Pharmacoresistance in rats with kainate-induced epilepsy

描述（由申请人提供）：大约30-40%的癫痫患者在抗癫痫药物（AED）治疗期间继续癫痫发作。 如果这些个体在用两种AED治疗后没有变得无癫痫，则被认为是难治性或“药物抗性”的，并且通常他们在可能包括三种或更多种AED的多药治疗方案期间继续癫痫发作。 最近一份来自NIH支持的研讨会的共识报告表明，在电或化学诱导的癫痫持续状态潜伏期后，自发复发性癫痫发作的慢性癫痫动物模型可能有助于为耐药性人群确定新的AED。 我们已经开发了一种重复测量的交叉协议，以测试潜在的AED在红藻氨酸诱导的癫痫大鼠。 在最初的研究中，这些大鼠在单次腹膜内注射托吡酯后显示出癫痫发作的剂量依赖性减少，但在最高剂量后继续癫痫发作（即，100 mg/kg）。 拟议的实验将使用行为分析的录像运动癫痫发作（盲法）在这种重复措施的交叉设计的变化，以解决以下问题：红藻氨酸诱导的癫痫大鼠的药物耐药高剂量的托吡酯持续数天？ 他们是否对卡马西平（可能是最广泛使用的AED）的类似治疗有耐药性？ 当托吡酯作为卡马西平连续治疗的“添加剂”时，这些大鼠是否对托吡酯产生药物抗性？ 最后，这些相同的实验方案中的一些将用于研究AED对植入颅内海马和硬膜下螺旋电极的大鼠实验中自发性电描记癫痫发作的影响，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测试这一假设，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。 本提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抗性，以及这种自发复发性癫痫发作的动物模型是否适合用于测试针对药物抗性癫痫设计的新型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.