Abstract：
Inflammation is an important pathogenic driving force in the genesis and development of epilepsy. The latest researches demonstrated that IL-17A mediated blood-brain barrier (BBB) dysfunction through disruption of tight junction protein expression. To investigate whether IL-17A is involved in BBB disruption after acute seizure attack, the pilocarpine model was established with C57BL/6 J (wild type, WT) and IL-17R-deficient mice in vivo and with primary cultured rat brain microvascular endothelial cells in vitro. The mortality rate and brain water content were evaluated at 24 h after status epilepticus, and IL-17A concentration, endothelial tight junction, adherens junction proteins, and albumin leakage were assessed at 0 h, 4 h, 12 h, and 24 h after status epilepticus (SE). IL-17R-deficient mice showed lessen severity of epilepsy than WT mice, accompanied by less albumin leakage, reduced brain water content, decreased IL-17A, and upregulated expression of target proteins (ZO-1, Occludin and VE-cadherin). IL-17R knockout abrogated abnormal upregulation of Src kinase and phosphorylated Src kinase in the setting of SE, and Src kinase inhibitor PP1 abrogated IL-17A-induced SE related endothelial injury in vitro. In conclusion, IL-17A inhibition might be a promising therapeutic option to attenuate endothelial cell injury and further BBB disruption by reducing Src kinase activation.
摘要：
炎症是癫痫发生发展的重要致病动力。最新研究表明，IL-17A通过破坏紧密连接蛋白的表达来介导血脑屏障（BBB）功能障碍。为了研究IL-17A是否参与急性癫痫发作后的BBB破坏，用C57BL/6J(野生型，WT）和体内IL-17R缺陷小鼠以及体外原代培养的大鼠脑微血管内皮细胞。在癫痫持续状态后24h评估死亡率和脑含水量，和IL-17A浓度，内皮紧密连接，粘附性连接蛋白，在0h时评估白蛋白渗漏，4h,12h,癫痫持续状态（SE）后24小时。IL-17R缺陷小鼠比WT小鼠癫痫严重程度减轻，伴随着较少的白蛋白泄漏，减少大脑含水量，降低IL-17A，并上调靶蛋白(ZO-1、Occludin和VE-cadherin)的表达。IL-17R敲除消除了SE设置中Src激酶和磷酸化Src激酶的异常上调，和Src激酶抑制剂PP1在体外消除了IL-17A诱导的SE相关内皮损伤。总之,IL-17A抑制可能是通过减少Src激酶激活来减轻内皮细胞损伤和进一步BBB破坏的有希望的治疗选择。
