Use of chronic epilepsy models in antiepileptic drug discovery: the effect of topiramate on spontaneous motor seizures in rats with kainate-induced epilepsy.
OBJECTIVE
Potential antiepileptic drugs (AEDs) are typically screened on acute seizures in normal animals, such as those induced in the maximal electroshock and pentylenetet-razole 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.
Grabenstatter
Heidi L
HL
Department of Biomedical Sciences, Anatomy and Neurobiology Section, Colorado State University, Fort Collins, Colorado 80523, USA.
Ferraro
Damien J
DJ
Williams
Philip A
PA
Chapman
Phillip L
PL
Dudek
F Edward
FE
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002908:Chronic Disease; D018592:Cross-Over Studies; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000706:statistics & numerical data; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D005632:Fructose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D007608:Kainic Acid; D010862:Pilocarpine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012107:Research Design / Q000592:standards; D012965:Sodium Chloride / Q000494:pharmacology; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D000077236:Topiramate
D000927:Anticonvulsants; D010862:Pilocarpine; D000077236:Topiramate; D005632:Fructose; D012965:Sodium Chloride; D007608:Kainic Acid