Pharmacoresistance in rats with kainate-induced epilepsy

描述(申请人提供)：约30-40%的癫痫患者在接受抗癫痫药物(AED)治疗期间仍有癫痫发作。如果这些人在接受两种AED治疗后没有完全缓解癫痫发作，那么他们被认为是顽固的或“耐药”的，而且通常他们在可能包括三种或更多AED的综合治疗方案中继续癫痫发作。美国国立卫生研究院支持的研讨会最近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过后，具有自发性反复发作的慢性癫痫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红藻氨酸诱导的癫痫大鼠的潜在AED。在最初的研究中，这些大鼠在单次腹腔注射托吡酯后表现出剂量依赖性的癫痫发作减少，但在最高剂量(即100毫克/公斤)后继续癫痫发作。拟议的实验将在重复测量交叉设计的变化过程中使用录像的运动性癫痫的行为分析(盲法)，以解决以下问题：患有红藻氨酸诱导的癫痫的大鼠是否对持续数天的高剂量托吡酯耐受？他们对卡马西平的类似治疗有抵抗力吗？卡马西平可能是最广泛使用的AED。在卡马西平持续治疗期间，当托吡酯被用作“附加物”时，这些大鼠对托吡酯有耐药性吗？最后，一些相同的实验方案将被用来研究AED对自发性癫痫发作的影响，在大鼠身上植入了颅内海马和硬膜下螺旋电极，这将使AED对非惊厥性癫痫的直接评估成为可能。这项研究的一个长期目标是检验这样的假设，即这些AED在癫痫形成过程的早期是有效的，但在癫痫发作更频繁和更严重的稍后时间点不是有效的。本方案中的实验旨在确定红藻氨酸诱导的癫痫大鼠是否表现出药物耐药性，以及这种自发性反复发作的动物模型是否适合测试针对药物耐药性癫痫设计的新的AED。

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.