Novel inflammatory targets to prevent posttraumatic epileptogenesis

描述（由申请人提供）：创伤性脑损伤（TBI）是西方社会获得性癫痫的主要原因，约占一般人群癫痫的4%。TBI后人类癫痫发生的机制仍然未知，并且没有治疗方法可以预防它甚至改变其发展。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。炎症是受伤的大脑和癫痫大脑的一致特征，并且几种炎症介质也影响癫痫发作的易感性。合理开发PTE的抗炎镇痛药需要了解创伤后癫痫发生所需的各种炎症成分。这一直阻碍了缺乏有效的治疗，防止创伤后癫痫。使用诱发进行性炎症和癫痫发生的PTE的病因学现实模型，我们最近已经鉴定了轻度局灶性冷却的强大抗癫痫发生作用（D 'Ambrosio等人，Ann Neurol doi：10.1002/ana.23764）。目前的建议旨在使用温和的局灶性冷却作为一种工具，以了解哪些方面的炎性过程中的病灶周围新皮层，成为癫痫病灶是必要的癫痫发生。我们将使用基因阵列，RT-PCR，基于Luminex的检测和免疫组织化学奠定必要的基础工作，以确定早期癫痫病灶中炎症的具体特征，这些特征可以作为预防性干预的目标。

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.