The ghrelin receptor agonist HM01 mimics the neuronal effects of ghrelin in the arcuate nucleus and attenuates anorexia-cachexia syndrome in tumor-bearing rats

Abstract

The gastric hormone ghrelin positively affects energy balance by increasing food intake and reducing energy expenditure. Ghrelin mimetics are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to characterize the action of the nonpeptidergic ghrelin receptor agonist HM01 on neuronal function, energy homeostasis and muscle mass in healthy rats and to evaluate its possible usefulness for the treatment of CACS in a rat tumor model. Using extracellular single-unit recordings, we tested whether HM01 mimics the effects of ghrelin on neuronal activity in the arcuate nucleus (Arc). Furthermore, we assessed the effect of chronic HM01 treatment on food intake (FI), body weight (BW), lean and fat volumes, and muscle mass in healthy rats. Using a hepatoma model, we investigated the possible beneficial effects of HM01 on tumor-induced anorexia, BW loss, muscle wasting, and metabolic rate. HM01 (10(-7)-10(-6) M) mimicked the effect of ghrelin (10(-8) M) by increasing the firing rate in 76% of Arc neurons. HM01 delivered chronically for 12 days via osmotic minipumps (50 μg/h) increased FI in healthy rats by 24%, paralleled by increased BW, higher fat and lean volumes, and higher muscle mass. Tumor-bearing rats treated with HM01 had 30% higher FI than tumor-bearing controls and were protected against BW loss. HM01 treatment resulted in higher muscle mass and fat mass. Moreover, tumor-bearing rats reduced their metabolic rate following HM01 treatment. Our studies substantiate the possible therapeutic usefulness of ghrelin receptor agonists like HM01 for the treatment of CACS and possibly other forms of disease-related anorexia and cachexia.

Therapeutic Potential of Targeting the Ghrelin Pathway

“…In rats, ghrelin treatment suppresses the cachectic weight loss induced by human melanoma cancer cell implantations [109]. Improved food intake and prevention of tissue wasting has further been observed upon ghrelin treatment in a mouse model of lung cancer-induced cachexia [110], as well as in a series of studies evaluating the role of ghrelin and its analogs in rodent tumor-bearing models of cachexia [108,111,112,113,114]. In line with these data, ghrelin stimulates feeding and lean body mass accrual in a rat model of chronic kidney disease-induced cachexia [115], attenuates cachexia in rats with heart failure [116], inhibits skeletal muscle breakdown after burn injury in rats [117] and inhibits angiotensin II-induced cachexia in mice [118].…”

From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation

“…GSK 894281 is an orally bioavailable BBB-penetrant ghrelin agonist which causes a prompt and dose-related output of faecal pellets after administration [326]. HM01 is another such agonist in preclinical trials as a colokinetic; again, its prokinetic action is attributed to its ability to cross the BBB and act on GHSR-1a’s present in the nerves of the lumbar section of the spinal cord [327,328,329,330]. …”

Oral Treatment with the Ghrelin Receptor Agonist HM01 Attenuates Cachexia in Mice Bearing Colon-26 (C26) Tumors

“…Given the orexigenic action of ghrelin [9,14,37] and ghrelin agonists [27,28,38] in rodents, it was unexpected that HM01 did not induce a clear increase in food intake in NTB animals, although HM01-treated mice consumed slightly more food in the first few days of treatment [27]. Therefore, the increase in body weight appears to be mediated by other mechanisms than increased energy intake.…”

“…Ghrelin is thought to counteract muscle degradation by IGF-1-dependent inhibition of proteolytic factors such as the E3 ubiquitin ligases muscle RING-finger protein-1 (MuRF-1) and muscle atrophy F-box (MAFbx)/atrogin-1 [12]. Although previous human clinical trials [23,24,25] and studies in rodent cancer models [26,27,28,29,30,31] confirmed therapeutic effectiveness of ghrelin or ghrelin analogues as anti-CACS treatment, currently no ghrelin-based drug is approved.…”

“…We recently characterized the effects of the GHS-R agonist HM01 on food intake and body weight gain in the rat Morris-7777 hepatoma tumor model [27]. HM01 is a small molecule compound with high receptor binding affinity, brain penetration, and a long plasma half-life time [32].…”