Behavioral and metabolic changes in immature rats during seizures induced by homocysteic acid: The protective effect of NMDA and non-NMDA receptor antagonists

Bilateral intracerebroventricular infusion of DL-homocysteic acid (DL-HCA) (600 nmol on each side) to immature 12-day-old rats induced generalized clo nic-tonic seizures, recurring frequently for at least 90 min, with a high r ate of survival. Electrographic recordings from sensorimotor cortex, hippoc ampus, and striatum demonstrated isolated spikes in the hippocampus and/or striatum as the first sign of DL-HCA action. Generalization of epileptic ac tivity occurred during generalized clonic-tonic seizures, but electroclinic al correlation was very low; dissociation between EEG pattern and motor phe nomena was common. Seizures were accompanied by large decreases of cortical glucose and glycogen and by similar to 7- to 10-fold accumulation of lacta te. ATP and phosphocreatine (PCr) levels remained unchanged even during lon glasting (3 h) convulsions. Metabolite levels became normalized during the recovery period (24 h). The examination of the effect of selected antagonis ts of NMDA [AP7 (18.5 and 37 mg/kg, respectively), MR-801 (0.5 mg/kg)] and non-NMDA [NBQX (10, 15 and 30 mg/kg, respectively)] receptors revealed that seizures could be attenuated or prevented (depending on the dose employed) by antagonists of both NMDA and non-NMDA receptors, as evaluated not only according to the suppression of behavioral manifestations of seizures, but also in terms of the protection of metabolite changes accompanying seizures . All antagonists employed, when given alone in the same doses as those use d for seizure protection, did not influence metabolite levels, with the exc eption of increased glucose concentrations. Furthermore, the pronounced ant iconvulsant effect could be achieved by the combined treatment with low sub threshold doses of NMDA (AP7) and non-NMDA (NBQX) receptor antagonists, whi ch may be of potential significance for a new approach to the treatment of epilepsy. (C) 2000 Academic Press.