Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced status epilepticus in mice.
Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced status epilepticus in mice.
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DOI：
10.1038/s41598-017-01325-y
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发表时间：
2017-04-26
影响因子：
4.6
通讯作者：
Nishibori M
中科院分区：
文献类型：
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作者：
Fu L;Liu K;Wake H;Teshigawara K;Yoshino T;Takahashi H;Mori S;Nishibori M
在各种病因的人类癫痫和癫痫发作的实验模型中，已经描述了脑组织中的炎症过程。高迁移率族蛋白1（HMGB 1）是目前公认的损伤相关分子模式（DAMPs）的代表。在本研究中，我们集中于抗HMGB 1抗体治疗是否可以减轻癫痫持续状态触发的BBB破坏和炎症反应，除了癫痫发作行为本身。采用毛果芸香碱和甲基东莨菪碱建立急性发作模型。抗HMGB 1单克隆抗体对血脑屏障渗漏和毛果芸香碱诱导的HMGB 1转位均有抑制作用。抗HMGB 1单抗可下调海马和大脑皮层炎症相关因子MCP-1、CXCL-1、TLR-4和IL-6的表达，并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。苏木精-伊红染色和TUNEL染色均显示抗HMGB 1单抗处理后凋亡细胞减少。抗HMGB 1单抗组Racine第5期的出现时间和潜伏期均显著延长。结果提示，抗HMGB 1单抗可阻断BBB通透性，减少HMGB 1转位，抑制炎症相关因子的表达，保护神经细胞凋亡，延长Racine 5期癫痫发作的发作时间和潜伏期。
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.