Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine-resistant amygdala kindling model

Objective: The lamotrigine-resistant amygdala kindling model uses repeated administration of a low dose of lamotrigine during the kindling process to produce resistance to lamotrigine, which also extends to some other antiseizure drugs (ASDs). This model of pharmacoresistant epilepsy has been incorporated into the testing scheme utilized by the Epilepsy Therapy Screening Program (ETSP). Although some ASDs have been evaluated in this model, a comprehensive evaluation of ASD prototypes has not been reported. Methods: Following depth electrode implantation and recovery, rats were exposed to lamotrigine (5 mg/kg, i.p.) prior to each stimulation during the kindling development process (similar to 3 weeks). A test dose of lamotrigine was used to confirm that fully kindled rats were lamotrigine-resistant. Efficacy (unambiguous protection against electrically elicited convulsive seizures) was defined as a Racine score < 3 in the absence of overt compound-induced side effects. Various ASDs, comprising several mechanistic classes, were administered to fully kindled, lamotrigine-resistant rats. Where possible, multiple doses of each drug were administered in order to obtain median effective dose (ED50) values. Results: Five sodium channel blockers tested (eslicarbazepine, lacosamide, lamotrigine, phenytoin, and rufinamide) were either not efficacious or effective only at doses that were not well-tolerated in this model. In contrast, compounds targeting either GABA receptors (clobazam, clonazepam, phenobarbital) or GABA-uptake proteins (tiagabine) produced dose-dependent efficacy against convulsive seizures. Compounds acting to modulate Ca2+ channels show differential activity: Ethosuximide was not effective, whereas gahapentin was moderately efficacious. Ezogabine and valproate were also highly effective, whereas topiramate and levetiracetam were not effective at the doses tested. Significance: These results strengthen the conclusion that the lamotrigine-resistant amygdala kindling model demonstrates pharmacoresistance to certain ASDs, including, but not limited to, sodium channel blockers, and supports the utility of the model for helping to identify compounds with potential efficacy against pharmacoresistant seizures.