Kindling alters the anticonvulsant efficacy of phenytoin in Wistar rats.
We have previously shown that subgroups can be selected from large groups of amygdala kindled Wistar rats which either respond consistently or do not respond to the anticonvulsant effect of phenytoin. Phenytoin nonresponders were proposed as a model for pharmaco-resistant temporal lobe epilepsy. In the present study we examined whether the differences of individual rats in response to phenytoin are already present before kindling or are a consequence of kindling. For this purpose, 52 rats were once tested with phenytoin, then kindled, and then repeatedly tested with phenytoin for selection of subgroups. For subgroup selection after kindling, the phenytoin prodrug fosphenytoin was used because of its water solubility and its improved tolerability and absorption after i.p. administration in rats. Before kindling, phenytoin significantly increased the afterdischarge threshold (ADT), i.e. a sensitive measure of focal seizure activity, but there was large individual variation with only 32 of the 52 rats reacting with an ADT increase, while the remaining rats showed either no effect or ADT decreases. After kindling, the selection resulted in 16 rats with consistent ADT increases in response to phenytoin and ten nonresponders (the remaining 26 rats showed variable responses). Unexpectedly, in rats which were responders after kindling, phenytoin exerted no significant anticonvulsant effect before kindling, while kindled nonresponders were very sensitive to phenytoin before kindling, indicating that the kindling process was responsible for the loss of anticonvulsant efficacy in kindled nonresponders and the development of phenytoin's efficacy in kindled responders. The present results substantiate that kindled subgroups of Wistar rats with different response to phenytoin are a valuable source for studying the mechanisms underlying the development of pharmaco-resistant limbic seizures.
Löscher
W
W
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Bünteweg 17, D-30559, Hannover, Germany. wloscher@pharma.tiho-hannover.de
Reissmüller
E
E
Ebert
U
U
D000679:Amygdala / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000494:pharmacology*; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D004827:Epilepsy / Q000523:psychology; D005260:Female; D007206:Individuality; D007696:Kindling, Neurologic / Q000502:physiology*; D010672:Phenytoin / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000503:physiopathology
D000927:Anticonvulsants; D010672:Phenytoin