Use of Chronic Epilepsy Models in Antiepileptic Drug Discovery: The Effect of Topiramate on Spontaneous Motor Seizures in Rats with Kainate‐induced Epilepsy

• Published in: Epilepsia (Copenhagen) Vol. 46; no. 1; pp. 8 - 14
• Main Authors: Grabenstatter, Heidi L., Ferraro, Damien J., Williams, Philip A., Chapman, Phillip L., Dudek, F. Edward
• Format: Journal Article
• Language: English
• Published: 350 Main Street , Malden , MA 02148 , USA and 9600 Garsington Road , Oxford , OX4 2XG , England Blackwell Science Inc 01.01.2005; Blackwell
• Subjects: Animals; Anticonvulsants - administration & dosage; Anticonvulsants - pharmacology; Anticonvulsants - therapeutic use; Anticonvulsants. Antiepileptics. Antiparkinson agents; Antiepileptic drug trials; Biological and medical sciences; Chronic Disease; Cross-Over Studies; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical - methods; Drug Evaluation, Preclinical - statistics & numerical data; Epilepsy - chemically induced; Epilepsy - drug therapy; Epilepsy - prevention & control; Fructose - administration & dosage; Fructose - analogs & derivatives; Fructose - pharmacology; Fructose - therapeutic use; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Injections, Intraperitoneal; Kainate; Kainic Acid; Medical sciences; Nervous system (semeiology, syndromes); Neurology; Neuropharmacology; Neuroprotective agent; Pharmacology. Drug treatments; Pilocarpine; Rats; Rats, Sprague-Dawley; Research Design - standards; Sodium Chloride - pharmacology; Status Epilepticus - chemically induced; Status Epilepticus - drug therapy; Status Epilepticus - prevention & control; Topiramate; Topiramate; Nervous system diseases; Rat; Epilepsy; Rodentia; Anticonvulsant; Discoveries; Epilepsy provoked by; Cerebral disorder; Vertebrata; Chronic; Mammalia; Animal; Antiepileptic drug trials- Topiramate-Kainate; Central nervous system disease; Models
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/j.0013-9580.2005.13404.x

Purpose: 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.