title: Des-acyl ghrelin attenuates pilocarpine-induced limbic seizures via the ghrelin receptor and not the orexin pathway.
abstract: Des-acyl ghrelin, widely accepted to work independently of the ghrelin receptor, is increasingly being implicated in a number of biological functions. The involvement of des-acyl ghrelin in epilepsy has only been recently reported. In this study, apart from unravelling the effect of des-acyl ghrelin on seizure thresholds and seizure severity in two models of pilocarpine-induced seizures, we mainly attempted to unravel its anticonvulsant mechanism of action. Since it was found that des-acyl ghrelin administration affected food intake via the orexin pathway, we first determined whether this pathway was responsible for des-acyl ghrelin's seizure-attenuating properties using the dual orexin receptor antagonist almorexant. We noted that, while des-acyl ghrelin showed dose-dependent anticonvulsant effects against focal pilocarpine-evoked seizures in rats, almorexant did not affect seizure severity and did not reverse des-acyl ghrelin's anticonvulsant effect. Subsequently, to investigate whether the ghrelin receptor was implicated in des-acyl ghrelin's anticonvulsant properties, we tested this peptide in ghrelin receptor deficient mice and wild type mice, all infused with pilocarpine intravenously. Unexpectedly, we found that des-acyl ghrelin significantly elevated seizure thresholds in C57Bl/6 and wild type mice but not in ghrelin receptor knock-out mice. Taken together, our results indicate the involvement of the ghrelin receptor in the anticonvulsant effects of des-acyl ghrelin on pilocarpine-induced seizures. We also show for the first time that dual antagonism of hippocampal orexin receptors does not affect seizure severity.
authors.affiliation: Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels 1090, Belgium; Department of Neurology, UZ Gent, De Pintelaan 185, Ghent 9000, Belgium.
authors.forename: Jeanelle
authors.initials: J
authors.lastname: Portelli
authors.affiliation: Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels 1090, Belgium.
authors.forename: Jessica
authors.initials: J
authors.lastname: Coppens
authors.affiliation: Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels 1090, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Demuyser
authors.affiliation: Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Vrije Universiteit Brussel, Laarbeeklaan 103, Brussels 1090, Belgium. Electronic address: ilse.smolders@vub.ac.be.
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D054439:Ghrelin / Q000494:pharmacology / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000068797:Orexins / Q000378:metabolism*; D010862:Pilocarpine; D051381:Rats; D017208:Rats, Wistar; D054440:Receptors, Ghrelin / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D054439:Ghrelin; D000068797:Orexins; D054440:Receptors, Ghrelin; C422650:ghrelin, des-n-octanoyl; D010862:Pilocarpine
keywords: Almorexant; Des-acyl ghrelin; Hippocampus; Mice; Orexin; Pilocarpine; Rats; Seizure