A Comparison of the Central versus Peripheral Gastrointestinal Prokinetic Activity of Two Novel Ghrelin Mimetics

Abstract

The gastrointestinal (GI) prokinetic effects of ghrelin occur through direct peripheral effects on ghrelin receptors within the enteric nervous system and via the ghrelin receptor on the vagus nerve, which activate a centrally mediated mechanism. However, the relative contribution of peripheral versus central effects to the overall prokinetic effect of ghrelin agonists requires further investigation. Here, we investigated the central versus peripheral prokinetic effect of ghrelin by using two novel ghrelin agonists:, a more peripherally acting ghrelin agonist. The pharmacokinetic profiles of both ghrelin agonists were evaluated after intravenous and oral administration in rats. The efficacy of HM01 and HM02 was assessed in a rat model of postoperative ileus (POI) induced by abdominal surgery and in a rodent defecation assay. Pharmacokinetic results in our models confirmed that HM01, but not HM02, was a brain-penetrant ghrelin agonist. Administration of either HM01 or HM02 reversed the delayed upper and lower gastrointestinal transit induced by abdominal surgery to levels resembling the non-POI controls. In the defecation test, HM01, but not HM02, significantly increased the weight of fecal pellets. Our findings suggest that, in a rodent model of POI, synthetic ghrelin agonists stimulate GI transit through a peripheral site of action. However, in the defecation assay, our data suggest that a ghrelin-mediated mechanism is located at a central site. Taken together, a ghrelin agonist with both central and peripheral prokinetic activity may show therapeutic potential to treat delayed GI transit disorders.

Nicotinamide Riboside Vitamin B3 Mitigated C26 Adenocarcinoma–Induced Cancer Cachexia

“…Cachexia alone indicates poor quality of life, which could lead to severe weight loss during chemotherapy. Many drugs, including appetite stimulants, such as ghrelin (a 28 amino acid orexigenic gut hormone), mimetics (Khatib et al, 2018;Mohammadi et al, 2019), thalidomide, cytokine inhibitors, such as MABp1 [a natural IgG1k human monoclonal antibody against IL-1α (Prado and Qian, 2019)], steroids, such as progesterone (Gharahdaghi et al, 2019;Solomon et al, 2019),…”

“…Cachexia alone indicates poor quality of life, which could lead to severe weight loss during chemotherapy. Many drugs, including appetite stimulants, such as ghrelin (a 28 amino acid orexigenic gut hormone), mimetics ( Khatib et al, 2018 ; Mohammadi et al, 2019 ), thalidomide, cytokine inhibitors, such as MABp1 [a natural IgG1k human monoclonal antibody against IL-1α ( Prado and Qian, 2019 )], steroids, such as progesterone ( Gharahdaghi et al, 2019 ; Solomon et al, 2019 ), nonsteroidal anti-inflammatory drugs, such as celecoxib ( Mantovani et al, 2010 ; Solheim et al, 2013 ), and branched-chain amino acids, such as leucine 2–4 g/day or eicosapentaenoic acids ( Pappalardo et al, 2015 ; Prado et al, 2020 ; Storck et al, 2020 ), have been investigated in the clinic, whereas others are still under investigation ( Ravasco, 2019 ). Although great progress has been made in understanding the underlying biological mechanisms of cachexia, further development is still awaited.…”

Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor

“…These results suggest that a peripheral site of action is involved in the stimulation of gastrointestinal transit induced by synthetic GHS-R1a agonists, while the increase of the weight of fecal pellets is mediated by a centrally located site. 129 Compound 61 also promoted motion-induced emesis more effectively than compound 63 in suncus murinus , suggesting that this effect is centrally induced, probably by the activation of GHS-R1a of the paraventricular hypothalamic nucleus. 130 …”

“…These results suggest that a peripheral site of action is involved in the stimulation of gastrointestinal transit induced by synthetic GHS-R1a agonists, while the increase of the weight of fecal pellets is mediated by a centrally located site. 129 Compound 61 also promoted motioninduced emesis more effectively than compound 63 in suncus murinus, suggesting that this effect is centrally induced, probably by the activation of GHS-R1a of the paraventricular hypothalamic nucleus. 130 Compound 5, another brain penetrant GHS-R1a agonist recently approved for veterinary use in cats and dogs, 131 effectively accelerated gastric emptying in mice 132 and stimulated defecation in a rat model of low fiber-induced constipation.…”

<p>Attenuation of Visceral and Somatic Nociception by Ghrelin Mimetics</p>

“…The doses for this study were selected based on previous experiments and publications on the efficacy of ghrelin mimetics. 26,27 The ghrelin antagonist, H0900 was supplied by Helsinn Healthcare SA, Lugano Switzerland, and administered via oral gavage as a suspension in a 1% methylcellulose solution at a volume of 0.5 mL per 100 g body weight. For all experiments with the antagonist H0900, a dose of 30 mg/kg was used.…”