The Free Radical Scavenger Edaravone Rescues Rats from Cerebral Infarction by Attenuating the Release of High-Mobility Group Box-1 in Neuronal Cells
The Free Radical Scavenger Edaravone Rescues Rats from Cerebral Infarction by Attenuating the Release of High-Mobility Group Box-1 in Neuronal Cells
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DOI：
10.1124/jpet.108.149484
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发表时间：
2009-06-01
影响因子：
3.5
通讯作者：
Maruyama, Ikuro
中科院分区：
文献类型：
--
作者：
Kikuchi, Kiyoshi;Kawahara, Ko-ichi;Maruyama, Ikuro
依达拉奉是一种有效的自由基清除剂，在日本临床上用于治疗脑梗死。在此，我们研究了依达拉奉在大鼠缺血/再灌注后48小时期间以及在氧 - 葡萄糖剥夺（OGD）的PC12细胞中对高迁移率族蛋白B1（HMGB1）动态的影响，HMGB1是缺血诱导的脑损伤的关键介质。再灌注2小时后，在脑梗死区域的细胞质和细胞周边均观察到HMGB1免疫反应性。静脉给予3和6 mg/kg依达拉奉显著抑制半暗带区域的核转位和HMGB1释放，并且在再灌注24小时后分别使总梗死面积减少26.5±10.4%和43.8±0.5%。此外，依达拉奉还降低了血浆HMGB1水平。在体外，依达拉奉呈剂量依赖性（1 - 10 μM）抑制OGD和H₂O₂诱导的PC12细胞中HMGB1的释放。此外，依达拉奉（3 - 30 μM）阻断了PC12细胞中由HMGB1触发的细胞凋亡。我们的研究结果表明依达拉奉具有一种新的神经保护机制，即抑制HMGB1的释放。
Edaravone, a potent free radical scavenger, is clinically used for the treatment of cerebral infarction in Japan. Here, we examined the effects of edaravone on the dynamics of high-mobility group box-1 (HMGB1), which is a key mediator of ischemic-induced brain damage, during a 48-h postischemia/reperfusion period in rats and in oxygen-glucose-deprived (OGD) PC12 cells. HMGB1 immunoreactivity was observed in both the cytoplasm and the periphery of cells in the cerebral infarction area 2 h after reperfusion. Intravenous administration of 3 and 6 mg/kg edaravone significantly inhibited nuclear translocation and HMGB1 release in the penumbra area and caused a 26.5 +/- 10.4 and 43.8 +/- 0.5% reduction, respectively, of the total infarct area at 24 h after reperfusion. Moreover, edaravone also decreased plasma HMGB1 levels. In vitro, edaravone dose-dependently (1-10 mu M) suppressed OGD- and H2O2-induced HMGB1 release in PC12 cells. Furthermore, edaravone (3-30 mu M) blocked HMGB1-triggered apoptosis in PC12 cells. Our findings suggest a novel neuroprotective mechanism for edaravone that abrogates the release of HMGB1.