Anti-emetic Action of the Brain-Penetrating New Ghrelin Agonist, HM01, Alone and in Combination With the 5-HT3 Antagonist, Palonosetron and With the NK1 Antagonist, Netupitant, Against Cisplatin- and Motion-Induced Emesis in Suncus murinus (House Musk Shrew)

Abstract

Ghrelin has well-known activity to stimulate appetite and weight gain. Evidence suggests that ghrelin may also have effects in reducing chemotherapy-induced emesis via growth hormone secretagogue receptors (GHS-R1A) in the brain. However, it is not known whether the stimulation of GHS-R1A has broad inhibitory anti-emetic effects. In the present studies, we used Suncus murinus to investigate the potential of the new and novel orally bioavailable brain-penetrating GHS-R1A mimetic, HM01 (1-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-3-methyl-3-[(4R)-1-Methyl-3,3-dimethyl-4-piperidyl]urea), to reduce emesis induced by a variety of emetic challenges. HM01 (1 to 30 mg/kg, p.o.) antagonized emesis induced by cisplatin (30 mg/kg, i.p.) and by motion (4 cm horizontal displacement, 1 Hz) but was ineffective against emesis induced by nicotine (5 mg/kg, s.c.) and copper sulfate (120 mg/kg by intragastric gavage). In other experiments, HM01 (3 mg/kg, p.o.) enhanced the anti-emetic control of a regimen of palonosetron (0.01 mg/kg, p.o.) alone and palonosetron (0.01 mg/kg p.o.) plus netupitant (1 mg/kg, p.o.). HM01 (10 mg/kg, p.o.) also had positive effects in increasing feeding and drinking in nicotine-treated animals, and it shortened the latency to drink in animals treated with cisplatin. These data indicate that brain-penetrating GHS-R1A agonists may have use alone and/or in combination with standard anti-emetic regimens for the treatment of chemotherapy-induced nausea and vomiting and motion sickness.Highlights- The novel orally bioavailable brain-penetrating GHS-R1A agonist, HM01 (1-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-3-methyl-3-[(4R)-1-Methyl-3,3-dimethyl-4-piperidyl]urea), antagonizes motion- and cisplatin-induced emesis.- HM01 did not reduce emesis induced by nicotine or by intragastric copper sulfate.- HM01 has positive effects on food consumption after treatment with nicotine.- HM01 has synergistic effects against cisplatin when combined with palonosetron and palonosetron/netupitant regimens.- It is suggested that GHS-R1A agonists may be protective against chemotherapy-induced nausea and vomiting in combination with traditional anti-emetics and against motion-induced emesis.

GDF15 Induces Anorexia through Nausea and Emesis

“…Cisplatin induced c-Fos co-localized with GFRAL-positive neurons in the AP/NTS in mice, supporting our hypothesis that GFRAL-positive neurons are stimulated by cisplatin treatment, presumably via induction of peripheral GDF15 secretion. Although we did not directly test whether GFD15 release following cisplatin treatment plays a causal role in cisplatin-induced anorexia, we did detect elevated GDF15 during the same time window of the onset of cisplatin-induced emesis or emetic-like behavior in humans and animal models (Alhadeff et al, 2015;Hesketh et al, 2003;Rudd et al, 2018;Yamamoto et al, 2014). Data in GFRAL KO mice (Hsu et al, 2017) and in tumor models using a GDF15 antibody (Johnen et al, 2007) would suggest that blunting GDF15-GFRAL signaling would lead to reduced chemotherapy-induced malaise.…”

“…In the rat, pica behavior (i.e., ingestion of non-nutritive food such as kaolin clay) is a validated proxy for nausea (Alhadeff et al, 2017;De Jonghe and Horn, 2008;Liu et al, 2005), while in both mice and rats, conditioned flavor avoidance (CFA) has been used as a conditioned behavioral assay to screen for potential noxious stimuli (Bodnar, 2018;Parker, 2014). In contrast, the house musk shrew (Suncus murinus) is an established preclinical model for chemotherapy-induced emesis, as this mammal vomits and shares an emetic profile similar to humans (De Jonghe and Horn, 2009;Horn et al, 2011;Matsuki et al, 1988;Rudd et al, 2018;Ueno et al, 1987).…”

The brain‐penetrating, orally bioavailable, ghrelin receptor agonist HM01 ameliorates motion‐induced emesis in Suncus murinus (house musk shrew)

“…The anti-emetic potential of HM01 has been reported previously (Rudd et al, 2018). A dose of 10 mgÁkg −1 (p.o.)…”

Sulprostone-Induced Gastric Dysrhythmia in the Ferret: Conventional and Advanced Analytical Approaches

“…To date, only limited information is available regarding DFA of GMA, probably because the time series of EGG recordings in humans have a short-duration. With the advent of radiotelemetric technology, long-term GMA from the antrum has been recorded in different species ( Percie du Sert et al, 2010 ; Rudd et al, 2018 ; Wang et al, 2018 ). Theoretically, the observed periodic trend in GMA may invalidate the power-law scaling behavior ( Hu et al, 2001 ).…”

“…In the ferrets, analysis of the DF and power partition of GMA revealed that GMA could be disrupted by emetics such as apomorphine ( Percie du Sert et al, 2009a ), cisplatin ( Percie du Sert et al, 2009a ), and exendin-4 ( Lu et al, 2017b ). In shrews, disrupted GMA was observed in animals following motion ( Percie du Sert et al, 2010 ; Rudd et al, 2018 ). MFDFA has been used to analyze stationary or non-stationary time series in electromyography (EMG), electroencephalography (EEG), electrocardiography (ECG), gait variability, glycemic variability and respiration ( Ihlen, 2012 ), in which signal shapes change in complexity.…”