Pharmacoresistant limbic epilepsy: model validation

描述(申请人提供)：尽管大多数癫痫患者通过现有药物成功地控制了他们的癫痫发作，但大约三分之一的患者在尝试多种药物治疗的情况下仍有癫痫发作。这一群体被定义为治疗抵抗，也是最需要更有效治疗的群体。尽管有迅速扩大的证据表明，治疗抵抗患者的大脑中存在可能改变药理学反应的多种变化，但治疗发现过程依赖于使用正常动物大脑中急性诱导的癫痫发作。这种方法很可能没有解决癫痫发作的产生机制和潜在的癫痫发作抑制机制，而这些机制可能是难治性癫痫所特有的。这项申请是对申请公告的回应，目的是改善这些患者的治疗发现过程。RFA正在寻求对边缘癫痫持续状态后模型的药物耐药性进行验证。在这个项目的过程中，我们将实现几个目标，以满足本RFA的主要目的。总体而言，我们将建立一个可用于测试潜在新疗法的工具，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，并将创建并验证在具有间歇性自发发作的慢性啮齿动物癫痫模型中给予化合物治疗剂量的方法。该项目将通过建立基线数据和引入新的方法来评估用于治疗癫痫的新化合物的治疗潜力，从而实现方案目标。

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.