Development of ghrelin resistance in a cancer cachexia rat model using human gastric cancer-derived 85As2 cells and the palliative effects of the Kampo medicine rikkunshito on the model

Abstract

Cancer cachexia (CC) is a multifactorial disease characterized by decreased food intake and loss of body weight due to reduced musculature with or without loss of fat mass. Patients with gastric cancer have a high incidence of cachexia. We previously established a novel CC rat model induced by human gastric cancer-derived 85As2 cells in order to examine the pathophysiology of CC and identify potential therapeutics. In patients with CC, anorexia is often observed, despite elevation of ghrelin, suggesting that ghrelin resistance may develop in these patients. In this study, we aimed to clarify the occurrence of ghrelin resistance in CC rats accompanied by anorexia and we investigated whether rikkunshito (RKT), a traditional Japanese Kampo medicine that potentiates ghrelin signaling, ameliorated CC-related anorexia through alleviation of ghrelin resistance. 85As2-tumor-bearing rats developed severe CC symptoms, including anorexia and loss of body weight/musculature, with the latter symptoms being greater in cachectic rats than in non-tumor-bearing or pair-fed rats. CC rats showed poor responses to intraperitoneal injection of ghrelin. In CC rats, plasma ghrelin levels were elevated and hypothalamic anorexigenic peptide mRNA levels were decreased, whereas hypothalamic growth hormone secretagogue receptor (GHS-R) mRNA was not affected. In vitro, RKT directly enhanced ghrelin-induced GHS-R activation. RKT administrated orally for 7 days partly alleviated the poor response to ghrelin and ameliorated anorexia without affecting the elevation of plasma ghrelin levels in CC rats. The expression of hypothalamic orexigenic neuropeptide Y mRNA but not hypothalamic GHS-R mRNA was increased by RKT. Thus, the 85As2 cell-induced CC rat model developed ghrelin resistance, possibly contributing to anorexia and body weight loss. The mechanism through which RKT ameliorated anorexia in the CC rat model may involve alleviation of ghrelin resistance by enhancement of ghrelin signaling. These findings suggest that RKT may be a promising agent for the treatment of CC.

Energy metabolism in cachexia

“…However, opposite to fasting, the increased ghrelin levels in cachexia fail to induce appetite and energy storage, potentially hinting to ghrelin resistance in these patients . Resistance to ghrelin action has been confirmed in cachectic rats .…”

Therapeutic potential of ghrelin and des-acyl ghrelin against chemotherapy-induced cardiotoxicity

“…2A) [12,13]. Cardiac dysfunction might have occurred in this model along with skeletal muscle loss or atrophy or both, although this has not been investigated so far.…”

“…We previously reported that the traditional Japanese medicine rikkunshito, prescribed for the treatment of gastrointestinal disorders [12,13], improved symptoms of cancer cachexia by reducing ghrelin resistance through the enhancement of ghrelin receptor-mediated signaling in our cancer cachexia model known about their underlying molecular mechanisms. In this study, we show the possible mechanisms underlying the preventive effect of ghrelin and des-acyl ghrelin against DOX-induced cardiotoxicity through in vitro and in vivo experiments.…”

Effect of hangebyakujutsutemmato on pregabalin‐induced dizziness in a rat model of neuropathic pain

“…There have been no previous studies on the treatment of rats with HBT. Based on previous studies involving kampo medicine, a dosage of 1 g/kg/day was used, which enabled us to demonstrate the effect of HBT on pregabalin‐induced dizziness. There is a need for further studies on the dose‐dependent effect of HBT.…”