UNIVERSITY OF MALTA

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UNIVERSITY OF MALTA
LIFE SCIENCE RESEARCH SEMINARS
Web: http://www.um.edu.mt/events/scisem/
Email: [email protected]
Abstract form
Title: Inactivation of the constitutively active ghrelin receptor attenuates
limbic seizure activity in rodents
Presenter: Jeanelle Portelli
Contact address: Department of Pharmaceutical Chemistry, Drug Analysis and Drug
Information, Center for Neuroscience C4N, Vrije Universiteit
Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
Tel: +32 2 477 4744
Fax: +32 2 477 4113
Email: [email protected]
Presentation date: 24th February 2012
Abstract
Ghrelin is a pleiotropic neuropeptide that has recently been implicated in epilepsy. Animal
studies performed to date indicate that ghrelin has anticonvulsant properties; however its
mechanism of anticonvulsant action remains unknown. The present study showed
anticonvulsant effects of ghrelin and the ghrelin-mimetic capromorelin against pilocarpineinduced seizures in rats and mice. Experiments with transgenic mice ascertained that ghrelin
requires the growth hormone secretagogue receptor (GHSR) for its anticonvulsant effect. To
our surprise, however, we found that the GHSR knockout mice had a higher seizure
threshold than their wildtype littermates when treated with pilocarpine. Using both in vivo
and in vitro models, we further discovered that abolishing the constitutive activity of GHSR
by inverse agonism results in the attenuation of seizures and epileptiform activity. We
confirmed that ghrelin’s potential to rapidly desensitize the GHSR is followed by
internalization of the receptor and a slow resensitization process. This, together with our
present novel findings that different ghrelin fragments possess similar agonistic potencies
but different desensitization characteristics on the GHSR, led us to elucidate that ghrelin
probably prohibited limbic seizures in rodents and epileptiform activity in hippocampal
slices due to its desensitizing effect on the GHSR. To the best of our knowledge, this
constitutes a novel mechanism of anticonvulsant action whereby an endogenous agonist
reduces the activity of a constitutively active receptor.
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