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

Abstract

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 (~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 (ED 50 ) 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 Ca 2+ channels show differential activity: Ethosuximide was not effective, whereas gabapentin 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.

Spontaneous recurrent seizures in an intra-amygdala kainate microinjection model of temporal lobe epilepsy are differentially sensitive to antiseizure drugs

“…Doses were chosen based on efficacy and toxicity results in pilot studies or from previously reported data in rats from established models including the LTG-kindled rat (LTG-R) model and the i.p. KA spontaneously seizing rat model of TLE ( Metcalf et al, 2019 ; Thomson et al, 2020 ). In all six experiments, separate cohorts of IAK mice were generated as described.…”

Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options

“…In contrast, valproate exerted potent anticonvulsant effects in lamotrigine-resistant kindled rats. More recently, Metcalf et al (2019) described the dose response effects of numerous ASDs in this model. Five sodium channel blockers (eslicarbazepine, lacosamide, lamotrigine, phenytoin, and rufinamide) were either not efficacious or effective only at doses that were not well-tolerated in this model.…”

Evaluation of subchronic administration of antiseizure drugs in spontaneously seizing rats

“…The dose tested (30 mg/ kg bid) was selected based on the literature 35 and acute models with this compound. 16 Treatment with LTG resulted in ataxia and lethargy, but these were not observed until several doses had been administered. This is suggestive of an accumulation effect of the drug or a metabolite, but verification of this observation was beyond the scope of this study.…”

“…Drugs chosen for testing in this model were selected from the cohort of currently available clinical treatments for epilepsy. Doses were chosen based on efficacy and toxicity results from previous standard 15,16 tests in rats, including the maximal electroshock ED 50, the LTG-kindled rat (LTG-R) model, 16 and the minimal motor impairment toxicity test, as well as from literature references. A complete list of drugs, including their abbreviations, doses, and frequency of administration are included in Table 1, along with literature references that were used to determine an appropriate subchronic dose.…”