Anticonvulsant efficacy of gabapentin and levetiracetam in phenytoin-resistant kindled rats.
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.
Löscher
W
W
Department of Pharmacology, School of Veterinary Medicine, Bünteweg 17, D-30559, Hannover, Germany. wloscher@pharma.tiho-hannover.de
Reissmüller
E
E
Ebert
U
U
D000085:Acetates / Q000494:pharmacology*; D000588:Amines; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003509:Cyclohexanecarboxylic Acids; D004341:Drug Evaluation; D004351:Drug Resistance; D005260:Female; D000077206:Gabapentin; D007696:Kindling, Neurologic; D000077287:Levetiracetam; D010672:Phenytoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000209:etiology / Q000503:physiopathology*; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D000077287:Levetiracetam; D005680:gamma-Aminobutyric Acid; D010672:Phenytoin; D000077206:Gabapentin; C043114:fosphenytoin; D010889:Piracetam