Wang Na, Han Xiong, Liu Haipeng, Zhao Ting, Li Jie, Feng Yan, Mi Xiujuan, Zhang Yanke, Chen Yanan, Wang Xuefeng
Department of Neurology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou 450003, China; Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing 400016, China.
Department of Neurology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou 450003, China.
Exp Neurol. 2017 Sep;295:23-35. doi: 10.1016/j.expneurol.2017.05.008. Epub 2017 May 18.
Accumulating evidence supports that activation of inflammatory pathways is a crucial factor contributing to the pathogenesis of seizures. In particular, the activation of interleukin-1 beta (IL-1β) system exerts proconvulsant effects in a large variety of seizure models. Myeloid differentiation factor 88 (MyD88) is a critical adaptor protein in the signaling cascade elicited by IL-1β. The present study aimed to investigate the expression pattern of MyD88 in rat models of seizures and in patients with refractory temporal lobe epilepsy (TLE), and to study the role of MyD88 in epileptic seizures. Our results revealed that MyD88 was up-regulated in the hippocampus of rats in the lithium-pilocarpine model of acute seizures. Importantly, MyD88 overexpression was also significantly present in the brain from chronic epileptic rats and the temporal neocortex specimens from drug-resistant TLE patients. In the acute seizure model, both the behavioral and electrographic seizure activities were record and analyzed in rats for 90min, starting immediately after pilocarpine injection. ST2825, a synthetic MyD88 inhibitor, was administered intracerebroventricularly (2.5-5.0-10μg in 2μl) 20min before pilocarpine injection. We found that ST2825 at doses of 5μg and 10μg significantly inhibited the pilocarpine-induced behavioral and electrographic seizures. Moreover, 10μg ST2825 prevented the proconvulsant actions of IL-1β. As previous evidence suggested that IL-1β proconvulsant effects was mediated by enhancing the phosphorylation level of the NR2B subunit of N-methyl-d-aspartate (NMDA) receptor, we then probed whether this molecular was involved in the effect of the pharmacological inhibition. Our results revealed that 10μg ST2825 markedly reversed the increased Tyr-phosphorylation of the NR2B subunit of NMDA receptor observed in the proconvulsant conditions of IL-1β and in seizures induced by pilocarpine alone. These findings indicate that altered expression of MyD88 might contribute to the pathogenesis of seizures and targeting of this adaptor protein might represent a novel therapeutic strategy to suppress seizure activities.
越来越多的证据支持炎症通路的激活是导致癫痫发作的关键因素。特别是，白细胞介素-1β（IL-1β）系统的激活在多种癫痫发作模型中发挥促惊厥作用。髓样分化因子88（MyD88）是IL-1β引发的信号级联反应中的关键衔接蛋白。本研究旨在调查MyD88在癫痫大鼠模型和难治性颞叶癫痫（TLE）患者中的表达模式，并研究MyD88在癫痫发作中的作用。我们的结果显示，在急性癫痫发作的锂-匹罗卡品模型中，大鼠海马中的MyD88上调。重要的是，慢性癫痫大鼠的大脑以及耐药TLE患者的颞叶新皮质标本中也明显存在MyD88过表达。在急性癫痫发作模型中，在匹罗卡品注射后立即开始对大鼠的行为和脑电图癫痫活动进行90分钟的记录和分析。在匹罗卡品注射前20分钟，通过脑室内注射（2μl中含2.5 - 5.0 - 10μg）给予合成的MyD88抑制剂ST2825。我们发现，5μg和10μg剂量的ST2825显著抑制了匹罗卡品诱导的行为和脑电图癫痫发作。此外，10μg的ST2825可预防IL-1β的促惊厥作用。正如先前的证据表明IL-1β的促惊厥作用是通过增强N-甲基-D-天冬氨酸（NMDA）受体NR2B亚基的磷酸化水平介导的，我们随后探究该分子是否参与了药理学抑制作用。我们的结果显示，10μg的ST2825显著逆转了在IL-1β促惊厥条件下以及单独由匹罗卡品诱导的癫痫发作中观察到的NMDA受体NR2B亚基酪氨酸磷酸化增加的情况。这些发现表明，MyD88表达的改变可能有助于癫痫发作的发病机制，针对这种衔接蛋白可能代表一种抑制癫痫发作活动的新治疗策略。
