The purpose of this study was to evaluate the influence of the
glycine site antagonist of the
NMDA receptor,
MRZ 2/576 (8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridazino[4,5-b]quinolin-5-
oxide choline salt), on the anticonvulsive activity of
carbamazepine,
oxcarbazepine,
diphenylhydantoin,
phenobarbital and
valproate against maximal electroshock (MES)-induced
seizures and
ethosuximide,
valproate and
clonazepam against
pentetrazole (PTZ)-induced
seizures in mice.
MRZ 2/576 applied intraperitoneally 5 min before electroconvulsions, at the dose of 10 and 15 mg/kg, significantly raised the convulsive threshold (from 6.9 to 8.8 and 10.8 mA respectively). At lower doses, it did not affect the threshold.
MRZ 2/576 applied at the dose of 5, 10 and 20 mg/kg did not influence the clonic phase of PTZ-induced
seizures, but protected the animals against the tonic phase. The
anticonvulsant effect of a given
antiepileptic drug was expressed as its ED(50) value (in mg/kg), which represents the dose of the
drug required to protect 50% of animals against MES or PTZ
seizures. MRZ2/576 co-administered at a subprotective dose (5 mg/kg) with
carbamazepine,
oxcarbazepine,
diphenylhydantoin,
phenobarbital or
valproate, significantly reduced their ED(50) values in MES test. Also, at the dose of 2.5 mg/kg it enhanced the protective activity of
carbamazepine and
valproate. At the lowest tested dose (1.25 mg/kg), it still potentiated the
anticonvulsant activity of
valproate. However,
MRZ 2/576 (5 mg/kg) applied with
valproate,
ethosuximide or
clonazepam did not influence their protective effects in the PTZ test. The combinations of
MRZ 2/576 with almost every studied
antiepileptic drug (providing a 50% protection against maximal electroshock or PTZ-induced
seizures) did not produce motor impairment in the chimney test nor long-term memory deficit measured in the passive avoidance task. Only
valproate alone or combined with
MRZ 2/576 impaired both of these measures. It may be concluded that
MRZ 2/576 enhanced the anticonvulsive activity of
antiepileptic drugs against MES without accompanying potentiation of adverse effects. However, there was no positive interaction in the PTZ test. Finally, pharmacokinetic interactions do not seem responsible for the obtained results because
MRZ 2/576 (5 mg/kg) did not alter the free plasma levels of the
antiepileptics tested in the present study.