Inactivation of the constitutively active ghrelin receptor attenuates limbic seizure activity in rodents.
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.
Center for Neurosciences, Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
Jeanelle
J
Portelli
Leen
L
Thielemans
Luc
L
Ver Donck
Ellen
E
Loyens
Jessica
J
Coppens
Najat
N
Aourz
Jeroen
J
Aerssens
Katia
K
Vermoesen
Ralph
R
Clinckers
Anneleen
A
Schallier
Yvette
Y
Michotte
Dieder
D
Moechars
Graham L
GL
Collingridge
Zuner A
ZA
Bortolotto
Ilse
I
Smolders
D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D054439:Ghrelin / Q000627:therapeutic use*; D049452:Green Fluorescent Proteins / Q000235:genetics; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D008032:Limbic System / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D018721:Muscarinic Agonists / Q000633:toxicity; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010862:Pilocarpine / Q000633:toxicity; D010880:Piperidines / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D054440:Receptors, Ghrelin / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D012720:Severity of Illness Index; D013045:Species Specificity; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; C433143:CP 424391; D054439:Ghrelin; D018721:Muscarinic Agonists; D010880:Piperidines; D011720:Pyrazoles; D054440:Receptors, Ghrelin; C485184:enhanced green fluorescent protein; D010862:Pilocarpine; D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid; D002118:Calcium