KINDLING INCREASES THE SENSITIVITY OF RATS TO ADVERSE-EFFECTS OF CERTAIN ANTIEPILEPTIC DRUGS

Development of novel antiepileptic drugs (AEDs) requires determining the margin between the desired anticonvulsant effect and undesired adverse effects (AE) (therapeutic index). For this purpose, drug-induced ''minimal neurological deficits'' (e.g., motor dysfunctions) are commonly quantified by simple tests, such as the rotarod test, in normal, i.e., nonepileptic animals. However, increasing evidence shows that chronic brain dysfunction associated with epilepsy may increase susceptibility to the AE of certain AEDs, e.g., N-methyl-D-aspartate (NMDA) receptor antagonists. The increased AE potential of such investigational drugs can be predicted by using kindled rats instead of normal rodents in preclinical drug evaluation studies. In the present experiments, we wished to determine whether kindled rats also exhibit an altered susceptibility to neurological adverse effects of standard AEDs, i.e., carbamazepine (CBZ), phenobarbital (PB), valproate (VPA), and diazepam (DZP). Abecarnil, a novel benzodiazepine (BZD) receptor agonist, was included in the study for comparison. All drugs were administered in diverse doses in kindled and nonkindled rats, and all behavioral alterations were scored in the cage and open field. Furthermore, the rotarod test was used to detect and quantify motor impairment induced by drug treatments. Kindled rats were more susceptible than nonkindled rats to motor impairment (ataxia and/or rotarod failures) induced by high doses of AEDs, although differences were noted between the drugs tested. VPA was the only drug that induced stereo-typed behavior; it was much more potent in this respect in kindled than nonkindled rats. Abecarnil did not differ substantially in its AE in either subgroup of animals. Our data indicate that epileptogenesis induced by kindling renders the brain more susceptible to certain AE of AEDs. To avoid overestimation of the therapeutic index, models such as kindling should be used during preclinical evaluation of new AEDs.