Abstracts

Potential antiepileptic drugs (AEDs) are typically screened on acute seizures, such as those induced in the maximal electroshock and pentylenetetrazol seizure models. Animal models of chronic epilepsy with spontaneous seizures may be useful for developing new drugs to treat the pharmacoresistant population. The present experiments evaluate the efficacy of topiramate (TPM) on spontaneous epileptic seizures in kainate-treated rats using a repeated-measures, cross-over protocol.
Kainic acid was administered in repeated, low doses (5 mg/kg) every hour until each Sprague-Dawley rat experienced convulsive status epilepticus for [gt]3 h. Five 1-month-long trials (n=6-8 rats) were conducted to assess the effects of 1, 3, 10, 30, and 100 mg/kg TPM on spontaneous seizures. Each trial involved six pairs of TPM and saline-control treatments administered IP on alternate days with a recovery day between each treatment day. Data analysis included a log transformation to compensate for clustering of seizures.
Using the protocol described above, TPM decreased the number of seizures that occurred during the first 6-h observation period (which began 1 h after the injection). TPM exerted a significant (p[lt]0.05) effect at doses of 10, 30, and 100 mg/kg, and the effects of TPM (1-100 mg/kg) were dose dependent. At a concentration of 30 mg/kg, TPM decreased the frequency of motor seizures by about half (49[plusmn]20%). Another analysis examined recovery from the single 30-mg/kg injections of TPM; the number of seizures observed during successive 6-hour periods was tabulated over the 2-day period between injections. A significant effect of TPM (p[lt]0.05) was observed for 12 h after the 30-mg/kg injection, and full recovery from the drug effect was complete within 24 h.
Using a single-injection treatment protocol with a repeated-measures cross-over design, TPM reduced spontaneous recurrent motor seizures in a dose-dependent manner (1-100 mg/kg). These data suggest that animal models with spontaneous seizures, such as kainate- and pilocarpine-treated rats, can be used efficiently for testing AEDs. Further experiments testing novel potential AEDs are needed to evaluate more rigorously whether this type of protocol will be useful for identifying drugs that are more efficacious for patients with pharmacoresistant injury-induced epilepsy.
[Supported by: Johnson and Johnson Pharmaceutical Research and Development, LLC]