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 G?q/11, G?i/o, G?12/13, and ?-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 G?q and G?12 biased ligand unable to recruit ?-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 G?q or G?12 signaling pathways are not responsible for mediating JMV-1843's anticonvulsive effects and suggest a possible involvement of ?-arrestin signaling in the anticonvulsive effects mediated by ghrelin-R modulation.

SUBMITTER: Buckinx A 

PROVIDER: S-EPMC6567032 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature