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

Abstract

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 Y1 receptor subtypes, which are enriched in the dentate area of the hippocampus, on EEG seizures induced by a local injection of 0.04 microg kainic acid in rats. Intrahippocampal administration of 10 microg BIBP3226 (N2- (diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]D-arginamide), a non-peptide selective antagonist at the NPY Y1 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 [Leu31,Pro34]NPY, an agonist at Y1 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 Y1 receptors in the hippocampus are involved in epileptic phenomena and suggest that selective Y1 receptor antagonists may be of value for attenuating limbic seizures.

Neuropeptide Y and Epilepsy

“…However, it became clear as more receptors were discovered and characterized that these agonist fragments were not adequately specific. Nevertheless, results from in vivo work with the first available antagonist, the Y 1 antagonist BIBP 3226, were intriguing, as they suggested that the activation of the Y 1 receptor was proconvulsant, and blockade of Y 1 receptors was anticonvulsant (43). Unfortunately, different antagonists needed for the unambiguous testing of the inhibitory role of NPY in the regulation of excitability either have not been available or their physical properties make them not amenable to in vivo experiments.…”

Structural and functional asymmetry in the normal and epileptic rat dentate gyrus

“…Not only do they contain glutamate, but they also contain BDNF, NPY, and other substances. Although BDNF appears to enhance mossy fiber transmission (Scharfman, 1997;Scharfman et al, 1999), NPY has been shown to have primarily inhibitory effects on synaptic transmission (Vezzani et al, 1999b; but see also Gariboldi et al, 1998).…”

“…Not only do they contain glutamate, but they also contain BDNF, NPY, and other substances. Although BDNF appears to enhance mossy fiber transmission (Scharfman, 1997;Scharfman et al, 1999), NPY has been shown to have primarily inhibitory effects on synaptic transmission (Vezzani et al, 1999b; but see also Gariboldi et al, 1998).Other factors, such as the distribution of inhibitory neurons or various afferents to the dentate gyrus, also could influence excitability, independent of mossy fiber sprouting. Thus, the relative paucity of NPY-immunoreactive inhibitory neurons close to the infrapyramidal blade and the relatively weak axonal projection of calretinin-immunoreactive fibers to the infrapyramidal blade could contribute to greater infrapyramidal excitability.…”

Plasticity of neuropeptide Y in the dentate gyrus after seizures, and its relevance to seizure-induced neurogenesis

“…Studies of Y1 receptor agonists reveal inhibitory effects on Ca 2+ entry into dendrites of granule cells [16]. Other studies suggest a potentially proconvulsant effect [17]. Studies in mouse slices indicate that Y1 receptors regulate t GIRK ((define)) potassium channel [18].…”

“…However, it is likely that the Y1 receptors are located in the SGZ, but are sparse enough not to generate a large signal, at least relative to other lamella. This is because physiological evidence indicates they are present [17]. And some Y1 binding is apparent in hilus, although it may be associated with mossy fibers [71].…”