Pharmacoresistance in rats with kainate-induced epilepsy

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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.