Adaptive upregulation of gastric and hypothalamic ghrelin receptors and increased plasma ghrelin in a model of cancer chemotherapy-induced dyspepsia

Malik, Nasser; Moore, Gary B.T.; Kaur, Rejbinder; Liu, Y.-L.; Wood, Steve; Morrow, Rachel; Sanger, Gareth J.; Andrews, Paul

doi:10.1016/j.regpep.2008.03.005

Cited by 24 publications

(15 citation statements)

References 28 publications

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“…In addition, we show that stimulation of the GhrR increases upper GI motility in both a basal state and in a model of opiate-induced bowel dysfunction. It has been suggested recently that the dual action of GhrR agonists to stimulate both feeding and GI motility may provide a compelling therapeutic strategy for reversing the gastroparesis and cachexia associated with chemotherapy in cancer patients (Malik et al, 2008). Our data support the notion that small-molecule ghrelin agonists may offer a well integrated therapeutic approach to the treatment of multiple GI hypomotility-related disorders.…”

Section: Discussionsupporting

confidence: 82%

Enhanced Gastrointestinal Motility with Orally Active Ghrelin Receptor Agonists

Charoenthongtrakul¹,

Giuliana²,

Longo³

et al. 2009

J Pharmacol Exp Ther

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The orexigenic peptide ghrelin has been shown to have prokinetic activity in the gastrointestinal (GI) system of several species, including humans. In this series of experiments, we have evaluated the prokinetic activity of novel, small-molecule ghrelin receptor (GhrR) agonists after parenteral and peroral dosing in mice and rats. Gastric emptying, small intestinal transport, and fecal output were determined after intraperitoneal and intracerebroventricular dosing of GhrR agonists, using ghrelin as a positive control. These same parameters were evaluated after oral gavage dosing of the synthetic agonists. Regardless of dose route, GhrR agonist treatment increased gastric emptying, small intestinal transit, and fecal output. However, fecal output was only increased by GhrR agonist treatment if mice were able to feed during the stimulatory period. Thus, GhrR agonists can stimulate upper GI motility, and the orexigenic action of the compounds can indirectly contribute to prokinetic activity along the entire GI tract. The orexigenic and prokinetic effects of either ghrelin or small-molecule GhrR agonists were selective for the GhrR because they were absent when evaluated in GhrR knockout mice. We next evaluated the efficacy of the synthetic GhrR agonists dosed in a model of opiate-induced bowel dysfunction induced by a single injection of morphine. Oral dosing of a GhrR agonist normalized GI motility in opiate-induced dysmotility. These data demonstrate the potential utility of GhrR agonists for treating gastrointestinal hypomotility disorders.

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Section: Discussionsupporting

confidence: 82%

Enhanced Gastrointestinal Motility with Orally Active Ghrelin Receptor Agonists

Charoenthongtrakul¹,

Giuliana²,

Longo³

et al. 2009

J Pharmacol Exp Ther

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“…However, the observed trend is consistent with rodent studies. For example, Malik et al (2008) found that ghrelin receptor mRNA expression in rat stomach was increased two days after treatment with cisplatin, at a time when the cisplatin-induced gastric stasis was at its greatest; there were no changes in ghrelin mRNA expression. This up-regulation of ghrelin receptor expression suggested that ghrelin might be operating as part of a defence mechanism against the damage caused by cisplatin; this hypothesis is proposed because of the known ability of ghrelin to inhibit cisplatin-induced emesis, promote appetite and increase gastric emptying (Liu et al 2006;Malik et al 2008).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we looked for changes in expression of the gastric motility stimulant motilin (Sanger 2008) and the receptors for ghrelin. The latter was included because of an association between ghrelin and changes in appetite and gastric motility (Inui et al 2004) and also because of a previous study in rats, which showed that the ghrelin receptor may be up-regulated following administration of cisplatin (Malik et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Effects of neo-adjuvant chemotherapy for oesophago-gastric cancer on neuro-muscular gastric function

Sung

Arasaradnam

Jarvie³

et al. 2012

Mol Biol Rep

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“…Emerging evidence reveals that besides acting through visceral vagal afferent associated gut-brain axis and blood-mediated signals directly on the level of the hypothalamus (i.e., an energy homeostatic process), ghrelin gene products are also deeply involved in modulating reward and motivation in enhancing the hedonic and incentive responding to food-related cues (Wellman et al, 2005;Malik et al, 2008a) or context (Smith et al, 2010). For instance, acyl ghrelin was reported to alter the appetitive and consummatory response to learned cues associated with food in mice and rats in nonhomeostatic brain feeding nuclei (Johnson et al, 2009).…”

Section: H Acyl Ghrelin Reward Feeding and Related Body Weight Regmentioning

confidence: 99%