Therapeutic effect of anti-HMGB1 antibody in a mouse model of 4-h middle cerebral artery occlusion: comparison with tissue plasminogen activator
Therapeutic effect of anti-HMGB1 antibody in a mouse model of 4-h middle cerebral artery occlusion: comparison with tissue plasminogen activator
复制标题
DOI：
10.1097/wnr.0000000000001780
复制
发表时间：
2022-05-04
期刊：
影响因子：
1.7
通讯作者：
Mishima，Kenichi
中科院分区：
文献类型：
--
作者：
Nakano，Takafumi;Tagashira，Yui;Mishima，Kenichi
目的延迟应用组织纤溶酶原激活剂(TPA)治疗增加了缺血性卒中患者脑出血的风险。我们先前证明，在大脑中动脉闭塞(MCAO)的4h小鼠模型中，在再灌注后给予tPA治疗会导致出血性并发症。本研究用抗高迁移率族蛋白1抗体(α-HMGB1)对4h大脑中动脉阻塞小鼠进行治疗，以评价α-HMGB1抗体在脑缺血延迟期、tPA治疗时间窗以外的治疗效果。方法将α-HMGB1抗体、tPA和对照Ig G溶解于生理盐水中，再灌注后尾静脉给药。2 4h后观察脑梗塞体积、出血量、脑肿胀程度、脑功能及促炎症细胞因子HMGB1、白介素6、肿瘤坏死因子α的水平。HMGB1抗体治疗可减少脑梗塞体积和肿胀，改善神经功能障碍和运动协调能力，无出血性并发症，可抑制α活性。结论αHMGB1抗体在脑缺血延迟期的治疗中可能是有效的，α治疗不再是一种合适的治疗方法。对于超过α治疗时间窗的患者，使用tPA HMGB1抗体治疗可能是一种有效的治疗选择。
ObjectiveDelayed tissue plasminogen activator (tPA) treatment increases the risk of intracerebral hemorrhage in patients with ischemic stroke. We previously demonstrated that tPA treatment caused hemorrhagic complications in a 4-h middle cerebral artery occlusion (MCAO) mouse model when administered after reperfusion. In the present study, we administered an anti-high mobility group box 1 (αHMGB1) antibody to 4-h MCAO mice to evaluate the usability of αHMGB1 antibody treatment in the delayed phase of ischemia, beyond the therapeutic time window of tPA.MethodsαHMGB1 antibody, tPA and control IgG were dissolved in normal saline and administered intravenously into the tail vein of the mice after reperfusion. Infarct volume, hemorrhagic volume, brain swelling, functional outcomes and levels of pro-inflammatory cytokines, such as HMGB1, interleukin (IL)-6 and tumor necrosis factor (TNF)-α, were evaluated 24 h after MCAO.ResultstPA treatment was not only ineffective but also caused a massive intracerebral hemorrhage. Treatment with αHMGB1 antibody reduced the infarct volume and swelling and ameliorated neurologic impairment and motor coordination without hemorrhagic complications by inhibiting HMGB1 activity. Moreover, the αHMGB1 antibody suppressed pathways of secondary inflammatory responses, such as IL-6 and TNF-α, after cerebral ischemia.ConclusionThese results indicate that αHMGB1 antibody may be therapeutically efficient in the delayed phase of ischemia, where tPA treatment is no longer an eligible option. Treatment with an αHMGB1 antibody may be an effective therapeutic option in patients who exceed the tPA therapeutic time window.