Inactivation of the constitutively active ghrelin receptor attenuates limbic seizure activity in rodents

Jeanelle Portelli, Leen Thielemans, Luc Ver Donck, Ellen Loyens, Jessica Coppens, Najat Aourz, Jeroen Aerssens, Katia Vermoesen, Ralph Clinckers, Anneleen Schallier, Yvette Michotte, Dieder Moechars, Graham L Collingridge, Zuner A Bortolotto, Ilse Smolders

Research output: Contribution to journalArticle (Academic Journal)peer-review

22 Citations (Scopus)

Abstract

Ghrelin is a pleiotropic neuropeptide that has been recently implicated in epilepsy. Animal studies performed to date indicate that ghrelin has anticonvulsant properties; however, its mechanism of anticonvulsant action is unknown. Here we show that the anticonvulsant effects of ghrelin are mediated via the growth hormone secretagogue receptor (GHSR). To our surprise, however, we found that the GHSR knockout mice had a higher seizure threshold than their wild-type littermates when treated with pilocarpine. Using both in vivo and in vitro models, we further discovered that inverse agonism and desensitization/internalization of the GHSR attenuate limbic seizures in rats and epileptiform activity in hippocampal slices. This constitutes a novel mechanism of anticonvulsant action, whereby an endogenous agonist reduces the activity of a constitutively active receptor.
Original languageEnglish
Pages (from-to)658-72
Number of pages15
JournalNeurotherapeutics
Volume9
Issue number3
DOIs
Publication statusPublished - 2012

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