Dataset Information

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

ABSTRACT:

Background and purpose

HM01, a novel, orally bioavailable, brain-penetrating agonist of ghrelin receptors, ameliorates emesis in Suncus murinus. This study compared HM01's activity against motion sickness with that of the less brain-penetrating ghrelin receptor agonist, HM02.

Experimental approach

The potential of HM01 and HM02 to relax isolated mesenteric arteries and to increase feeding was investigated. Radio telemetry was used to record gastric slow waves and body temperature. Plethysmography was used to measure respiratory function. HM01 and HM02 were administered p.o. 1 hr prior to provocative motion, and c-Fos expression in brain sections was assessed.

Key results

HM01 and HM02 both relaxed precontracted arteries, yielding EC₅₀ values of 2.5 ± 0.5 and 3.5 ± 0.4 nM respectively. HM01 increased feeding, but HM02 did not. Both compounds caused hypothermia and bradygastria. Motion induced 123 ± 24 emetic events. HM01, but not HM02, reduced motion-induced emesis by 67.6%. Motion increased c-Fos expression in the nucleus tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMNV), medial vestibular nucleus (MVe), central nucleus of the amygdala, and paraventricular hypothalamic nucleus (PVH). HM01 alone increased c-Fos expression in the area postrema, NTS, DMNV, PVH, and arcuate hypothalamic nucleus; HM02 had a similar pattern except it did not increase c-Fos in the PVH. Both compounds antagonized the motion-induced increases in c-Fos expression in the MVe.

Conclusions and implications

HM01 is more effective than HM02 in preventing motion-induced emesis. The difference in potency may relate to activation of ghrelin receptors in the PVH.

SUBMITTER: Tu L

PROVIDER: S-EPMC7060360 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

Project description:Purpose: Cancer patients receiving cisplatin therapy often experience side-effects such as nausea and emesis, but current anti-emetic regimens are suboptimal. Thus, to enable the development of efficacious anti-emetic treatments, the mechanisms of cisplatin-induced emesis must be determined. We therefore investigated these mechanisms in Suncus murinus, an insectivore that is capable of vomiting. Methods: We used a microelectrode array system to examine the effect of cisplatin on the spatiotemporal properties of slow waves in stomach antrum, duodenum, ileum and colon tissues isolated from S. murinus. In addition, we used a multi-wire radiotelemetry system to record conscious animals' gastric myoelectric activity, core body temperature, blood pressure (BP) and heart rate viability over 96-h periods. Furthermore, we used whole-body plethysmography to simultaneously monitor animals' respiratory activity. At the end of in vivo experiments, the stomach antrum was collected and immunohistochemistry was performed to identify c-Kit and cluster of differentiation 45 (CD45)-positive cells. Results: Our acute in vitro studies revealed that cisplatin (1-10 μM) treatment had acute region-dependent effects on pacemaking activity along the gastrointestinal tract, such that the stomach and colon responded oppositely to the duodenum and ileum. S. murinus treated with cisplatin for 90 min had a significantly lower dominant frequency (DF) in the ileum and a longer waveform period in the ileum and colon. Our 96-h recordings showed that cisplatin inhibited food and water intake and caused weight loss during the early and delayed phases. Moreover, cisplatin decreased the DF, increased the percentage power of bradygastria, and evoked a hypothermic response during the acute and delayed phases. Reductions in BP and respiratory rate were also observed. Finally, we demonstrated that treatment with cisplatin caused inflammation in the antrum of the stomach and reduced the density of the interstitial cells of Cajal (ICC). Conclusion: These studies indicate that cisplatin treatment of S. murinus disrupted ICC networking and viability and also affected general homeostatic mechanisms of the cardiovascular system and gastrointestinal tract. The effect on the gastrointestinal tract appeared to be region-specific. Further investigations are required to comprehensively understand these mechanistic effects of cisplatin and their relationship to emesis.