INFLUENCE OF D-CYCLOSERINE ON THE ANTICONVULSANT ACTIVITY OF PHENYTOIN AND CARBAMAZEPINE AGAINST ELECTROCONVULSIONS IN MICE

Purpose: 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 demonstr ated that DCS exhibits anticonvulsant activity in a variety of experim ental epilepsy models. In this study, we determined the influence of D CS in subprotective doses on the anticonvulsant action of phenytoin (P HT) and carbamazepine (CBZ) in mice. Methods: Two electroconvulsive te sts were used, i.e., determination of seizure threshold and maximal el ectroshock seizures, Antiepileptic drug-induced motor and long-term me mory deficits were quantified by using the chimney test and the passiv e-avoidance test, respectively. In addition, plasma levels of PI-IT an d CBZ were measured by fluorescence polarization immunoassay to exclud e any pharmacokinetic interactions. Results: DCS, when used alone in d oses of 80 and 160 mg/kg, significantly increased the threshold for el ectroconvulsive seizures. DCS in a wide range of doses (1.25-40 mg/kg) was combined with either PHT or CBZ and tested in electroconvulsive t ests. DCS, at doses of 2.5 and 10 mg/kg, was the most effective in pot entiating the threshold-increasing action of PI-IT; higher doses of DC S (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 w ith 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; PI-IT-induced memory adverse effects were counteracted by DCS (10 mg/kg). There was no such effect on CBZ-induced memory impair ment, and a worsening influence was observed. Any pharmacokinetic inte ractions were excluded by measuring total and free plasma levels of bo th antiepileptic drugs. Conclusion: Our results suggest that combining DCS with PI-IT and CBZ may be beneficial in treating epileptic seizur es.