Differential Effects of a Full and Biased Ghrelin Receptor Agonist in a Mouse Kindling Model.

Abstract

The ghrelin system has received substantial recognition as a potential target for novel anti-seizure drugs. Ghrelin receptor (ghrelin-R) signaling is complex, involving Gαq/11, Gαi/o, Gα12/13, and β-arrestin pathways. In this study, we aimed to deepen our understanding regarding signaling pathways downstream the ghrelin-R responsible for mediating anticonvulsive effects in a kindling model. Mice were administered the proconvulsive dopamine 1 receptor-agonist, SKF81297, to gradually induce a kindled state. Prior to every SKF81297 injection, mice were treated with a ghrelin-R full agonist (JMV-1843), a Gαq and Gα12 biased ligand unable to recruit β-arrestin (YIL781), a ghrelin-R antagonist (JMV-2959), or saline. Mice treated with JMV-1843 had fewer and less severe seizures compared to saline-treated controls, while mice treated with YIL781 experienced longer and more severe seizures. JMV-2959 treatment did not lead to differences in seizure severity and number. Altogether, these results indicate that the Gαq or Gα12 signaling pathways are not responsible for mediating JMV-1843's anticonvulsive effects and suggest a possible involvement of β-arrestin signaling in the anticonvulsive effects mediated by ghrelin-R modulation.

• Authors: An Buckinx, Yana Van Den Herrewegen, Anouk Pierre, Eleonora Cottone, Khoubaib Ben Haj Salah, Jean-Alain Fehrentz, Ron Kooijman, Dimitri De Bundel, Ilse Smolders
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 20 Issue 10 (May 20 2019) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 31137460 (Publication Type: Journal Article)

Chemical References

• Benzazepines
• Dopamine Agonists
• Indoles
• N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide
• Piperidines
• Quinazolinones
• Receptors, Ghrelin
• Triazoles
• YIL 781
• beta-Arrestins
• SK&F 81297
• macimorelin
• Tryptophan
• Glycine

Topics

• Animals
• Benzazepines (pharmacology)
• Brain (drug effects, metabolism, physiology)
• Dopamine Agonists (pharmacology)
• Glycine (analogs & derivatives, pharmacology)
• Indoles (pharmacology)
• Kindling, Neurologic
• Male
• Mice
• Mice, Inbred C57BL
• Piperidines (pharmacology)
• Quinazolinones (pharmacology)
• Receptors, Ghrelin (agonists, antagonists & inhibitors)
• Triazoles (pharmacology)
• Tryptophan (analogs & derivatives, pharmacology)
• beta-Arrestins (pharmacology)