Cheon So Yeong, Kim So Yeon, Kam Eun Hee, Lee Jae Hoon, Kim Jeong Min, Kim Eun Jung, Kim Tae Whan, Koo Bon-Nyeo
Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
Int J Med Sci. 2017 Apr 8;14(5):425-433. doi: 10.7150/ijms.18037. eCollection 2017.
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 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.
组织型纤溶酶原激活剂（tPA）是缺血性中风的唯一治疗方法。然而，tPA可诱发颅内出血（ICH），这是tPA治疗后缺血性中风患者死亡的主要原因。目前，尚无改善缺血后tPA诱导的脑损伤的治疗策略。因此，我们研究了预先使用异氟醚的效果，异氟醚是一种挥发性麻醉剂，对缺血性中风模型中的神经功能障碍、脑水肿和梗死体积具有有益作用。在本研究中，我们使用氧/葡萄糖剥夺和再灌注（OGD/R）条件来模拟缺血性中风。在内皮细胞培养基中测量基质金属蛋白酶（MMP）活性。此外，进行神经元细胞培养以研究预先使用异氟醚对OGD/R期间tPA诱导损伤后神经元细胞存活的影响。异氟醚预处理可预防tPA诱导的MMP-2和MMP-9活性，并在OGD/R后抑制tPA触发的LRP/NF-κB/Cox-2信号传导。在tPA + OGD/R后与内皮细胞条件培养基（EC-CM）孵育的神经元细胞显示促凋亡分子上调。然而，与异氟醚预处理的EC-CM孵育的神经元显示抗凋亡分子增加。我们的研究结果表明，异氟醚预处理可减轻tPA加剧的脑缺血损伤，其机制是通过减少内皮细胞中tPA诱导的LRP/NF-κB/Cox-2、内皮MMP-2和MMP-9激活，以及OGD/R后神经元中随后的促凋亡分子。
