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.

Biased signaling: A viable strategy to drug ghrelin receptors for the treatment of obesity

“…For instance, recent data showed that mice treated with YIL781 suffered from longer and more severe seizures compared to saline-treated controls, whereas treating mice with JMV1843 induced fewer and less severe seizures. While both GHSR agonists activated Gα q and Gα 12 pathways [65,66,75], only JMV1843 recruited β-arrestin proteins to the receptor [65,66]. Together, these results indicate that Gα q and Gα 12 signaling pathways are not involved in mediating the anticonvulsant action of JMV18430 and suggest a possible involvement of the β-arrestin signaling in inducing the anticonvulsive effect (Fig.…”

Translational potential of the ghrelin receptor agonist macimorelin for seizure suppression in pharmacoresistant epilepsy

“…Placement of measuring electrodes (E363/3/SPC Invivo 1), implantation of the radio-telemetric transmitter (ETA-F10, DSI) and injection of kainic acid (KA) (200 ng in 50 nl; unilaterally in the right CA1 region of the hippocampus [anterio-posterior: −2 mm; medio-lateral: −1.5 mm; dorso-ventral: −2.1 mm relative to bregma]) were performed as previously described [19,36]. Sham-operated control mice received an identical, but non-functional transmitter and electrodes, and saline intrahippocampal injection stereotaxically positioned at the same coordinates.…”

“…Ghrelin and ghrelin-R agonists exerted anticonvulsant effects [15][16][17][18][19][20], increased neuronal survival [21][22][23] and suppressed inflammation [16,24] in rodent seizure and status epilepticus (SE) models.…”

Identification of a Putative β‐Arrestin Superagonist of the Growth Hormone Secretagogue Receptor (GHSR)

“…Although the functional consequence of each signaling pathway has not been fully characterized, the orexigenic effect, the most pronounced effect of the ghrelin peptide, has been shown to be mediated by the Gα q/11 pathway [15] . Moreover, the importance of the β‐arrestin pathway in psychostimulant reward and the antiepileptic effect mediated by ghrelin suggest that this signal transduction pathway may be a potential drug target for treating both addiction and epilepsy [16,17] . However, further investigation of this area has been hampered due to the paucity of β‐arrestin‐biased GHSR modulators.…”

“…[15] Moreover, the importance of the β-arrestin pathway in psychostimulant reward and the antiepileptic effect mediated by ghrelin suggest that this signal transduction pathway may be a potential drug target for treating both addiction and epilepsy. [16,17] However, further investigation of this area has been hampered due to the paucity of β-arrestin-biased GHSR modulators.…”