Evaluation of models of pharmacoresistant epilepsy

University Of Utah, Salt Lake City UT

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Abstract

DESCRIPTION (provided by applicant): Despite recent advances in the treatment of epilepsy, more than 35-40% of the 2.5 million Americans receiving antiepileptic drugs (AED) remain refractory to existing AED therapies. In order to better understand the etiology of pharmacorestance to AED and to facilitate the development of innovative therapeutic approaches for the management of pharmacoresistant epilepsy, there is a great need to validate and systematically characterize drug effects in both in vivo and in vitro animal models that display persistent seizure activity (or seizure-like activity in vitro) which is refractory or responds poorly to at least two differentially acting AED at maximal tolerated doses. The goal of the current proposal is therefore to test the hypothesis that "the 'entorhinal-hippocampal slice' and the "lamotrigine (LTG)-resistant kindled rat' models are pharmacoresistant to established antiepileptic drugs and that AED found effective in one or both of these models would be novel relative to the currently available AED." This hypothesis will be tested by utilizing a two-tiered approach wherein the effects of multiple standard and investigational AED will be assessed according to the following two Specific Aims. Specific Aim 1 will evaluate the ability of a battery of mechanistically distinct established and investigational AED to eliminate spontaneous, electrographic seizure-like activity recorded in the medial entorhinal cortex in brain slices obtained from animals treated with kainic acid (KA). Specific Aim 2 will evaluate the ability of a battery of mechanistically distinct established and investigational AED to suppress focal and generalized seizures in LTG-resistant amygdala-kindled rats. Dose-response relationships will be determined in vitro for at least thirteen different "standard" and "investigational" AED therapies: phenytoin, carbamazepine, valproate, ethosuxamide, vigabatrin, topiramate, lamotrigine, felbamate, levetiracetam, harkoseride, tiagabine, valrocemide, and retigabine. Furthermore, these drugs will be evaluated in vivo for their ability to inhibit focal and generalized seizure activity in both the traditional and lamotrigine-resistant amygdala kindled rat models of temporal lobe epilepsy. These experiments will establish a comparative database for traditional and nontraditional AED in both in vitro and in vivo models, provide insight towards the predictive value of pharmacoresistance observed with in vitro screening paradigms for identifying pharmacoresistance observed with in vivo models of pharmacoresistant epilepsy, and set the stage for the development of future therapeutic interventions for the treatment of pharmacoresistant epilepsy.