TWEAK-Fn14通路介导炎性反应在癫痫病理机制中的作用

Inflammatory reaction in brain is a common and important factor participating in the physiological and pathological processes of epilepsy. Proinflammatory cytokine secreted by central nervous system during seizure can induce the inflammatory cascade reaction, which may lead increased neuronal excitability and spontaneous recurrent epileptic seizures. TWEAK, a kind of new inflammatory factor, can produce the bio-effects by combining with its receptor named Fn14. At present, there is no research about the function of TWEAK-Fn14 pathway in epilepsy pathogenesis has been reported. In our previous study, we found seizures could induce the increased expression of TWEAK in brain tissures of epileptic patients. Based on the previous studies, we hypothesized that TWEAK, as an essential inflammatory factor, may play a crucial role in the vicious cycles between inflammation and epilepsy, by arousing inflammatory reaction, neurons apoptosis and blood-brain barrier permeability change. In this study, we will apply in vivo and vitro studies by using molecular biology and nerve electrophysiology technologies to detect dynamic changes of TWEAK- Fn14 in epilepsy and to clarify its role in inflammatory reaction in epileptic brain by intervening TWEAK and blocking up bonding between TWEAK and Fn14, and to provide clinical and experimental basis for researching new therapeutic targets.

大脑炎性反应是构成癫痫发生发展病理机制的常见且重要的因素，癫痫发作时大脑分泌促炎性细胞因子，引起炎性级联反应，使神经元兴奋性增高, 诱导癫痫反复发作。TWEAK是一种新的促炎性因子，与受体Fn14结合产生生物效应。TWEAK-Fn14通路在癫痫中的研究未见报道。课题组前期实验结果发现癫痫发作引起TWEAK表达上调，推测TWEAK和Fnl4结合激活下游通路参与炎症反应、神经细胞凋亡、血脑屏障通透性改变，引起神经兴奋性增高，导致癫痫反复发作，形成慢性脑部炎症与癫痫间的恶性循环。该课题利用分子生物学，神经电生理技术对癫痫临床标本、在体及离体癫痫模型三方面的研究，探讨癫痫脑内TWEAK- Fn14的动态变化，干预TWEAK和阻断TWEAK-Fn14结合了解能否通过介导脑内炎症反应，调节ERK通路参与癫痫发作修饰，进而影响癫痫发生发展，从炎性反应角度为寻找癫痫治疗新的作用靶点提供临床及实验理论依据。

大脑炎性反应是构成癫痫发生发展病理机制的常见且重要的因素，癫痫发作时大脑分泌促炎性细胞因子，引起炎性级联反应，使神经元兴奋性增高, 诱导癫痫反复发作。TWEAK是一种新的促炎性因子，与受体Fn14结合产生生物效应。我们利用分子生物学，神经电生理技术对癫痫临床标本、癫痫模型进行研究，发现TWEAK及Fn14在患者及大鼠模型的脑组织中均有mRNA及蛋白表达升高；TWEAK表达的变化对动物模型行为学有影响，导致癫痫潜伏期缩短，发作严重程度增高。CXCL13及其受体CXCR5已被证实在中枢神经系统中有高表达并参与炎性反应过程。为进一步证实炎性反应在癫痫发生发展中的作用机制。我们在难治性颞叶癫痫患者脑组织以及匹罗卡品诱导颞叶癫痫大鼠模型中检测炎性因子CXCL13 及 CXCR5的表达情况。我们发现CXCL13及其受体CXCR5在患者及大鼠模型的脑组织中均有mRNA及蛋白表达升高，包括急性期及慢性期。CXCL13-CXCR5 信号通路可能参与难治性癫痫的病理机制。本课题利用多种技术，从mRNA及蛋白层面说明两种炎性因子通路TWEAK-Fn14及CXCL13-CXCR5在癫痫患者脑组织及癫痫动物模型脑组织中的表达改变，在动物模型中证实了TWEAK-Fn14通路可影响癫痫发作程度。为进一步说明两种炎性通路在癫痫中的作用机制提供有力基础，为炎性机制在癫痫中的作用或作为新治疗靶点提供有力证据。