Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy
Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy
复制标题
DOI：
10.1016/j.nbd.2016.12.007
复制
发表时间：
2017-03-01
影响因子：
6.1
通讯作者：
Vezzani, Annamaria
中科院分区：
文献类型：
--
作者：
Iori, Valentina;Iyer, Anand M.;Vezzani, Annamaria
我们最近发现，前脑激活的IL-1受体/Toll样受体（IL-1 R1/TLR 4）先天免疫信号在啮齿动物癫痫发作的神经元过度兴奋中起着关键作用。由于该途径在人类致痫灶的神经元和神经胶质中被激活，因此它代表了开发干扰导致自发性癫痫发作的癫痫发生机制的药物的潜在靶点。缺乏这类药物是一个未得到满足的主要临床需求。因此，我们在已建立的获得性癫痫小鼠模型中测试了抑制IL-1 R1/TLR 4信号传导的新疗法。我们使用表观遗传学方法，通过注射损害IL 1 R1/TLR 4信号转导的微小（mi）RNA-146 a的合成模拟物，或者我们用抗肿瘤药物阻断受体活化。这两种干预措施在癫痫发作后短暂应用于小鼠时，可预防疾病进展并显着减少慢性癫痫复发，而抗惊厥药物卡马西平无效。我们的结论是，IL-1 R1/TLR 4是一个新的潜在的治疗目标，为实现疾病的修改诊断癫痫患者。(C)2016 Elsevier Inc. All rights reserved.
We recently discovered that forebrain activation of the IL-1 receptor/Toll-like receptor (IL-1R1/TLR4) innate immunity signal plays a pivotal role in neuronal hyperexcitability underlying seizures in rodents. Since this pathway is activated in neurons and glia in human epileptogenic foci, it represents a potential target for developing drugs interfering with the mechanisms of epileptogenesis that lead to spontaneous seizures. The lack of such drugs represents a major unmet clinical need. We tested therefore novel therapies inhibiting the IL-1R1/TLR4 signaling in an established murine model of acquired epilepsy. We used an epigenetic approach by injecting a synthetic mimic of micro(mi)RNA-146a that impairs IL1R1/TLR4 signal transduction, or we blocked receptor activation with antiinflammatory drugs. Both interventions when transiently applied to mice after epilepsy onset, prevented disease progression and dramatically reduced chronic seizure recurrence, while the anticonvulsant drug carbamazepine was ineffective. We conclude that IL-1R1/TLR4 is a novel potential therapeutic target for attaining disease-modifications in patients with diagnosed epilepsy. (C) 2016 Elsevier Inc. All rights reserved.