Neurotherapeutics

, Volume 9, Issue 3, pp 658–672

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

Authors

  • Jeanelle Portelli
    • Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug InformationVrije Universiteit Brussel
  • Leen Thielemans
    • Janssen Research and Development, a Division of Janssen Pharmaceutica NV
  • Luc Ver Donck
    • Janssen Research and Development, a Division of Janssen Pharmaceutica NV
  • Ellen Loyens
    • Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug InformationVrije Universiteit Brussel
  • Jessica Coppens
    • Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug InformationVrije Universiteit Brussel
  • Najat Aourz
    • Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug InformationVrije Universiteit Brussel
  • Jeroen Aerssens
    • Janssen Research and Development, a Division of Janssen Pharmaceutica NV
  • Katia Vermoesen
    • Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug InformationVrije Universiteit Brussel
  • Ralph Clinckers
    • Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug InformationVrije Universiteit Brussel
  • Anneleen Schallier
    • Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug InformationVrije Universiteit Brussel
  • Yvette Michotte
    • Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug InformationVrije Universiteit Brussel
  • Dieder Moechars
    • Janssen Research and Development, a Division of Janssen Pharmaceutica NV
  • Graham L. Collingridge
    • MRC Centre for Synaptic Plasticity, School of Physiology and PharmacologyUniversity of Bristol
    • Department of Brain and Cognitive Sciences, College of Natural SciencesSeoul National University
  • Zuner A. Bortolotto
    • MRC Centre for Synaptic Plasticity, School of Physiology and PharmacologyUniversity of Bristol
    • Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug InformationVrije Universiteit Brussel
Original Article

DOI: 10.1007/s13311-012-0125-x

Cite this article as:
Portelli, J., Thielemans, L., Ver Donck, L. et al. Neurotherapeutics (2012) 9: 658. doi:10.1007/s13311-012-0125-x

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.

Keywords

EpilepsySeizuresGhrelinGHSRHippocampusPilocarpine

Supplementary material

13311_2012_125_MOESM1_ESM.pdf (511 kb)
ESM 1(PDF 510 kb)

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2012