Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats
Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats
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DOI：
10.1096/fj.07-8770com
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发表时间：
2007-12-01
期刊：
影响因子：
4.8
通讯作者：
Nishibori, Masahiro
中科院分区：
文献类型：
--
作者：
Liu, Keyue;Mori, Shuji;Nishibori, Masahiro
高迁移率族盒-1 (HMGB1) 最初被鉴定为一种结构核蛋白，在细胞外空间表现出炎症细胞因子样活性。在这里，我们表明，即使在再灌注开始后施用mAb，用中和性抗HMGB1单克隆抗体（mAb；200μg，两次）治疗也能显着改善大鼠中大脑中动脉闭塞2小时诱发的脑梗塞。与梗塞面积减少 90% 一致，伴随的运动功能神经缺陷也得到显着改善。抗HMGB1 mAb抑制血脑屏障通透性增加、小胶质细胞活化、TNF-α和iNOS表达，并抑制MMP-9活性，而对血流影响很小。脑室内注射 HMGB1 会增加梗塞的严重程度。免疫组织化学研究表明，受影响区域细胞核中的 HMGB1 免疫反应性降低或消失，表明 HMGB1 释放到细胞外空间。这些结果表明，HMGB1通过放大缺血区域的多种炎症反应，在脑梗塞的发展中发挥着关键作用，并且可能是一个非常合适的治疗靶点。静脉注射中和性抗HMGB1 mAb为缺血性中风提供了一种新的治疗策略。
The high mobility group box-1 (HMGB1), originally identified as an architectural nuclear protein, exhibits an inflammatory cytokine- like activity in the extracellular space. Here we show that treatment with neutralizing anti- HMGB1 monoclonal antibody ( mAb; 200 mu g, twice) remarkably ameliorated brain infarction induced by 2- h occlusion of the middle cerebral artery in rats, even when the mAb was administered after the start of reperfusion. Consistent with the 90% reduction in infarct size, the accompanying neurological deficits in locomotor function were significantly improved. Anti- HMGB1 mAb inhibited the increased permeability of the blood- brain barrier, the activation of microglia, the expression of TNF-alpha and iNOS, and suppressed the activity of MMP- 9, whereas it had little effect on blood flow. Intracerebroventricular injection of HMGB1 increased the severity of infarction. Immunohistochemical study revealed that HMGB1 immunoreactivity in the cell nuclei decreased or disappeared in the affected areas, suggesting the release of HMGB1 into the extracellular space. These results indicate that HMGB1 plays a critical role in the development of brain infarction through the amplification of plural inflammatory responses in the ischemic region and could be an outstandingly suitable target for the treatment. Intravenous injection of neutralizing anti- HMGB1 mAb provides a novel therapeutic strategy for ischemic stroke.