Imperatorin enhances the protective activity of conventional antiepileptic drugs against maximal electroshock-induced seizures in mice

The effects of imperatorin (8-isopentenyloxypsoralen; 9-(3-methylbut-2-enyloxy)-7H-faro[3,2-g]chromen-7-one) on the anticonvulsant activity of four conventional antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) were studied in the mouse maximal electroshock seizure model. Results indicate that imperatorin (30 and 40 mg/kg, i.p.) significantly potentiated the anticonvulsant activity of carbamazepine against maximal electroshock-induced seizures by reducing its median effective dose (ED50) from 10.3 to 6.8 (by 34%; P < 0.05) and 6.0 mg/kg (by 42%; P < 0.01), respectively. Similarly, imperatorin (40 mg/kg, i.p.) markedly enhanced the antielectroshock action of phenobarbital and phenytoin, by lowering their ED50 values from 19.6 to 12.2 mg/kg (by 38%; P < 0.05-phenobarbital) and from 12.8 to 8.5 mg/ kg (by 34%; P < 0.05-phenytoin) in the maximal electroshock seizure test. In contrast, imperatorin (40 mg/kg, i.p.) did not affect the protective action of valproate against maximal electroshock-induced seizures in mice. Imperatorin at lower doses of 20 and 30 mg/kg had no significant effect on the anticonvulsant activities of conventional antiepileptic drugs in the mouse maximal electroshock seizure model. Pharmacokinetic evaluation of interaction between imperatorin (30 mg/kg, i.p.) and carbamazepine (6.8 mg/kg, i.p.) revealed a significant increase in total brain carbamazepine concentration after imperatorin administration, indicating a pharmacokinetic nature of interaction between these drugs. In cases of phenobarbital and phenytoin, imperatorin (40 mg/kg, i.p.) did not alter significantly total brain concentrations of phenytoin and phenobarbital in mice, and thus, the observed interactions in the maximal electroshock seizure test between imperatorin and phenobarbital or phenytoin were pharmacodynamic in nature. The present study demonstrates that imperatorin enhanced the antiseizure effects of carbamazepine, phenobarbital and phenytoin in the mouse maximal electroshock seizure model. However, the combination of imperatorin with carbamazepinc, despite its beneficial effects in terms of seizure suppression in mice, was complicated by a pharmacokinetic increase in total brain carbamazepine concentration in experimental animals. In contrast, the combinations of imperatorin with phenytoin and phenobarbital, due to their beneficial antiseizure effects and no pharmacokinetic interactions between drugs in the brain compartment of experimental animals, deserve more attention and are of pivotal importance for epileptic patients as advantageous combinations from a clinical viewpoint. (c) 2007 Elsevier B.V All rights reserved.