Pharmacoresistant limbic epilepsy: model validation

描述（由申请人提供）：虽然大多数癫痫患者的癫痫发作通过目前可用的药物成功控制，但大约三分之一的癫痫发作尽管尝试了多种药物治疗。这组患者被定义为治疗耐药，这是最需要更有效治疗的群体。尽管越来越多的证据表明，耐药患者的大脑中存在多种变化，可能会改变药物反应谱，但治疗发现过程依赖于在正常动物大脑中使用急性诱发癫痫发作。这种方法很可能无法解决癫痫发作产生的机制和潜在的癫痫发作抑制，这可能是治疗抵抗性癫痫所特有的。此申请是为了响应请求应用公告，以改善这些患者的治疗发现过程。RFA正在寻求在癫痫持续状态后边缘癫痫模型中验证药物耐药性。在这个项目的过程中，我们将实现几个目标，这些目标将满足RFA的主要目的。总的来说，我们将建立一种工具，可用于测试潜在的新疗法，但作为实现这一目标的步骤，我们将确定使用该模型的最有效方法，我们将创建和验证在慢性癫痫间歇性自发发作的啮齿动物模型中施用治疗剂量的化合物的方法。该项目将通过建立基线数据和引入新的方法来评估治疗癫痫的新化合物的治疗潜力，从而实现该计划的目标。

DESCRIPTION (provided by applicant): Although the majority of the patients with epilepsy have their seizures successfully controlled by currently available medications, approximately one third continue to have seizures in spite therapy attempts with multiple medications. This group of patients is defined as therapy resistant, and it is the group that is in greatest need of more effective therapies. Although there is rapidly expanding evidence that there are multiple changes in the brains of therapy resistant patients that may alter the pharmacological response profile, the therapy discovery process has depended on the use of acutely induced seizures in brains from normal animals. It is very likely that this approach fails to address mechanisms of seizure generation and potential seizure suppression that may be unique to therapy resistant epilepsy. This application is in response to a Request for Applications announcement to improve the therapy discovery process for these patients. The RFA is seeking validation of pharmacoresistance in a post status epilepticus model of limbic epilepsy. In the course of this project we will achieve several goals that will meet the primary purpose of this RFA. Overall we will establish a tool that can be used to test potential new therapies, but as steps in meeting this goal we will determine the most efficient way of using the model, and we will create and validate methods for administering therapeutic doses of compounds in a chronic rodent model of epilepsy with intermittent spontaneous seizures. This project will meet the program goals by establishing baseline data and introducing new methods for evaluating the therapeutic potential of novel compounds for the treatment of epilepsy.