Therapeutic Applications of Ghrelin Agonists in the Treatment of Gastroparesis

Shin, Andrea; Wo, John M.

doi:10.1007/s11894-015-0430-8

Cited by 21 publications

(8 citation statements)

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“…Mice with a global or neuron-specific deletion of GHSR1a are resistant to diet-induced obesity and display improved insulin sensitivity 26 , 27 , suggesting that inhibiting ghrelin actions could promote weight loss and decrease insulin resistance. Additionally, the stimulation of the ghrelin pathway is a promising approach for the treatment of cachexia 28 and diabetic gastroparesis 29 , 30 . Understanding how MRAP2 enhances the activity of GHSR1a activity may uncover new strategies to modulate ghrelin action and inform drug discovery efforts targeting GHSR1a.…”

Section: Discussionmentioning

confidence: 99%

MRAP2 regulates ghrelin receptor signaling and hunger sensing

et al. 2017

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Ghrelin is the only known circulating orexigenic hormone. It is primarily secreted by the stomach and acts at its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), in the hypothalamus to signal hunger and promote food intake. The melanocortin receptor accessory protein 2 (MRAP2) was previously shown to regulate energy homeostasis through the modulation of the activity of the melanocortin-4 receptor and prokineticin receptors. In this study we identify MRAP2 as a partner of ghrelin-GHSR1a signaling. We show that MRAP2 interacts with GHSR1a and potentiates ghrelin-stimulated signaling both in vitro and in vivo. We demonstrate that in the absence of MRAP2, fasting fails to activate agouti-related protein neurons. In addition, we show that the orexigenic effect of ghrelin is lost in mice lacking MRAP2. Our results suggest that MRAP2 is an important modulator of the energy homeostasis machinery that operates through the regulation of multiple GPCRs throughout the hypothalamus.

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Section: Discussionmentioning

confidence: 99%

MRAP2 regulates ghrelin receptor signaling and hunger sensing

et al. 2017

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“…Ghrelin receptor agonists have been extensively profiled in humans primarily focusing on frailty , gastroparesis and cachexia . However, despite ghrelin and its receptor being discovered nearly 20 years ago, no ghrelin receptor antagonist had safely progressed to humans to facilitate our basic understanding of the role of endogenous ghrelin via the ghrelin receptor in obesity, diabetes, addiction, or psychiatric disorders .…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of PF‐05190457: The first oral ghrelin receptor inverse agonist to be profiled in healthy subjects

Denney

Sonnenberg

Carvajal‐Gonzalez

et al. 2016

Brit J Clinical Pharma

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AIMTo evaluate safety, tolerability and pharmacokinetics of oral PF-05190457, an oral ghrelin receptor inverse agonist, in healthy adults. METHODSSingle (SAD) and multiple ascending dose (MAD) studies were randomised, placebo-controlled, double-blind studies. Thirty-five healthy men (age 38.2 ± 10.4 years; body mass index 24.8 ± 3.1 kg m -2 [mean ± standard deviation]) received ≥1 dose (2, 10, 40 [divided], 50, 100, 150, and 300 [single or divided] mg) of PF-05190457 and/or placebo in the SAD. In the MAD study, 35 healthy men (age 39.7 ± 10.1 years; body mass index 25.9 ± 3.3 kg m -2 ) received ≥1 dose (2, 10, 40 and 100 mg twice daily) of PF-05190457 and/or placebo daily for 2 weeks. RESULTSPF-05190457 absorption was rapid with a T max of 0.5-3 hours and a half-life between 8.2-9.8 hours. PF-05190457 dosedependently blocked ghrelin (1 pmol kg -1 min -1 )-induced growth hormone (GH) release with (mean [90% confidence interval]) 77% [63-85%] inhibition at 100 mg. PF-05190457 (150 mg) delayed gastric emptying lag time by 30% [7-58%] and half emptying time by 20% [7-35%] with a corresponding decrease in postprandial glucose by 9 mg dL -1 . The most frequent adverse event reported by 30 subjects at doses ≥50 mg was somnolence. PF-05190457 plasma concentrations also increased heart rate up to 13.4 [4.8-58.2] beats min -1 and, similar to the effect on glucose and ghrelin-induced GH, was lost within 2 weeks. CONCLUSIONSPF-05190457 is a well-tolerated first-in-class ghrelin receptor inverse agonist with acceptable pharmacokinetics for oral daily dosing. Blocking ghrelin receptors inhibits ghrelin-induced GH, and increases heart rate, effects that underwent tachyphylaxis with chronic dosing. PF-051940457 has the potential to treat centrally-acting disorders such as insomnia. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• PF-05190457 is a selective inverse agonist of the ghrelin receptor with a nonclinical profile supporting human dosing.• Endogenous ghrelin and exogenous infusions in healthy subjects release growth hormone, stimulate hunger and increases gastric motility WHAT THIS STUDY ADDS• PF-05190457 is the first reported ghrelin receptor inverse agonist profiled in humans. It is safe and well-tolerated in healthy subjects with pharmacokinetics supporting daily oral dosing.• PF-05190457 blocks ghrelin receptors in healthy subjects, dose-dependently increases heart rate, delays gastric emptying, induces somnolence and maximal inhibition for 2 weeks yields tachyphylaxis. Tables of Links IntroductionGhrelin is an endogenous 28-amino acid acylated peptide synthesised within the stomach fundus associated with modulating growth hormone secretion, gastric motility, gastric acid secretion and hunger. Acylated ghrelin is the only peripheral hunger-stimulating hormone that elevates preprandially in plasma, suggesting a role in meal initiation in humans [3]. Circulating endogenous baseline and pulsatile patterns of total ghrelin are inhibited in obese subjects following gastric bypass surgery [4,5]; however, not all studies ha...

