Anticonvulsant effects by combined treatment with a glycine(B) receptor antagonist and a polyamine site antagonist in amygdala-kindled rats

Antagonists of binding sites within the NMDA receptor complex, i.e., L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(H)quinolone), a brain penetrating glycine, receptor antagonist, and ifenprodil, a polyamine site antagonist, were tested for anticonvulsant properties in fully amygdala-kindled rats, a model of limbic epilepsy. Both drugs were not able to significantly change seizure parameters (focal afterdischarge threshold, seizure severity, and duration of seizure and afterdischarges), when administered intraperitoneally up to doses which produced severe motor impairment. However, the combination of 10 mg/kg ifenprodil and 5 mg/kg L-701,324 had a pronounced anticonvulsant effect on afterdischarge threshold and seizure severity without concomitant increase of adverse effects. These findings support the hypothesis that drugs acting only at one site of the NMDA receptor complex are ineffective, while combinations of such drugs may synergistically act to suppress limbic seizures, thus providing an adequate strategy for the treatment of this type of refractory epilepsy. (C) 1997 Elsevier Science B.V.