Department of Brain Ischemia and Neurodegeneration, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona E-08036, Spain.
J Cereb Blood Flow Metab. 2010 Mar;30(3):638-52. doi: 10.1038/jcbfm.2009.237. Epub 2009 Nov 11.
Oxidative and nitrosative stress are targets for intervention after ischemia/reperfusion. The aim of this study was to explore the effect of CR-6, a vitamin-E analogue that is antioxidant and scavenger of nitrogen-reactive species. Sprague-Dawley rats had the middle cerebral artery (MCA) occluded either for 90 mins or permanently. Cortical perfusion was continuously monitored by laser-Doppler flowmetry. CR-6 (100 mg/kg) was administered orally either at 2 and 8 h after MCA occlusion, or at 2 h only. Infarct volume, neurological deficit, and signs of reperfusion injury were evaluated. CR-6 was detected in plasma and brain by HPLC. CR-6 reduced glutathione consumption in the ischemic brain and superoxide generation in the isolated MCA. CR-6 decreased infarct volume and attenuated the neurological deficit at 1 and 7 days after ischemia/reperfusion, but not after permanent ischemia. Immediately after reperfusion, cortical blood flow values returned to their baseline (+/-20%) in several animals, whereas others showed hyper-perfusion (>20% of baseline). Reactive hyperemia was associated with adverse events such as increased cortical BBB leakage, edema, protein nitrotyrosination, COX-2 expression, and neutrophil accumulation; and with a poorer outcome, and CR-6 attenuated these effects. In conclusion, oral CR-6 administration after transient ischemia protects the brain from reperfusion injury.
氧化应激和硝化应激是缺血/再灌注后干预的靶点。本研究旨在探讨 CR-6 的作用，CR-6 是一种抗氧化剂和氮反应性物质的清除剂，是维生素 E 的类似物。Sprague-Dawley 大鼠的大脑中动脉（MCA）被阻断 90 分钟或永久性阻断。通过激光多普勒血流仪连续监测皮质灌注。CR-6（100mg/kg）在 MCA 闭塞后 2 小时和 8 小时或仅在 2 小时口服给药。评估梗塞体积、神经功能缺损和再灌注损伤的迹象。通过 HPLC 在血浆和脑中检测到 CR-6。CR-6 减少了缺血大脑中的还原型谷胱甘肽消耗和分离 MCA 中的超氧化物生成。CR-6 减少了缺血/再灌注后 1 天和 7 天的梗塞体积和神经功能缺损，但对永久性缺血没有影响。再灌注后，几例动物的皮质血流值立即恢复到基线（+/-20%），而其他动物则出现高灌注（>基线的 20%）。反应性充血与不良事件相关，如皮质 BBB 渗漏增加、水肿、蛋白硝基酪氨酸化、COX-2 表达和中性粒细胞积聚；并且与较差的结果相关，CR-6 减轻了这些影响。总之，短暂性缺血后口服 CR-6 给药可保护大脑免受再灌注损伤。
