Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
Sci Rep. 2017 Apr 26;7(1):1179. doi: 10.1038/s41598-017-01325-y.
Inflammatory processes in brain tissue have been described in human epilepsy of various etiologies and in experimental models of seizures. High mobility group box-1 (HMGB1) is now recognized as representative of damage-associated molecular patterns (DAMPs). In the present study, we focused on whether anti-HMGB1 antibody treatment could relieve status epilepticus- triggered BBB breakdown and inflammation response in addition to the seizure behavior itself. Pilocarpine and methyl-scopolamine were used to establish the acute seizure model. Anti-HMGB1 mAb showed inhibitory effects on leakage of the BBB, and on the HMGB1 translocation induced by pilocarpine. The expression of inflammation-related factors, such as MCP-1, CXCL-1, TLR-4, and IL-6 in hippocampus and cerebral cortex were down-regulated by anti-HMGB1 mAb associated with the number of activated astrocytes, microglial cells as well as the expression of IL-1β. Both hematoxylin & eosin and TUNEL staining showed that the apoptotic cells could be reduced after anti-HMGB1 mAb treatment. The onset and latency of Racine stage five were significantly prolonged in the anti-HMGB1 mAb group. These results suggested that anti-HMGB1 mAb prevented the BBB permeability, reduced HMGB1 translocation while inhibiting the expression of inflammation-related factors, protected against neural cell apoptosis and prolonged Racine stage 5 seizure onset and latency.
在各种病因引起的人类癫痫和癫痫发作的实验模型中，脑组织中的炎症过程已经被描述过。高迁移率族蛋白 B1（HMGB1）现在被认为是损伤相关分子模式（DAMPs）的代表。在本研究中，我们专注于抗 HMGB1 抗体治疗是否除了癫痫发作本身之外，还能缓解癫痫持续状态引发的 BBB 破坏和炎症反应。匹罗卡品和甲基东莨菪碱用于建立急性癫痫发作模型。抗 HMGB1 mAb 对 BBB 渗漏和匹罗卡品诱导的 HMGB1 易位具有抑制作用。与激活的星形胶质细胞、小胶质细胞数量以及 IL-1β 的表达相关的炎症相关因子，如 MCP-1、CXCL-1、TLR-4 和 IL-6，在海马和大脑皮层中的表达均被抗 HMGB1 mAb 下调。苏木精和伊红（H&E）以及 TUNEL 染色显示，抗 HMGB1 mAb 治疗后可减少凋亡细胞。抗 HMGB1 mAb 组 Racine 阶段五的发作起始和潜伏期显著延长。这些结果表明，抗 HMGB1 mAb 可防止 BBB 通透性增加，减少 HMGB1 易位，同时抑制炎症相关因子的表达，防止神经细胞凋亡，并延长 Racine 阶段 5 癫痫发作的起始和潜伏期。
