Anticonvulsant efficacy of topiramate in phenytoin-resistant kindled rats

Purpose: We evaluated the anticonvulsant efficacy of topiramate (TPM), a st ructurally novel antiepileptic drug (AED), in amygdala kindled rats that ha d been preselected with respect to their response to phenytoin (PHT). Methods: Anticonvulsant response was tested by determining the afterdischar ge threshold (ADT; i.e., a sensitive measure for drug effects on focal seiz ure activity). By repeated testing with the PHT prodrug fosphenytoin (FOS) three groups of kindled rats were separated: rats in which consistent antic onvulsant effects were obtained (PHT responders), rats that showed no antic onvulsant response (PHT nonresponders), and rats with variable responses (v ariable PHT responders). The latter, largest group was used to evaluate at which doses and pretreatment times TPM exerted significant anticonvulsant e ffects on ADT. For this purpose, TPM was tested at four doses (20, 40, 80, 160 mg/kg i.p.) and two pretreatment times (1 and 4 h). The most effective treatment protocol was then used for TPM testing in PHT responders and nonr esponders. Results: TPM proved to be an effective AED in the kindling model. At 40 mg/ kg, significant ADT increases were obtained after both 1 and 4 h after admi nistration. In addition to the effect on focal seizure threshold, seizure s everity and duration recorded at ADT were decreased by TPM, indicating that this drug acts on both seizure threshold and seizure spread. In PHT nonres ponders, TPM significantly increased ADT, which is in line with its proven efficacy in patients with refractory partial epilepsy in whom phenytoin has failed. However, TPM was more efficacious in increasing ADT in PHT respond ers than in nonresponders, substantiating that the difference between these groups of kindled rats extends to other AEDs. Repeated testing of kindled rats with TPM indicated that, similar to PHT, there are individual kindled rats without anticonvulsant response to TPM (i.e., TPM nonresponders). Conclusions: The data of this study substantiate that PHT nonresponders are a unique model for the search of new AEDs with improved efficacy in refrac tory partial epilepsy.