Blocking GluN2B subunits reverses the enhanced seizure susceptibility after prolonged febrile seizures with a wide therapeutic time-window
Blocking GluN2B subunits reverses the enhanced seizure susceptibility after prolonged febrile seizures with a wide therapeutic time-window
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阻断 GluN2B 亚基可逆转长时间热性惊厥后增强的癫痫易感性，并具有较宽的治疗时间窗
DOI：
10.1016/j.expneurol.2016.05.034
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发表时间：
2016-09-01
影响因子：
5.3
通讯作者：
Chen, Zhong
中科院分区：
文献类型：
--
作者：
Chen, Bin;Feng, Bo;Chen, Zhong
发热性癫痫(FSS)是婴儿最常见的惊厥事件，与成年后的颞叶癫痫(TLE)密切相关。因此，迫切需要研究FSS如何促进癫痫的发生，寻找潜在的治疗靶点。在本研究中，我们发现GIuN2B Tyr1472的磷酸化在延长FSS后24小时逐渐达到峰值，并在随后的7天内持续升高。在先前的研究中，IL-1β治疗模拟了延长FSS对成人癫痫易感性的影响，增加了GIuN2B Tyr1472的磷酸化。IL-1受体拮抗剂(IL-1ra)和IL-1R1缺失都足以逆转FSS诱导的GIuN2B Tyr1472的过度磷酸化。GIuN2B拮抗剂ifenprodil表现出较宽的治疗时间窗(3天)，可逆转延长FSS或IL-1β治疗后增强的癫痫敏感性。我们的研究表明，IL-1β一过性增加所介导的GIuN2B磷酸化参与了延长FSS后成人癫痫敏感性的增强，提示含有GIuN2B的NMDAR是一种新的潜在的药物靶点，具有广阔的治疗时间窗来预防婴幼儿FSS患者的癫痫发生。(C)2016 Elsevier Inc.保留所有权利。
Febrile seizures (FSs), the most common type of convulsive events in infants, are closely associated with temporal lobe epilepsy (TLE) in adulthood. It is urgent to investigate how FSs promote epileptogenesis and find the potential therapeutic targets. In the present study, we showed that the phosphorylation of GIuN2B Tyr1472 gradually reached peak level at 24 h after prolonged FSs and remained elevated during 7 days thereafter. IL-1 beta treatment alone, which in previous study mimicked the effect of prolonged FSs on adult seizure susceptibility, increased GIuN2B Tyr1472 phosphorylation. Both IL-1 receptor antagonist (IL-1Ra) and IL-1R1 deletion were sufficient to reverse the prolonged FSs induced hyper-phosphorylation of GIuN2B Tyr1472. GIuN2B antagonist ifenprodil showed a wide therapeutic time-window (3 days) to reverse the enhanced seizure susceptibility after prolonged FSs or IL-1 beta treatment. Our study demonstrated that GIuN2B phosphorylation at Tyr1472 site mediated by the transient increase of IL-1 beta was involved in the enhanced adult seizure susceptibility after prolonged FSs, implicating GIuN2B-containing NMDAR is a new potential drug target with a wide therapeutic time window to prevent epileptogenesis in patients with infantile FSs. (C) 2016 Elsevier Inc All rights reserved.