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

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-1843s anticonvulsive effects and suggest a possible involvement of -arrestin signaling in the anticonvulsive effects mediated by ghrelin-R modulation.