Cortistatin-8, a synthetic cortistatin-derived ghrelin receptor ligand, does not modify the endocrine responses to acylated ghrelin or hexarelin in humans.
Cortistatin (CST), a neuropeptide with high structural homology with somatostatin (SST), binds all SST receptor (SST-R) subtypes but, unlike SST, also shows high binding affinity to ghrelin receptor (GHS-R1a). CST exerts the same endocrine activities of SST in humans, suggesting that the activation of the SST-R might mask the potential interaction with ghrelin system. CST-8, a synthetic CST-analogue devoid of any binding affinity to SST-R but capable to bind the GHS-R1a, has been reported able to exert antagonistic effects on ghrelin actions either in vitro or in vivo in animals. We studied the effects of CST-8 (2.0 microg/kg i.v. as a bolus or 2.0 microg/kg/h i.v. as infusion) on both spontaneous and ghrelin- or hexarelin- (1.0 microg/kg i.v. as bolus) stimulated GH, PRL, ACTH and cortisol secretion in 6 normal volunteers. During saline, no change occurred in GH and PRL levels while a spontaneous ACTH and cortisol decrease was observed. As expected, both ghrelin and hexarelin stimulated GH, PRL, ACTH and cortisol secretion (p<0.05). CST-8, administered either as bolus or as continuous infusion, did not modify both spontaneous and ghrelin- or hexarelin-stimulated GH, PRL, ACTH and cortisol secretion. In conclusion, CST-8 seems devoid of any modulatory action on either spontaneous or ghrelin-stimulated somatotroph, lactotroph and corticotroph secretion in humans in vivo. These negative results do not per se exclude that, even at these doses, CST-8 might have some neuroendocrine effects after prolonged treatment or that, at higher doses, may be able to effectively antagonize ghrelin action in humans. However, these data strongly suggest that CST-8 is not a promising candidate as GHS-R1a antagonist for human studies to explore the functional interaction between ghrelin and cortistatin systems.
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy.
F
F
Prodam
A
A
Benso
E
E
Gramaglia
B
B
Lucatello
F
F
Riganti
A J
AJ
van der Lely
R
R
Deghenghi
G
G
Muccioli
E
E
Ghigo
F
F
Broglio
D000215:Acylation; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D054439:Ghrelin / Q000737:chemistry / Q000494:pharmacology*; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008024:Ligands; D008297:Male; D009479:Neuropeptides / Q000009:adverse effects / Q000494:pharmacology*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011388:Prolactin / Q000097:blood; D054440:Receptors, Ghrelin / Q000187:drug effects*
D054439:Ghrelin; D008024:Ligands; D009479:Neuropeptides; D009842:Oligopeptides; D054440:Receptors, Ghrelin; C099323:cortistatin; C528326:cortistatin-8; C086184:hexarelin; D019382:Human Growth Hormone; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D006854:Hydrocortisone