Anticonvulsant and neurotoxic effects of a novel 1,2,4-triazole-3-thione derivative (TPF-34) and its isobolographic interaction profile with classical antiepileptic drugs in mice.

Abstract

Anticonvulsant and acute toxic effects of 5-[(3-fluorophenyl)ethyl]-4-(n-hexyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPF-34)-a candidate for novel antiepileptic drug-were examined in the maximal electroshock-induced seizure (MES) model and rotarod test in mice. The interaction profile of TPF-34 with four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) was also studied in the mouse MES model. Both ED50 and TD50 values for TPF-34 were determined at four treatment times (15, 30, 60 and 120min after i.p. administration) in the MES model and rotarod test in adult male albino Swiss mice, respectively. The influence of TPF-34 on the protective anticonvulsant action of carbamazepine, phenobarbital, phenytoin and valproate in the mouse MES model was assessed with isobolographic analysis of interaction. Total brain antiepileptic drug concentrations were measured with fluorescence polarization immunoassay. TPF-34, when administered alone at four pretreatment times (15, 30, 60 and 120min before experiments), possessed a favorable preclinical profile with the protective index (a ratio of TD50 and ED50 values) ranging from 2.89 to 3.53. Moreover, TPF-34, when combined with carbamazepine, phenobarbital, phenytoin and valproate, exerted an additive interaction in the MES model in mice. TPF-34 had no impact on total brain antiepileptic drug concentrations in mice. A protective index value higher than 3 allows recommending TPF-34 as a promising antiepileptic drug candidate for further preclinical testing using other experimental seizure models. The additive interaction of TPF-34 with carbamazepine, phenobarbital, phenytoin and valproate in the mouse MES model is worthy of recommendation to further clinical studies.