The goal of this research is to test the hypothesis that as epileptogenesis progresses, the duration and intensity of seizures increases due to cellular and molecular alterations and rats with kainate-induced epilepsy become refractory to pharmacotherapy. The dose effects of the traditional AED, carbamazepine, on spontaneous convulsive seizure activity will be tested late vs. early during the process of epileptogenisis to evaluate whether pharmacoresistance develops over time. As seizure frequency increases during prolonged epileptogenesis, if the hypothesis is correct, we expect to observe a reduced response of spontaneous convulsive seizures to carbamazepine at 6 months vs. 2 months after status epilepticus. The development of refractoriness in sub-clinical, nonconvulsive seizures (i.e., complex partial seizures) will be studied using chronically epileptic animals implanted with a depth-recording electrode in the dentate granule cell layer of the dentate gyrus. The seizure duration and inter-seizure interval will be measured using chronic in vivo recordings to evaluate the potential that electrographic seizures become pharmacoresistant to carbamazepine over time (i.e., 2 month vs. 6 months).
We aim to test whether the progressive development of pharmacoresistance persists during prolonged, high-dose carbamazepine treatment and if a treatment regime of this nature will completely suppress all convulsive seizures. We believe these studies will provide valuable pre-clinical data related to the development of pharmacoresistance. ? ?
|Grabenstatter, Heidi L; Clark, Suzanne; Dudek, F Edward (2007) Anticonvulsant effects of carbamazepine on spontaneous seizures in rats with kainate-induced epilepsy: comparison of intraperitoneal injections with drug-in-food protocols. Epilepsia 48:2287-95|