Screening and characterization of antiepileptic drugs with rapidly recurring hippocampal seizures in rats

Abstract

A method to efficiently screen antiepileptic drugs (AED) for their actions against complex partial and secondarily generalized seizures is presented. The procedure relies on rapidly recurring hippocampal seizures (RRHS) in rats which are first used to bring epileptic responses to a stable, fully kindled state and then to test 3 parameters--behavioral seizures, electrographic seizures, and afterdischarge thresholds--before and after drug administration. With the methods described, the effects of a given drug treatment can be thoroughly determined in a single study period. Quantitative determinations of dose-response, time-action and relative potency characteristics are readily ascertained. A battery of known AED, encompassing those in common clinical use, was studied with this system. Kindled motor seizures (classes 4 and 5) were more readily suppressed than limbic behavioral seizures (classes 1-3). Electrographic seizures were usually, but not always, shortened concurrently with suppression of behavioral seizures. Under the conditions of this study, afterdischarge thresholds were not elevated, indicating that a critical role of AED is to counteract seizure spread and prolongation. The overall behavior of the RRHS test system with AED was identical to that with traditional amygdala kindled seizures and results were in good agreement with the clinical responsiveness of the kinds of seizures that these experimental systems model. The features of RRHS make it a useful system for screening new agents for antiepileptic effects, even in circumstances where little or no information about the drug under study is available.