后死亡的主要原因。目前，没有治疗策略来改善缺血后tPA诱导的脑损伤。因此，我们研究了预处理异氟烷的作用，异氟烷是一种挥发性麻醉剂，对缺血性卒中模型中的神经功能障碍、脑水肿和梗死体积具有有益作用。在这项研究中，我们使用氧/葡萄糖剥夺和再灌注（OGD/R）条件下，模拟缺血性中风在体外。在内皮细胞培养基中测定基质金属蛋白酶（MMP）活性。此外，进行神经元细胞培养以研究预处理的异氟烷对在OGD/R期间tPA诱导的损伤后的神经元细胞存活的影响。异氟醚预处理可抑制tPA诱导的MMP-2和MMP-9活性，并抑制OGD/R后tPA触发的LRP/NF-κB/考克斯-2信号通路。在tPA + OGD/R后，用内皮细胞条件培养基（EC-CM）孵育的神经细胞显示促凋亡分子的上调。然而，与异氟烷预处理的EC-CM孵育的神经元显示增加的抗凋亡分子。我们的研究结果表明，异氟醚预处理可以减轻tPA加重的脑缺血损伤，通过减少tPA诱导的内皮细胞LRP/NF-κB/考克斯-2，内皮细胞MMP-2和MMP-9的激活，以及随后的促凋亡分子在OGD/R后。
Tissue-type plasminogen activator (tPA) is the only treatment for ischemic stroke. However, tPA could induce the intracranial hemorrhage (ICH), which is the main cause of death in ischemic stroke patient after tPA treatment. At present, there is no treatment strategy to ameliorate tPA-induced brain injury after ischemia. Therefore, we investigated the effect of pre-treated isoflurane, which is a volatile anesthetic and has beneficial effects on neurological dysfunction, brain edema and infarct volume in ischemic stroke model. In this study, we used oxygen/glucose deprivation and reperfusion (OGD/R) condition to mimic an ischemic stroke in vitro. Matrix metalloproteinases (MMP) activity was measured in endothelial cell media. Also, neuronal cell culture was performed to investigate the effect of pretreated isoflurane on the neuronal cell survival after tPA-induced injury during OGD/R. Isoflurane pretreatment prevented tPA-induced MMP-2 and MMP-9 activity and suppressed tPA-triggered LRP/NF-κB/Cox-2 signaling after OGD/R. Neuronal cells, incubated with endothelial cell conditioned medium (EC-CM) after tPA + OGD/R, showed upregulation of pro-apoptotic molecules. However, neurons incubated with isoflurane-pretreated EC-CM showed increased anti-apoptotic molecules. Our findings suggest that isoflurane pretreatment could attenuate tPA-exaggerated brain ischemic injury, by reducing tPA-induced LRP/NF-κB/Cox-2 in endothelial cells, endothelial MMP-2 and MMP-9 activation, and subsequent pro-apoptotic molecule in neurons after OGD/R.