Nrf2 activator ameliorates hemorrhagic transformation in focal cerebral ischemia under warfarin anticoagulation
Nrf2 activator ameliorates hemorrhagic transformation in focal cerebral ischemia under warfarin anticoagulation
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DOI：
10.1016/j.nbd.2016.02.001
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发表时间：
2016-05-01
影响因子：
6.1
通讯作者：
Hara, Hideaki
中科院分区：
文献类型：
--
作者：
Imai, Takahiko;Takagi, Toshinori;Hara, Hideaki
背景与目的：氧化应激是缺血再灌注损伤（IRI）中神经细胞死亡的主要原因。核因子-红细胞2相关因子2（Nrf 2）是参与抗氧化反应的重要因子。我们以前报道过，甲基巴多索龙（BARD），Nrf 2激活剂，防止IRI诱导的损伤。在这项研究中，我们研究了在血脑屏障（BBB）protection.Methods背景下，BARD对出血性转化的影响：小鼠接受华法林（4.0 mg/kg，p.o.）预处理。IRI随后在华法林给药后18 h通过短暂大脑中动脉闭塞（MCAO）6 h诱导。再灌注后立即静脉注射BARD（0.06、02、0.6或2.0 mg/kg）或生理盐水。于MCAO后24 h评价梗死体积、神经功能评分、颅内出血量和血脑屏障通透性。观察术后7 d存活率及行为功能恢复情况。结果：BARD可抑制华法林介导的颅内出血量的增加，但不影响脑梗死体积。BBB渗透性也受到抑制的管理BARD。Western blotting显示，BARD增加了BBB组分如内皮细胞、周细胞和紧密连接蛋白的表达。结论：BARD通过保护内皮细胞、周细胞和紧密连接蛋白的表达，抑制华法林预处理引起的急性出血，改善血脑屏障破坏。这些结果表明，Nrf 2激活剂可能是一种有效的治疗抗凝药物引起的出血性转化。(C)2016 Elsevier Inc. All rights reserved.
Background and purpose: Oxidative stress has been reported to be a main cause of neuronal cell death in ischemia reperfusion injury (IRI). Nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important factor involved in anti oxidative responses. We previously reported that bardoxolone methyl (BARD), an Nrf2 activator, prevented damage induced by IRI. In this study, we investigated the effect of BARD on hemorrhagic transformation in the context of blood brain barrier (BBB) protection.Methods: Mice received pre-treatment with warfarin (4.0 mg/kg, p.o.). IRI was subsequently induced 18 h after the warfarin administration by transient middle cerebral artery occlusion (MCAO) for 6 h. BARD (0.06, 02, 0.6 or 2.0 mg/kg) or saline was injected intravenously immediately after reperfusion. The infarct volume, neurological score, intracranial hemorrhage volume, and BBB permeability were evaluated 24 h after MCAO. The survival rate and behavioral functional recovery were evaluated for 7 days following IRI. Furthermore, the effects of BARD on BBB components were investigated by western blotting and immunostaining analysis.Results: BARD suppressed warfarin-mediated increases in the intracranial hemorrhage volume without affecting the infarct volume. BBB permeability was also suppressed by administration of BARD. Western blotting showed that BARD increased expression of BBB components such as endothelial cells, pericytes, and tight junction proteins. Furthermore, immunostaining showed that BARD induced localization of Nrf2 to endothelial cells and pericytes.Conclusions: BARD suppressed the exacerbation hemorrhage caused by warfarin pretreatment and ameliorated BBB disruption by protecting endothelial cells, pericytes, and tight junction protein expressions. These results indicate that Nrf2 activators may be an effective therapy against hemorrhagic transformation caused by anticoagulant drugs. (C) 2016 Elsevier Inc. All rights reserved.