Pharmacoresistance in rats with kainate-induced epilepsy

描述（由申请人提供）：大约30-40%的癫痫患者在使用抗癫痫药物（AED）治疗期间继续发作。如果这些患者在使用两个AED治疗后仍未消除癫痫发作，则被认为是难治性或“耐药”，并且在可能使用三个或更多AED的综合治疗方案中，他们通常仍有癫痫发作。美国国立卫生研究院支持的一个研讨会最近发表的一份共识报告表明，在电或化学诱导的癫痫持续状态潜伏期后，慢性癫痫自发性复发发作的动物模型可能有助于为耐药人群识别新的AED。我们已经开发了一种重复测量交叉方案来测试kainate诱导癫痫大鼠的潜在AED。在一项初步研究中，这些大鼠在单次腹腔注射托吡酯后癫痫发作呈剂量依赖性减少，但在最高剂量（即100 mg/kg）后仍有癫痫发作。拟议的实验将在重复测量交叉设计的变化过程中使用运动癫痫录像（采用盲法）的行为分析来解决以下问题：kainate诱导的癫痫大鼠对持续数天的高剂量托吡酯是否具有耐药性？它们是否对卡马西平（可能是最广泛使用的AED）的类似治疗产生耐药性？当托吡酯在卡马西平持续治疗期间作为“附加”使用时，这些大鼠对托吡酯是否有耐药性？最后，一些相同的实验方案将用于研究AED对自发性电图癫痫发作的影响，在实验中，大鼠已经植入了颅内海马和硬膜下螺钉电极，这将允许直接评估AED对非惊厥性癫痫发作的影响。这项研究的一个长期目标是验证这种假设，即这些AED在癫痫发生过程的早期有效，但在癫痫发作更频繁和严重的后期时间点无效。本实验旨在确定盐酸盐诱导的癫痫大鼠是否具有药物抗性，以及该动物模型是否适合用于抗药癫痫的新型AED实验。

DESCRIPTION (provided by applicant): Approximately 30-40% of people with epilepsy continue to have seizures during treatment with antiepileptic drugs (AED). These individuals are considered to be intractable or "pharmacoresistant" if they do not become seizure-free after treatment with two AED, and often they continue to have seizures during polytherapy protocols that may include three or more AED. A recent consensus report from an NIH-supported workshop has suggested that animal models of chronic epilepsy with spontaneous recurrent seizures, following a latent period from electrically or chemically induced status epilepticus, may be useful for identifying new AED for the pharmacoresistant population. We have developed a repeated-measures crossover protocol to test potential AED in rats with kainate-induced epilepsy. In an initial study, these rats showed a dose-dependent decrease in seizures after single intraperitoneal injections of topiramate, but continued to have seizures after the highest dose (i.e., 100 mg/kg). The proposed experiments will use behavioral analysis of videotaped motor seizures (with blind procedures) during variations of this repeated-measures cross-over design to address the following issues: Are rats with kainate-induced epilepsy pharmacoresistant to high doses of topiramate lasting several days? Are they resistant to similar treatments of carbamazepine, which is probably the most widely used AED? Are these rats pharmacoresistant to topiramate when it is used as an "add-on" during continuous treatment with carbamazepine? Finally, some of these same experimental protocols will be used to study the effects of AED on spontaneous electrographic seizures in experiments on rats that have been implanted with intracranial hippocampal and subdural screw electrodes, which will allow direct assessment of AED on non-convulsive seizures. One long-term goal of this research is to test the hypothesis that these AED are effective early in the epileptogenic process, but not at later time points when seizures are more frequent and severe. The experiments in this proposal aim to determine whether rats with kainate-induced epilepsy show pharmacoresistance, and whether this animal model of spontaneous recurrent seizures is suitable for testing new AED designed against pharmacoresistant epilepsy.