Ghrelin signaling in the gut, its physiological properties, and therapeutic potential

Abstract

This review aims to summarize the road that led to the current knowledge concerning the prokinetic properties of ghrelin with a focus on the therapeutic potential of ghrelin receptor agonists in the treatment of hypomotility disorders. In addition, we outline some of the problems that could be at the basis of the negative outcome of the trials with ghrelin agonists and question whether the right target groups were selected. It is clear that a new approach is needed to develop marketable drugs with this class of gastroprokinetic agents.

Relamorelin Relieves Constipation and Accelerates Colonic Transit in a Phase 2, Placebo-Controlled, Randomized Trial

“…7 Ghrelin receptors are expressed throughout the gastrointestinal tract, including expression in the colon in rodents and human beings. 8,9 Hence, ghrelin agonists are being developed as prokinetic agents that may prove useful in the treatment of gastrointestinal motility disorders such as gastroparesis and postoperative ileus. Ghrelin agonists have been proposed for the treatment of gastrointestinal motility disorders.…”

“…Ghrelin agonists have been proposed for the treatment of gastrointestinal motility disorders. 10 Relamorelin is a pentapeptide synthetic ghrelin analog that binds to the growth hormone secretagogue-1a receptor with approximately 3-fold greater affinity than natural ghrelin. The ability of relamorelin to stimulate growth hormone release is comparable with that of native ghrelin.…”

Therapeutic Applications of Ghrelin Agonists in the Treatment of Gastroparesis

“…Originally identified in 1999 as the natural ligand for the growth hormone secretagogue receptor (GHS-1a) or ghrelin receptor (GRLN-R) [19,20], ghrelin is an orexigenic hormone produced mainly in the oxyntic mucosa of the stomach [22] with significant sequence similarity to motilin [23]. It is derived from the human ghrelin gene via alternative splicing [24] and synthesized from precursor peptides that undergo post-translational processing [25].…”

Future Treatment of Constipation-associated Disorders: Role of Relamorelin and Other Ghrelin Receptor Agonists

“…18 While administered either peripherally or centrally, ghrelin stimulates food intake through GRLN-Rs on vagal afferents or via the bloodstream. 15,19 Moreover, by targeting hypothalamic neurons and the sympathetic nervous system, ghrelin regulates lipid-metabolizing enzymes in adipocytes. 20 Ghrelin also interacts with the reproductive, cardiovascular and immune systems.…”