Novel inflammatory targets to prevent posttraumatic epileptogenesis

描述(申请人提供)：创伤性脑损伤(TBI)是西方社会获得性癫痫的主要原因，约占普通人群癫痫的4%。颅脑损伤后人类癫痫的发生机制尚不清楚，目前还没有预防甚至改变其发生发展的治疗方法。因此，许多颅脑损伤患者会患上创伤后癫痫(PTE)，需要终生治疗。越来越多的证据表明，炎症在获得性癫痫发生中起着重要作用。炎症是损伤脑和癫痫脑的一贯特征，几种炎症介质也影响癫痫的易感性。合理开发PTE的抗炎预防措施需要了解创伤后癫痫发生所必需的各种炎症成分。由于缺乏有效的治疗方法来预防创伤后癫痫的发生，这一点受到了阻碍。使用一个病因学上真实的PTE模型，诱导进行性炎症和癫痫发生，我们最近发现了温和局灶降温的强大的抗癫痫作用(D‘Ambrosio等，Ann Neurol DOI：10.1002/Ana.23764)。目前的建议旨在利用轻度局灶冷却作为一种工具，以了解成为癫痫灶的周围新皮质中的哪些方面的炎症过程是癫痫发生所必需的。我们将使用基因阵列、RT-PCR、基于Luminex的分析和免疫组织化学方法来奠定必要的基础工作，以确定可以作为预防性干预靶点的早期癫痫灶中的特定炎症特征。

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.