Department of Neurology, Nanfang Hospital, Southern Medical University Guangzhou, Guangdong 510515, China.
Department of Neurology, Nanfang Hospital, Southern Medical University Guangzhou, Guangdong 510515, China.
Neuroscience. 2017 Sep 30;360:128-138. doi: 10.1016/j.neuroscience.2017.07.052. Epub 2017 Aug 2.
Excessive inflammatory response produced after cardiac arrest and cardiopulmonary resuscitation (CA/CPR) is one of major causes of cerebral injury. High mobility group box 1 (HMGB1) is a pro-inflammatory cytokine and its role in brain injury after CA/CPR is unclear. Herein we investigated whether blocking HMGB1 signaling could ease brain injury after CA/CPR. Male Sprague-Dawley rats (n=181) were subjected to 8-min Asphyxia CA model or Sham operation. The ELISA data revealed both resuscitated patients and animals had elevated HMGB1 level in sera, compared with the healthy volunteers or Sham operative rats, respectively (P<0.01). Rats successfully resuscitated from CA were then randomly treated with either membrane permeable (TAT-fused) HMGB1 binding heptamer peptide (HBHP) or Scramble peptide. Results showed that HBHP treatment markedly improved 7-day survival rate, reduced neurological deficit scores, and prevented neuronal and dendrite loss in hippocampal CA1 region. Moreover, HBHP inhibited the activation of microglia and astrocytes and downregulated the mRNA and protein expressions of proinflammatory factors. We finally blocked toll-like receptor-4 (TLR4, one of HMGB1 receptors) with a specific antagonist TAK-242 before CA induction to confirm the detrimental effect of HMGB1 signaling and found blocking TLR4 could also attenuate the neuronal degeneration, as well as reduce NF-κB-mediated inflammatory signaling. Our findings indicate that CA/CPR can induce HMGB1 release to serum, while blocking HMGB1 signaling with peptide may improve the survival and attenuate post-resuscitation brain injury in the rat model of CA/CPR. TLR4 antagonist may also offer neuroprotective effects through weakening HMGB1-mediated proinflammatory reactions.
心脏骤停和心肺复苏（CA/CPR）后产生的过度炎症反应是脑损伤的主要原因之一。高迁移率族蛋白 1（HMGB1）是一种促炎细胞因子，但其在 CA/CPR 后脑损伤中的作用尚不清楚。在此，我们研究了阻断 HMGB1 信号是否可以减轻 CA/CPR 后的脑损伤。雄性 Sprague-Dawley 大鼠（n=181）接受 8 分钟窒息性 CA 模型或假手术。ELISA 数据显示，与健康志愿者或假手术大鼠相比，复苏的患者和动物的血清 HMGB1 水平均升高（P<0.01）。然后，成功从 CA 中复苏的大鼠被随机给予膜通透性（TAT 融合）HMGB1 结合七肽（HBHP）或乱序肽治疗。结果表明，HBHP 治疗显著提高了 7 天生存率，降低了神经功能缺损评分，并防止了海马 CA1 区神经元和树突丢失。此外，HBHP 抑制了小胶质细胞和星形胶质细胞的激活，并下调了促炎因子的 mRNA 和蛋白表达。我们最后在 CA 诱导前用特异性拮抗剂 TAK-242 阻断 TLR4（HMGB1 的一种受体）以确认 HMGB1 信号的有害作用，发现阻断 TLR4 也可以减轻神经元变性，并减少 NF-κB 介导的炎症信号。我们的研究结果表明，CA/CPR 可诱导 HMGB1 释放到血清中，而用肽阻断 HMGB1 信号可能会改善大鼠 CA/CPR 模型的存活率并减轻复苏后脑损伤。TLR4 拮抗剂也可能通过减弱 HMGB1 介导的促炎反应提供神经保护作用。
