Gross Adi, Benninger Felix, Madar Ravit, Illouz Tomer, Griffioen Kathleen, Steiner Israel, Offen Daniel, Okun Eitan
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel.
Epilepsia. 2017 Apr;58(4):586-596. doi: 10.1111/epi.13688. Epub 2017 Feb 6.
Epilepsy 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).
To 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 1 month. 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)α and interferon (IFN)β.
Our data indicate that TLR3 deficiency reduced SRS, microglial activation, and the levels of the proinflammatory cytokines TNFα and IFNβ, and increased survival following SE.
This 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.
癫痫影响着全球6000万人。尽管抗癫痫药物有所发展，但仍有高达35%的患者药物难治，癫痫发作无法得到控制。Toll样受体（TLRs）是非特异性先天炎症反应的核心组成部分。由于最近发现TLR3与神经元可塑性有关，我们推测它可能在癫痫持续状态（SE）后癫痫的发展中起作用。
为了测试TLR3在癫痫发生中的作用，我们在TLR3缺陷小鼠及其各自的野生型对照中使用匹鲁卡品模型诱导SE。在这个模型中，单次SE事件会导致自发性反复癫痫发作（SRS）。SE后两周，给小鼠植入无线脑电图（EEG）发射器，持续1个月。使用不同组的小鼠评估TLR3缺陷对SE的影响，评估指标包括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）α和干扰素（IFN）β的表达。
我们的数据表明，TLR3缺陷减少了SRS、小胶质细胞激活以及促炎细胞因子TNFα和IFNβ的水平，并提高了SE后的存活率。
本研究揭示了癫痫病理生理学的新见解以及TLR3对疾病进展的作用。我们的结果确定TLR3通路是SE未来潜在的治疗靶点。
