Pilocarpine-induced epilepsy in mice alters seizure thresholds and the efficacy of antiepileptic drugs in the 6-Hertz psychomotor seizure model

Abstract

The 6-Hz psychomotor seizure model in mice is increasingly been used as a model for differentiation of anticonvulsant activity during development of new antiepileptic drugs (AEDs). It was previously proposed as a useful model of AED-resistant seizures, but more recent data have cast doubt on this proposal. The aim of the present study was to determine whether performing the 6-Hz test not in normal but epileptic mice renders the 6-Hz test more resistant to AEDs. Furthermore, thresholds for induction of 6-Hz seizures, maximal electroshock seizures (MES) and pentylenetetrazole (PTZ) seizures were compared in normal and epileptic mice, using the pilocarpine model. Epileptic mice had a significantly lower threshold for induction of 6-Hz seizures and were more susceptible to PTZ, whereas the MES threshold was not altered. Unexpectedly, 6-Hz seizures were not more resistant to AEDs in epileptic vs. nonepileptic mice, but instead showed an increased sensitivity to the anticonvulsant effects of some AEDs, particularly levetiracetam. The anticonvulsant ED50 of levetiracetam in the 6-Hz test (using a 32mA stimulus) was 17.6mg/kg in nonepileptic mice, but only 1.5mg/kg in epileptic mice. The data indicate that the complex pathophysiological and functional alterations associated with epilepsy in mice may strikingly alter the sensitivity of acutely induced seizures to an AED.

Keywords: AED; CC; ED; Hertz; Hz; Levetiracetam; MES; PTZ; Pharmacoresistance; Phenobarbital; Phenytoin; Retigabine; SE; SV2A; TLE; antiepileptic drug; convulsant current; effective dose; maximal electroshock seizure; pentylenetetrazole; status epilepticus; synaptic vesicle protein 2A; temporal lobe epilepsy.