Transgenic Rats Overexpressing Neuropeptide Y (NPY) Are Less Susceptible to Kainate-Induced Seizures and to Kindling Epileptogenesis
Abstract number :
1.077
Submission category :
Year :
2000
Submission ID :
964
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Marco Gobbi, Daniela Moneta, Teresa Ravizza, Marisa Aliprandi, Luisa Pirona, Michael Michalkiewicz, Christoph Schwarzer, Sabine Furtinger, Gunther Sperk, Annamaria Vezzani, Mario Negri Inst for Pharmacol Research, Milano, Italy; West Virginia Univ, Morgan
Rationale Electrophysiological and pharmacological studies in experimental models of seizures and in human epileptic tissue indicate that NPY and its peptide analogs potently inhibit epileptic activity. This action appears to be mediated by presynaptic NPY Y2 receptors inhibiting glutamate release and possibly by NPY Y5 receptors. In this study, we investigated the effect of endogenous NPY on seizures and epileptogenesis using transgenic (Tg) rats overexpressing this peptide under the control of the natural promoter. Methods Seizures were induced in adult male rats by intracerebroventricular injection of 0.3 g kainate or by electrical kindling of the hippocampus. Seizures were monitored and quantified by EEG analysis using hippocampal and cortical electrodes and by behavioral observation according to Racine scale. NPY receptor subtypes were measured by receptor autoradiography and in situ hybridization analysis of mRNA. NPY was measured by immunocytochemistry and expression of its mRNA. Results Tg rats showed a significant reduction in the number of seizures induced by kainate and in their duration by 30 and 55% respectively (p<0.05 and 0.01) compared to wild-type littermates (WT) . Tg rats were also less susceptible to epileptogenesis as shown by a 65% increase in the number of stimuli inducing stage 5 seizures (p<0.01). NPY mRNA was significantly increased in CA1 pyramidal neurons of Tg rats compared to WT. NPY immunoreactivity was increased by seizures in hilar interneurons and mossy fibre terminals at a similar extent in the two experimental groups. NPY Y2 receptors increased in granule cell-mossy fibre system while Y5 receptors were reduced in various hippocampal subfields, 24-48 h after seizures. These changes were similar in Tg rats and WT. Discussion These findings indicate that NPY in the limbic system has a potent inhibitory action on seizures and epileptogenesis and suggest that Y2 receptors may represent novel pharmacological targets for controlling seizures. This work was supported by NHLBI-NIH and NATO CRG.972956