Influence of 5-(3-chlorophenyl)-4-(4-methylphenyl)-2, 4-dihydro-3H-1, 2, 4-triazole-3-thione on the anticonvulsant action of 4 classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Background: The aim of this study was to determine the effects of 5-(3-chlorophenyl)-4-(4-methylphenyl)-2, 4-dihydro-3H-1, 2, 4-triazole-3-thione (TP10) on the protective action of 4 classical antiepileptic drugs - carbamazepine, phenobarbital, phenytoin and valproate - against maximal electroshock-induced seizures in mice. Methods: Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by an electric current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered viaauricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured, together with total brain antiepileptic drug concentrations. Results: TP10 administered intraperitoneally at 10mg/kg significantly elevated the threshold for electroconvulsions in mice. TP10 at doses of 2.5 and 5 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, TP10 (5 mg/kg) significantly enhanced the anticonvulsant activity of valproate, but not that of carbamazepine, phenobarbital or phenytoin in the maximal electro-shock seizure test in mice. Pharmacokinetic experiments revealed that TP10 significantly elevated total brain concentrations of valproate in mice. Conclusions: The enhanced anticonvulsant action of valproate by TP10 in the mouse maximal electroshock-induced seizure model was associated with a pharmacokinetic increase in total brain valproate concentrations in mice. The combinations of TP10 with carbamazepine, phenobarbital and phenytoin were neutral from a preclinical viewpoint.