Novel inflammatory targets to prevent posttraumatic epileptogenesis

描述（由申请人提供）：在西方社会，创伤性脑损伤（TBI）是获得性癫痫的主要原因，约占普通人群癫痫的4%。脑外伤后人类癫痫发生的机制尚不清楚，也没有任何治疗方法可以预防甚至改变其发展。因此，许多头部损伤患者发展为创伤后癫痫（PTE），需要终身治疗。越来越多的证据表明炎症在获得性癫痫发生中的作用。炎症是损伤脑和癫痫脑的一致特征，几种炎症介质也影响癫痫易感性。合理开发抗炎预防PTE需要了解创伤后癫痫发生所必需的炎症的不同成分。由于缺乏预防创伤后癫痫发生的有效治疗方法，这一研究受到了阻碍。使用病因学上现实的PTE模型，诱导进行性炎症和癫痫发生，我们最近发现轻度局灶性冷却具有强大的抗癫痫作用（D'Ambrosio等人，Ann Neurol doi: 10.1002/ana.23764）。目前的建议旨在使用轻度局灶冷却作为一种工具，以了解哪些方面的炎症过程在病灶周围的新皮层，成为癫痫灶是必要的癫痫发生。我们将使用基因阵列，RT-PCR，基于luminex的分析和免疫组织化学来奠定必要的基础工作，以确定早期癫痫病灶炎症的特定特征，这些特征可以针对预防性干预。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the leading cause of acquired epilepsy in western societies, and accounts for ~4% of epilepsy in the general population. The mechanisms of human epileptogenesis after TBI remain unknown, and no treatment exists to prevent it or even modify its development. Thus, many head injury patients develop posttraumatic epilepsy (PTE) and require life-long treatment. Mounting evidence indicates a role for inflammation in acquired epileptogenesis. Inflammation is a consistent feature of both the injured brain and of the epileptic brain, and several inflammatory mediators also affect seizure susceptibility. The rational development of anti-inflammatory prophylaxes for PTE requires understanding of the diverse components of inflammation that are necessary for posttraumatic epileptogenesis. This has been hindered by the lack of an effective treatment that prevents posttraumatic epileptogenesis. Using an etiologically realistic model of PTE that induces progressive inflammation and epileptogenesis, we have recently identified a powerful antiepileptogenic effect of mild focal cooling (D'Ambrosio et al., Ann Neurol doi: 10.1002/ana.23764). The present proposal aims to use mild focal cooling as a tool to understand which aspects of the inflammatory processes in the perilesional neocortex that becomes the epileptic focus are necessary for epileptogenesis. We will use gene-array, RT-PCR, Luminex-based assays and immunohistochemistry to lay the ground work necessary to identify specific features of inflammation in the incipient epileptic focus that can be targeted fo prophylactic intervention.