Int J Med Sci 2017; 14(5):425-433. doi:10.7150/ijms.18037
Isoflurane preconditioning inhibits the effects of tissue-type plasminogen activator on brain endothelial cell in an in vitro model of ischemic stroke
1. Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea;
2. Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
* These authors contributed equally to this work.
Cheon SY, Kim SY, Kam EH, Lee JH, Kim JM, Kim EJ, Kim TW, Koo BN. Isoflurane preconditioning inhibits the effects of tissue-type plasminogen activator on brain endothelial cell in an in vitro model of ischemic stroke. Int J Med Sci 2017; 14(5):425-433. doi:10.7150/ijms.18037. Available from http://www.medsci.org/v14p0425.htm
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.
Keywords: Tissue-type plasminogen activator, isoflurane, oxygen/glucose deprivation, endothelial cell, matrix metalloproteinase, neuronal cell.