Use of chronic epilepsy models in antiepileptic drug discovery: The effect of topiramate on spontaneous motor seizures in rats with kainate-induced epilepsy

Purpose: Potential antiepileptic drugs (AEDs) are typically screened on acute seizures in normal animals, such as those induced in the maximal electroshock and pentylenetetrazole models. As a proof-of-principle test, the present experiments used spontaneous epileptic seizures in kainate-treated rats to examine the efficacy of topiramate (TPM) with a repeated-measures, crossover protocol. Methods: Kainic acid was administered in repeated low doses (5 mg/kg) every hour until each Sprague-Dawley rat experienced convulsive status epilepticus for > 3 h. Six 1-month trials (n = 6-10 rats) assessed the effects of 0.3-100 mg/kg TPM on spontaneous seizures. Each trial involved six pairs of TPM and saline-control treatments administered as intraperitoneal injections on alternate days with a recovery day between each treatment day. Data analysis included a log transformation to compensate for the asymmetric distribution of values and the heterogeneous variances, which appeared to arise from clustering of seizures. Results: A significant effect of TPM was observed for 12 h (i.e., two 6-h periods) after a 30-mg/kg injection, and full recovery from the drug effect was complete within 43 h. TPM exerted a significant effect at doses of 10, 30, and 100 mg/kg, and the effects of TPM (0.3-100 mg/kg) were dose dependent. Conclusions: These data suggest that animal models with spontaneous seizures, such as kainate- and pilocarpine-treated rats, can be used efficiently for rapid testing of AEDs with a repeated-measures, crossover protocol. Furthermore, the results indicate that this design allows both dose-effect and time-course-of-recovery studies.