Abstracts

We have previously demonstrated that intracerebroventricular (icv) injection of NPY potently suppresses absence seizures in a model of genetic generalised epilepsy, Genetic Absence Epilepsy Rats of Strasbourg (GAERS)¹. Here we investigated the Y receptor subtype(s) on which NPY exerts this anti-absence effect. Cumulative duration of seizures was quantitated in adult male GAERS on 90-minute post-injection EEG recording in two experiments: (i) Post antagonists of Y[sub]1[/sub] - BIBP3226 (20 nmol, Boehringer Ingelheim), Y[sub]2[/sub] - BIIE0246 (20 nmol, Boehringer Ingelheim), Y[sub]5[/sub] - NPY5RA972 (20 nmol, Astra Zeneca) or vehicle followed by NPY (6 mmol) (n=7). (ii) Post subtype selective agonists of Y[sub]1[/sub] (Leu³¹Pro³⁴, 2.5 nmol,), Y[sub]2[/sub] (Gift of E Potter, Ac[Leu ^28,31]NPY24-36 3 nmol,), Y[sub]5[/sub] receptors (Gift of A Beck-Sickinger, hPP(1-17), Ala(31), Aib(32)]NPY 3 nmol,) NPY (3 nmol) or vehicle. Results were analysed using ANOVA for repeated measures with planned comparisons (n=7 for both studies). GAERS spent 14% of time in seizures. NPY injection was still able to suppress seizures (vs. vehicle alone) following the Y[sub]1[/sub]- (45.3% suppression) and Y[sub]5[/sub]-antagonists (80.1% suppression) compared to following vehicle (all P[lt]0.05), but not following the Y[sub]2[/sub]-antagonist (5.1% suppression, P=0.46). Conversely, injection of the Y[sub]1[/sub] and Y[sub]5[/sub] selective agonists resulted in significantly less mean seizure suppression than NPY (37.4% and 53.9% vs. 83.2% suppression, P[lt]0.05) while the Y[sub]2[/sub] agonist had similar effects to NPY (62.3% suppression, P=0.57). Food intake was not increased following injection of the Y[sub]2[/sub] agonist, unlike following NPY or the other Y-subtype agonists. These data provide evidence that Y[sub]2[/sub] receptors are more important than Y[sub]1[/sub] and Y[sub]5[/sub] receptors in mediating the effect of NPY to suppress absence seizures in a genetic rat model. Drugs acting on Y[sub]2[/sub] receptors may represent targets for novel drugs effective against genetic generalised epilepsies without resulting in appetite stimulation. (Supported by The Friends of The Royal Melbourne Hospital Neuroscience.)