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“…This supports a potential beneficial effect to improve nutritional and metabolic status of PD patients who have loss of appetite and body weight and reduced circulating ghrelin levels during the postprandial recuperation phase (Unger et al, 2011; Song et al, 2017). It is also of relevance that some ghrelin receptor agonists have moved to clinical trials for gastroparesis and constipation (Acosta et al, 2015; Mulak and Bonaz, 2015; Shin and Wo, 2015; Mosińska et al, 2017). Collectively, these findings suggest that ghrelin agonists may be of benefit to alleviate PD symptoms (Ramprasad et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Multiple Beneficial Effects of Ghrelin Agonist, HM01 on Homeostasis Alterations in 6-Hydroxydopamine Model of Parkinson’s Disease in Male Rats

Minalyan

Gabrielyan

Pietra

et al. 2019

Front. Integr. Neurosci.

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Background and objective : Developing therapy for non-motor symptoms of Parkinson’s disease (PD) is important for improving patients’ quality of life. Previously, we reported that the ghrelin receptor agonist, HM01 normalized the decreased 4-h fecal output and levodopa-inhibited gastric emptying in 6-OHDA rats, and activated selective areas in brain and spinal cord. In this study, we evaluated whether chronic HM01 treatment influences motor functions and/or has beneficial effects on non-motor symptoms including alterations of body weight and composition, defecation, feeding and water intake in 6-OHDA rats. Methods : Male rats were microinjected unilaterally into the medial forebrain bundle with either vehicle or 6-OHDA. Three weeks later, we assessed basal body weight, and 24-h fecal output (pellets, weight, dry weight and water content), water intake and food intake (ingested and spillage). Then, HM01 (3 mg/kg) or vehicle was given per gavage daily for 10–12 days and the same parameters were re-assessed daily. Motor behavior (stepping and rotations tests), body composition were monitored before and after the HM01 treatment. Results : 6-OHDA rats showed motor deficits in rotation test induced by apomorphine and stepping test. They also displayed a significant reduction in body weight, water consumption, fecal weight and water content and an increase in food spillage compared to vehicle microinjected rats. Daily oral treatment of HM01 did not modify motor alterations compared to vehicle but significantly increased the body weight, fat mass, and 24-h fecal weight, fecal water content, food and water intake in 6-OHDA rats, while HM01 had no significant effect in vehicle microinjected rats. Fecal weight and water content were both correlated with water intake, but not with food intake. Fat mass, but not body weight, was correlated with food intake. HM01 effects were significant after 24 h and remained similar during the treatment. Conclusions : Chronic treatment with ghrelin agonist, HM01 improved several non-motor symptoms in the rat PD model induced by 6-OHDA lesion including the decrease in body weight, water consumption, fecal weight and water content, and increased food intake while not improving the motor deficits. These findings provide pre-clinical evidence of potential benefits of ghrelin agonists to alleviate non-motor symptoms in PD patients.

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Therapeutic Applications of Ghrelin Agonists in the Treatment of Gastroparesis

Cited by 21 publications

References 100 publications

MRAP2 regulates ghrelin receptor signaling and hunger sensing

MRAP2 regulates ghrelin receptor signaling and hunger sensing

Pharmacokinetics and pharmacodynamics of PF‐05190457: The first oral ghrelin receptor inverse agonist to be profiled in healthy subjects

Multiple Beneficial Effects of Ghrelin Agonist, HM01 on Homeostasis Alterations in 6-Hydroxydopamine Model of Parkinson’s Disease in Male Rats

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