Anti-high mobility group box-1 (HMGB1) antibody inhibits hemorrhage-induced brain injury and improved neurological deficits in rats.
Anti-high mobility group box-1 (HMGB1) antibody inhibits hemorrhage-induced brain injury and improved neurological deficits in rats.
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DOI：
10.1038/srep46243
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发表时间：
2017-04-10
影响因子：
4.6
通讯作者：
Nishibori M
中科院分区：
文献类型：
--
作者：
Wang D;Liu K;Wake H;Teshigawara K;Mori S;Nishibori M
脑出血（intracerebral hemorrhage，ICH）是一种严重的临床问题，目前尚无有效的治疗方法。临床前和临床研究的现有证据表明，炎症机制参与了ICH诱导的继发性脑损伤的进展。高迁移率族蛋白1（HMGB 1）是一种广泛存在的非组蛋白DNA结合蛋白，也是一种重要的促炎分子。在这里，我们表明，治疗与中和抗HMGB 1单克隆抗体（1毫克/公斤，静脉注射两次）显着改善ICH损伤诱导的局部注射胶原酶IV在大鼠纹状体。在ICH后24 h，给予抗HMGB 1 mAb可抑制HMGB 1释放到血肿周围区域的细胞外空间，降低血清HMGB 1水平，并通过保护血脑屏障完整性减轻脑水肿，与减少活化的小胶质细胞和炎症相关因子的表达相关。因此，抗HMGB 1单克隆抗体降低了氧化应激，改善了大鼠的行为表现。这些结果有力地表明，HMGB 1通过放大多种炎症反应在ICH诱导的继发性损伤的发展中起着关键作用。静脉注射中和性抗HMGB 1单克隆抗体有可能成为脑出血的一种新的治疗策略。
As one of the most lethal stroke subtypes, intracerebral hemorrhage (ICH) is acknowledged as a serious clinical problem lacking effective treatment. Available evidence from preclinical and clinical studies suggests that inflammatory mechanisms are involved in the progression of ICH-induced secondary brain injury. High mobility group box-1 (HMGB1) is a ubiquitous and abundant nonhistone DNA-binding protein, and is also an important proinflammatory molecule once released into the extracellular space from the nuclei. Here, we show that treatment with neutralizing anti-HMGB1 mAb (1 mg/kg, i.v. twice) remarkably ameliorated ICH-injury induced by local injection of collagenase IV in the striatum of rats. Administration of anti-HMGB1 mAb inhibited the release of HMGB1 into the extracellular space in the peri-hematomal region, reduced serum HMGB1 levels and decreased brain edema by protecting blood-brain barrier integrity, in association with decreased activated microglia and the expression of inflammation-related factors at 24 h after ICH. Consequently, anti-HMGB1 mAb reduced the oxidative stress and improved the behavioral performance of rats. These results strongly indicate that HMGB1 plays a critical role in the development of ICH-induced secondary injury through the amplification of plural inflammatory responses. Intravenous injection of neutralizing anti-HMGB1 mAb has potential as a novel therapeutic strategy for ICH.