Influence of N-(p-acetylphenyl)-p-isopropoxyphenylsuccinimide on the protective action of classical antiepileptic drugs against maximal electroshock-induced seizures in mice

Abstract

The aim of this study was to determine the effects of N-(p-acetylphenyl)-p-isopropoxyphenylsuccinimide (APIPPS) on the protective action of four classical antiepileptic drugs (AEDs: carbamazepine [CBZ], phenobarbital [PB], phenytoin [PHT] and valproate [VPA]) in the maximal electroshock (MES)-induced seizures in mice. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Total brain AED concentrations were measured with fluorescence polarization immunoassay to ascertain whether any observed effects were consequent to a pharmacodynamic and/or a pharmacokinetic interaction between APIPPS and classical AEDs. Results indicate that APIPPS administered intraperitoneally at a dose of 150 mg/kg significantly elevated the threshold for electroconvulsions in mice. APIPPS at lower doses of 25, 50 and 100 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, APIPPS at 100 mg/kg significantly enhanced the anticonvulsant activity of PB and VPA, but not that of CBZ or PHT, in the MES test in mice. APIPPS at a dose of 50 mg/kg significantly potentiated the anticonvulsant action of VPA, but not that of PB in the mouse MES model. Pharmacokinetic experiment revealed that APIPPS did not alter total brain concentrations of PB or VPA in mice. Summing up, the enhanced anticonvulsant action of PB and VPA by APIPPS in the mouse MES model and lack of pharmacokinetic interactions between drugs, make the combinations of APIPPS with PB and VPA of importance for further experimental and clinical studies. The combinations of APIPPS with CBZ and PHT are neutral from a preclinical viewpoint.