Toll-like receptor 3 deficiency decreases epileptogenesis in a pilocarpine model of SE-induced epilepsy in mice
Toll-like receptor 3 deficiency decreases epileptogenesis in a pilocarpine model of SE-induced epilepsy in mice
复制标题
DOI：
10.1111/epi.13688
复制
发表时间：
2017-04-01
期刊：
影响因子：
5.6
通讯作者：
Okun, Eitan
中科院分区：
文献类型：
--
作者：
Gross, Adi;Benninger, Felix;Okun, Eitan
目的癫痫影响着全球6000万人。尽管抗癫痫药物的发展，高达35%的患者是药物难治性与无法控制的癫痫发作。Toll样受体（TLR）是非特异性先天性炎症反应的中心组分。由于TLR3最近被牵连在神经元可塑性，我们假设，它可能有助于癫痫持续状态（SE）后癫痫的发展。MethodsTo测试TLR3参与癫痫发生，我们使用毛果芸香碱模型SE TLR3缺陷小鼠和各自的野生型对照。在该模型中，单个SE事件导致自发性复发性癫痫发作（SRS）。SE后两周，小鼠植入无线脑电图（EEG）发射器长达1个月。TLR3缺乏对SE的影响使用单独的小鼠队列进行评估，包括EEG活动、癫痫发作进展、海马小胶质细胞分布以及促炎细胞因子肿瘤坏死因子（TNF）和干扰素（IFN）的表达。显著性本研究揭示了癫痫的病理生理学和TLR3对疾病进展的贡献的新见解。我们的研究结果确定TLR3途径作为SE的潜在未来治疗靶点。
ObjectiveEpilepsy affects 60 million people worldwide. Despite the development of antiepileptic drugs, up to 35% of patients are drug refractory with uncontrollable seizures. Toll-like receptors (TLRs) are central components of the nonspecific innate inflammatory response. Because TLR3 was recently implicated in neuronal plasticity, we hypothesized that it may contribute to the development of epilepsy after status epilepticus (SE).MethodsTo test the involvement of TLR3 in epileptogenesis, we used the pilocarpine model for SE in TLR3-deficient mice and their respective wild-type controls. In this model, a single SE event leads to spontaneous recurrent seizures (SRS). Two weeks after SE, mice were implanted with wireless electroencephalography (EEG) transmitters for up to 1month. The impact of TLR3 deficiency on SE was assessed using separate cohorts of mice regarding EEG activity, seizure progression, hippocampal microglial distribution, and expression of the proinflammatory cytokines tumor necrosis factor (TNF) and interferon (IFN).ResultsOur data indicate that TLR3 deficiency reduced SRS, microglial activation, and the levels of the proinflammatory cytokines TNF and IFN, and increased survival following SE.SignificanceThis study reveals novel insights into the pathophysiology of epilepsy and the contribution of TLR3 to disease progression. Our results identify the TLR3 pathway as a potential future therapeutic target in SE.