Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures
Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures
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DOI：
10.1038/nm.2127
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发表时间：
2010-04-01
期刊：
影响因子：
82.9
通讯作者：
Vezzani, Annamaria
中科院分区：
文献类型：
--
作者：
Maroso, Mattia;Balosso, Silvia;Vezzani, Annamaria
脑炎症是癫痫的一个主要因素，但特异性炎症介质对神经元兴奋性的影响尚不完全清楚。在C57BL/6小鼠急性和慢性癫痫模型中，我们发现了一条惊痫前通路，涉及神经元和神经胶质中高迁移性组盒-1 （HMGB1）的释放及其与toll样受体4 （TLR4）的相互作用，TLR4是先天免疫的关键受体。HMGB1和TLR4拮抗剂延缓癫痫发作沉淀，减少急慢性癫痫发作复发。tlr4缺陷C3H/HeJ小鼠对盐酸盐诱导的癫痫发作具有抗性。HMGB1的前惊厥作用，像白细胞介素-1 β (IL-1 β)一样，部分是由对伊芬丙地尔敏感的n-甲基- d -天冬氨酸（NMDA）受体介导的。HMGB1和TLR4在人癫痫组织中的表达增加，与在小鼠慢性癫痫模型中观察到的一样，表明HMGB1-TLR4轴在人癫痫中起作用。因此，HMGB1-TLR4信号可能有助于人类癫痫发作的产生和持续，并可能在目前耐药的癫痫中获得抗惊厥作用。
Brain inflammation is a major factor in epilepsy, but the impact of specific inflammatory mediators on neuronal excitability is incompletely understood. Using models of acute and chronic seizures in C57BL/6 mice, we discovered a proconvulsant pathway involving high-mobility group box-1 (HMGB1) release from neurons and glia and its interaction with Toll-like receptor 4 (TLR4), a key receptor of innate immunity. Antagonists of HMGB1 and TLR4 retard seizure precipitation and decrease acute and chronic seizure recurrence. TLR4-defective C3H/HeJ mice are resistant to kainate-induced seizures. The proconvulsant effects of HMGB1, like those of interleukin-1 beta (IL-1 beta), are partly mediated by ifenprodil-sensitive N-methyl-D-aspartate (NMDA) receptors. Increased expression of HMGB1 and TLR4 in human epileptogenic tissue, like that observed in the mouse model of chronic seizures, suggests a role for the HMGB1-TLR4 axis in human epilepsy. Thus, HMGB1-TLR4 signaling may contribute to generating and perpetuating seizures in humans and might be targeted to attain anticonvulsant effects in epilepsies that are currently resistant to drugs.