Anticonvulsant drug effects in the direct cortical ramp-stimulation model in rats: comparison with conventional seizure models.
A modified cortical ramp stimulation (CRS) model has been developed allowing repeated determinations of seizure threshold at short time intervals in individual rats without inducing postictal threshold increases. Anticonvulsant potency of the standard antiepileptic drugs carbamazepine, phenytoin, phenobarbital, valproate, diazepam and ethosuximide in the CRS model was compared with respective drug potencies in two more traditional seizure models with transcorneal stimulus application, i.e., the minimal electroshock seizure threshold (minEST) and the maximal electroshock seizure threshold (maxEST). In the CRS model, two different types of threshold were determined, the threshold for localized seizures (TLS) and the threshold for generalized seizures (TGS). When screw electrodes were implanted over the primary motor cortex, TLS was characterized by unilateral forelimb clonus, tonic abduction of contralateral forelimb, and head adversion. When ramp-shaped stimulation was continued above the TLS current, bilateral clonic forelimb seizures with loss of posture developed, which was defined as TGS. In contrast to TLS, TGS could not be repeatedly determined at short time intervals because of postictal threshold increase. TLS was dose-dependently increased by carbamazepine, phenobarbital, valproate and diazepam, although phenytoin showed a truncated dose-response, and ethosuximide was ineffective. In comparison to TLS, drug-induced increases in TGS were more marked. All drugs dose-dependently increased minEST and, except ethosuximide, maxEST. For comparison of drug potencies, doses increasing seizure thresholds by 20 or 50% were calculated from dose-response curves. Respective comparisons showed marked differences in drug potencies between models, indicating that the CRS method presents a model of another, more pharmacoresistant seizure type than seizure types induced in traditional models, such as transcorneal electroshock. Based on the location of electrodes in the frontal neocortex, the characteristic seizure pattern, and the low pharmacological sensitivity of the seizures to standard antiepileptics, the modified CRS model most likely represents a new model of localization-related seizures occurring in frontal lobe epilepsy and may thus be used in the search for novel drugs with higher efficacy against this difficult-to-treat type of epilepsy.
Krupp
E
E
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Löscher
W
W
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D002220:Carbamazepine / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004569:Electroencephalography; D005260:Female; D010634:Phenobarbital / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000517:prevention & control*; D013997:Time Factors; D014635:Valproic Acid / Q000627:therapeutic use
D000927:Anticonvulsants; D002220:Carbamazepine; D014635:Valproic Acid; D010634:Phenobarbital