We evaluated the
anticonvulsant efficacy of the new
antiepileptic drugs (AEDs)
gabapentin and
levetiracetam in amygdala kindled rats that had been preselected with respect to their response to
phenytoin.
Anticonvulsant response was tested by determining the afterdischarge threshold (ADT), i.e. a sensitive measure for
drug effects on
focal seizure activity. By repeated testing with the
phenytoin prodrug fosphenytoin, three groups of kindled rats were separated: rats in which consistent
anticonvulsant effects were obtained (
phenytoin responders), rats which showed no
anticonvulsant response (
phenytoin nonresponders), and rats with variable responses (variable
phenytoin responders). The latter, largest group was used to evaluate at which doses
gabapentin and
levetiracetam exerted significant
anticonvulsant effects on ADT 1 h after i.p.
drug administration. Effective doses were then used for
drug testing in
phenytoin responders and nonresponders. Both
gabapentin and
levetiracetam proved to be effective
anticonvulsant drugs in the kindling model by significantly increasing the ADT. In addition, both drugs markedly decreased seizure severity recorded at ADT currents, indicating that these drugs affect seizure threshold in the epileptic focus and seizure spread from the focus in the kindling model. When the threshold for secondary
generalized seizures (GST) was determined in addition to ADT,
gabapentin and
levetiracetam strikingly increased this threshold compared to predrug control. In
phenytoin nonresponders,
gabapentin and
levetiracetam significantly increased ADT and GST, which is in line with their proven efficacy in patients with refractory
partial epilepsy in whom older AEDs have failed. In
phenytoin responders,
gabapentin tended to be more efficacious in increasing ADT and GST than in nonresponders, substantiating that the difference between these groups of kindled rats extends to other AEDs. In contrast to
gabapentin,
levetiracetam was more efficacious in increasing ADT in nonresponders than in responders. The data of this study substantiate that
phenytoin nonresponders are a unique model for the search of new AEDs with improved efficacy in refractory
partial epilepsy.