Modafinil and its metabolites enhance the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

Abstract Rationale: Seizures occur when the excitability of brain circuits is not sufficiently restrained by inhibitory mechanisms. Although modafinil is reported to reduce GABA-activated currents and extracellular GABA levels in the brain, the drug exerts anticonvulsant effects in animal studies. Objectives: The aim of this study was to determine the effects of modafinil and its metabolites (sulfone and carboxylic acid) on the anticonvulsant action of four classical antiepileptic drugs (AEDs) - carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA). Methods: Anticonvulsant activity was assessed with the maximal electroshock seizure threshold (MEST) test and MES test in mice. Brain concentrations of AEDs were measured to ascertain any pharmacokinetic contribution to the observed anticonvulsant effects. Results: Intraperitoneal injection of 75 mg kg^-1 of modafinil or its metabolites significantly elevated the threshold for electroconvulsions in mice, whereas 50 mg kg^-1 of each compound enhanced the anticonvulsant activity of CBZ, PHT, and VPA, but not that of PB. A 25-mg kg^-1 dose of modafinil or its sulfone metabolite enhanced anticonvulsant activity of VPA. Modafinil and its metabolites (50 mg kg^-1) did not alter total brain concentrations of PB and VPA but did elevate CBZ and PHT. Conclusions: Enhancement of anticonvulsant actions of VPA by modafinil in the mouse MES model is a pharmacodynamic effect. Collectively, our data suggest that modafinil may be a safe and beneficial adjunct to the therapeutic effects of AEDs in human patients.