The use of chronic models of temporal lobe epilepsy in antiepileptic drug development
Date
2007
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Abstract
A chronic animal model with altered ion channels, transmitter receptors and/or neural circuitry similar to temporal lobe epilepsy (TLE) may be useful in the discovery of new antiepileptic drugs (AEDs). The hypothesis was that rats with kainate-induced epilepsy are pharmacosensitive to AEDs, but high doses do not block all spontaneous seizures (i.e., these rats are "pharmacoresistant"). A repeated-measures cross-over protocol was used to show single intraperitoneal injections of topiramate, RWJ-333369, and carbamazepine reduced the frequency of spontaneous motor seizures. The same protocol with administration of 30 mg/kg and 100 mg/kg carbamazepine in specially-formulated food pellets was as effective as intraperitoneal injections, and 100 mg/kg carbamazepine administered in food three times per day completely suppressed motor seizures in 50% of the animals for a prolonged time period (i.e., 24 h) while reducing any stress to the animals. Video-EEG showed carbamazepine preferentially reduced spontaneous convulsive seizures compared to nonconvulsive seizures at 100 mg/kg, reduced seizure duration in some animals at 100 mg/kg, and caused a subtle decrease in the maximum frequency of population spikes during seizures at 30 mg/kg. These data suggest that animal models of TLE with spontaneous seizures can be used efficiently to test AEDs, and that this repeated-measures cross-over protocol is amenable to both dose-effect and time-course-of-recovery studies for the direct comparison of AEDs. This approach can provide statistical power to compensate for seizure clusters and variability across animals. These experiments also show that rats with kainate-induced epilepsy are pharmacosensitive to standard and experimental AEDs; additional studies are required to determine if this model is also pharmacoresistant.
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Subject
antiepileptic drugs
carbamazepine
drug development
epilepsy
kaninic acid
RWJ-333369
spontaneous seizures
temporal lobe epilepsy
topiramate
neurology