Effect of xanthotoxin (8-methoxypsoralen) on the anticonvulsant activity of classical antiepileptic drugs against maximal electroshock-induced seizures in mice

The effects of xanthotoxin (8-methoxypsoralen) on the anticonvulsant activity of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) were studied in the mouse maximal electroshock seizure model. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (25 mA, 500 V. 50 Hz, 02 s stimulus duration) delivered via auricular electrodes. Total brain concentrations of antiepileptic drugs were measured by fluorescence polarization immunoassay to ascertain any pharmacokinetic contribution to the observed anticonvulsant effects. Results indicate that xanthotoxin (50 and 100 mg/kg, i.p.) significantly potentiated the anticonvulsant activity of carbamazepine against maximal electroshock-induced seizures (P < 0.05 and P < 0.001, respectively). Similarly, xanthotoxin (100 mg/kg, i.p.) markedly enhanced the anticonvulsant action of valproate in the maximal electroshock seizure test (P < 0.001). In contrast, xanthotoxin (100 mg/kg, i.p.) did not affect the protective action of phenobarbital and phenytoin against maximal electroshock-induced seizures in mice. Moreover, xanthotoxin (100 mg/kg, i.p.) significantly increased total brain concentrations of carbamazepine (P < 0.001) and valproate (P < 0.05), but not those of phenytoin and phenobarbital, indicating pharmacokinetic nature of interactions between drugs. In conclusion, the combinations of xanthotoxin with carbamazepine and valproate, despite their beneficial effects in terms of seizure suppression in mice, were probably due to a pharmacokinetic increase in total brain concentrations of these antiepileptic drugs in experimental animals. (C) 2015 Elsevier B.V. All rights reserved.