Anticonvulsant properties of BIBP3226, a non-peptide selective antagonist at neuropeptide Y Y1 receptors

Several lines of evidence indicate that neuropeptide Y (NPY)-mediated neurotransmission in the hippocampus is altered by limbic seizures. The functional consequences of this change are still unresolved and clearly depend on the type of NPY receptors involved. We have investigated the role of NPY Y-1 receptor subtypes, which are enriched in the dentate area of the hippocampus, on EEG seizures induced by a local injection of 0.04 mu g kainic acid in rats. Intrahippocampal administration of 10 mu g BIBP3226 (N-2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]D-arginamide), a non-peptide selective antagonist at the NPY Y-1 receptors, increased threefold on average (P < 0.01) the time to onset of seizures and reduced the number of seizures and the total time in seizures three-and fourfold, respectively (P < 0.01). Its inactive S-enantiomer BIBP3435 was ineffective on seizure activity. One microgram [Leu(31),pro(34)]NPY, agonist at Y-1 receptors, did not modify per se the EEG sequelae induced by kainic acid but it antagonized the anticonvulsant effect of BIBP3226. These results indicate that NPY Y-1 receptors in the hippocampus are involved in epileptic phenomena and suggest that selective Y-1 receptor antagonists may be of value for attenuating limbic seizures.