Department of Pharmacology and Therapeutic Innovation, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Department of Pharmacology and Therapeutic Innovation, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
J Pharmacol Exp Ther. 2018 Apr;365(1):27-36. doi: 10.1124/jpet.117.245340. Epub 2018 Jan 12.
High-mobility group box 1 (HMGB1) is increased in the cerebrospinal fluid (CSF) and serum during the early and late phases of brain ischemia and is known to contribute to brain damage. However, detailed characterization underlying cell type-specific HMGB1 release and pathophysiological roles of extracellularly released HMGB1 in ischemic brain remain unclear. Here, we examined cell type-specific HMGB1 release and the therapeutic potential of amlexanox, an inhibitor of nonclassical release, and of an anti-HMGB1 antibody against ischemic brain damage. HMGB1 depletion from neuronal nuclei was observed within 3 hours after transient middle cerebral artery occlusion (tMCAO), whereas the intracerebroventricular (i.c.v.) pretreatment with amlexanox blocked HMGB1 release from neurons, resulting in HMGB1 redistribution in the nuclei and cytoplasm. HMGB1 was selectively released from astrocytes 27 hours after tMCAO and this HMGB1 release was blocked by late treatment with amlexanox (i.c.v.) 24 hours after tMCAO. Proximity extension assay revealed that the HMGB1 level was elevated in the CSF at 3 and 27 hours after tMCAO. This late treatment with amlexanox significantly protected the brain from ischemic damage, but its pretreatment 30 minutes before tMCAO failed to show any protection. The late treatment (i.c.v.) with anti-HMGB1 antibody 24 hours after tMCAO also ameliorated ischemic brain damage 48 hours after tMCAO. Thus, the inhibition of brain damage by late treatment with amlexanox or anti-HMGB1 antibody indicates that late HMGB1 release plays a role in the maintenance of stroke-induced brain damage, and the inhibition of this release would be a novel therapeutic target for protection of ischemic brain damage.
高迁移率族蛋白 B1（HMGB1）在脑缺血的早期和晚期阶段增加，在脑脊液（CSF）和血清中，已知其有助于脑损伤。然而，细胞类型特异性 HMGB1 释放的详细特征和细胞外释放的 HMGB1 在缺血性脑内的病理生理作用仍不清楚。在这里，我们检查了细胞类型特异性 HMGB1 释放以及非经典释放抑制剂氨来占诺和抗 HMGB1 抗体对缺血性脑损伤的治疗潜力。在短暂性大脑中动脉闭塞（tMCAO）后 3 小时内观察到神经元核 HMGB1 耗竭，而氨来占诺的脑室内（i.c.v.）预处理阻止了神经元释放 HMGB1，导致 HMGB1 在核和细胞质中的重新分布。HMGB1 选择性地从星形胶质细胞中释放，在 tMCAO 后 27 小时，这种 HMGB1 释放被 tMCAO 后 24 小时的晚期氨来占诺（i.c.v.）治疗阻断。邻近延伸分析显示，tMCAO 后 3 和 27 小时 CSF 中 HMGB1 水平升高。这种晚期氨来占诺治疗显著保护大脑免受缺血性损伤，但在 tMCAO 前 30 分钟的预处理未能显示出任何保护作用。tMCAO 后 24 小时的晚期抗 HMGB1 抗体（i.c.v.）治疗也改善了 tMCAO 后 48 小时的缺血性脑损伤。因此，晚期氨来占诺或抗 HMGB1 抗体治疗对脑损伤的抑制表明，晚期 HMGB1 释放在维持卒中诱导的脑损伤中起作用，抑制这种释放将成为保护缺血性脑损伤的新治疗靶点。
