Influence of D-cycloserine on the anticonvulsant activity of phenytoin and carbamazepine against electroconvulsions in mice.

Abstract

D-Cycloserine (DCS) is a high-efficacy partial agonist at the strychnine-insensitive glycine modulatory site within the N-methyl-D-aspartate (NMDA)-receptor/ionophore complex. Previous studies demonstrated that DCS exhibits anticonvulsant activity in a variety of experimental epilepsy models. In this study, we determined the influence of DCS in subprotective doses on the anticonvulsant action of phenytoin (PHT) and carbamazepine (CBZ) in mice. Two electroconvulsive tests were used, i.e., determination of seizure threshold and maximal electroshock seizures. Antiepileptic drug-induced motor and long-term memory deficits were quantified by using the chimney test and the passive-avoidance test, respectively. In addition, plasma levels of PHT and CBZ were measured by fluorescence polarization immunoassay to exclude any pharmacokinetic interactions. DCS, when used alone in doses of 80 and 160 mg/kg, significantly increased the threshold for electroconvulsive seizures. DCS in a wide range of doses (1.25-40 mg/kg) was combined with either PHT or CBZ and tested in electroconvulsive tests. DCS, at doses of 2.5 and 10 mg/kg, was the most effective in potentiating the threshold-increasing action of PHT; higher doses of DCS (20 and 40 mg/kg) were required to achieve a similar effect of CBZ. In maximal electroshock-induced seizures, DCS (10 mg/kg) augmented the protective action of PHT, but was ineffective at a dose of 40 mg/kg with CBZ. DCS did not potentiate the neurotoxicity produced by PHT and CBZ in the chimney test. Both PHT and CBZ induced impairments of long-term memory; PHT-induced memory adverse effects were counteracted by DCS (10 mg/kg). There was no such effect on CBZ-induced memory impairment, and a worsening influence was observed. Any pharmacokinetic interactions were excluded by measuring total and free plasma levels of both antiepileptic drugs. Our results suggest that combining DCS with PHT and CBZ may be beneficial in treating epileptic seizures.