Shuichi Muto

Decreased plasma ghrelin contributes to anorexia following novelty stress

We hypothesized that anorexia induced by novelty stress caused by exposure to a novel environment may be due to activation of corticotropin-releasing factor (CRF) and subsequently mediated by decreasing peripheral ghrelin concentration via serotonin (5-HT) and melanocortin-4 receptors (MC4R). Each mouse was transferred from group-housed cages to individual cages to establish the novelty stress. We observed the effect of changes in feeding behavior in a novel environment using the method of transferring group-housed mice to individual cages. We investigated the effect of an intracerebroventricular injection of antagonists/agonists of CRF1/2 receptors (CRF1/2Rs), 5-HT(1B)/(2C) receptors (5-HT(1B)/(2C)R), and MC4R to clarify the role of each receptor on the decrease in food intake. Plasma ghrelin levels were also measured. The novelty stress caused a reduction in food intake that was abolished by administering a CRF1R antagonist. Three hours after the novelty stress, appetite reduction was associated with reduced levels of neuropeptide Y/agouti-related peptide mRNA, increased levels of proopiomelanocortin mRNA in the hypothalamus, and a decrease in plasma ghrelin level. Administering a CRF1R antagonist, a 5-HT(1B)/(2C)R antagonist, an MC4R antagonist, exogenous ghrelin, and an enhancer of ghrelin secretion, rikkunshito, resolved the reduction in food intake 3 h after the novelty stress by enhancing circulating ghrelin concentrations. We showed that anorexia during a novelty stress is a process in which CRF1R is activated at the early stage of appetite loss and is subsequently activated by a 5-HT(1B)/(2C)R and MC4R stimulus, leading to decreased peripheral ghrelin concentrations.

Rikkunshito Ameliorates the Aging-Associated Decrease in Ghrelin Receptor Reactivity via Phosphodiesterase III Inhibition

Aging is associated with decreased food intake, a phenomenon termed the anorexia of aging. In this study, we sought to clarify changes in peripheral and central appetite-related factors in aged mice. Furthermore, we investigated the effects of rikkunshito, a traditional Japanese medicine, on age-related anorexia. C57BL/6J mice that were 6 or 75 wk old were studied. We investigated changes in food intake, ghrelin and leptin levels, and the expression of appetite-related genes with age. In addition, we verified the effects of ghrelin, rikkunshito, phosphodiesterase 3 (PDE3), and phosphoinositide 3-kinase inhibitors on appetite. Food intake was significantly decreased in 75-wk-old mice compared with the 6-wk-old mice. In 75-wk-old mice, plasma acylated ghrelin levels under fasting conditions were lower than in 6-wk-old mice, whereas leptin levels under feeding conditions were substantially higher. The expression levels of hypothalamic preproghrelin under feeding conditions and the expression levels of neuropeptide Y and agouti-related protein under fasting conditions were lower compared with those of the 6-wk-old mice. Ghrelin supplementation (33 microg/kg) failed to increase food intake in 75-wk-old mice. Conversely, oral administration of LY294002, a phosphoinositide 3-kinase inhibitor, and cilostamide, a PDE3 inhibitor, increased food intake in 75-wk-old mice. Moreover, rikkunshito increased food intake in aged mice. The components of rikkunshito (nobiletin, isoliquiritigenin, and heptamethoxyflavone) had inhibitory effects on PDE3. These results suggest that dysregulation of ghrelin secretion and ghrelin resistance in the appetite control system occurred in aged mice and that rikkunshito ameliorated aging-associated anorexia via inhibition of PDE3.

10-Gingerol, a component of rikkunshito, improves cisplatin-induced anorexia by inhibiting acylated ghrelin degradation

Rikkunshito (RKT), a Japanese traditional medicine, has been shown to stimulate food intake in rats with cisplatin-induced anorexia; however, the underlying mechanisms remain unknown. In this study, we investigated whether RKT is involved in the degradation of peripheral ghrelin. RKT inhibited decreases in plasma ghrelin level and enhanced acyl- to desacyl-ghrelin (A/D) ratio in cisplatin-treated rats. Several components of RKT demonstrated inhibitory activity against ghrelin deacylating enzymes. In addition, 10-gingerol, a component of RKT, inhibited exogenous ghrelin deacylation. Therefore, RKT may enhance plasma acyl-ghrelin level, at least in part, by inhibiting the circulating ghrelin degrading enzyme.

Impaired ghrelin signaling is associated with gastrointestinal dysmotility in rats with gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is often associated with decreased upper gastrointestinal motility, and ghrelin is an appetite-stimulating hormone known to increase gastrointestinal motility. We investigated whether ghrelin signaling is impaired in rats with GERD and studied its involvement in upper gastrointestinal motility. GERD was induced surgically in Wistar rats. Rats were injected intravenously with ghrelin (3 nmol/rat), after which gastric emptying, food intake, gastroduodenal motility, and growth hormone (GH) release were investigated. Furthermore, plasma ghrelin levels and the expression of ghrelin-related genes in the stomach and hypothalamus were examined. In addition, we administered ghrelin to GERD rats treated with rikkunshito, a Kampo medicine, and examined its effects on gastroduodenal motility. GERD rats showed a considerable decrease in gastric emptying, food intake, and antral motility. Ghrelin administration significantly increased gastric emptying, food intake, and antral and duodenal motility in sham-operated rats, but not in GERD rats. The effect of ghrelin on GH release was also attenuated in GERD rats, which had significantly increased plasma ghrelin levels and expression of orexigenic neuropeptide Y/agouti-related peptide mRNA in the hypothalamus. The number of ghrelin-positive cells in the gastric body decreased in GERD rats, but the expression of gastric preproghrelin and GH secretagogue receptor mRNA was not affected. However, when ghrelin was exogenously administered to GERD rats treated with rikkunshito, a significant increase in antral motility was observed. These results suggest that gastrointestinal dysmotility is associated with impaired ghrelin signaling in GERD rats and that rikkunshito restores gastrointestinal motility by improving the ghrelin response.

Rikkunshito as a ghrelin enhancer.

Rikkunshito is a kampo herbal medicine which is widely used in Japan for the treatment of the upper gastrointestinal symptoms of patients with functional dyspepsia, gastroesophageal reflux disease, dyspeptic symptoms of postgastrointestinal surgery patients, and chemotherapy-induced dyspepsia in cancer patients. Recently, very unique characteristics of rikkunshito have been unveiled; oral administration of rikkunshito potentiates orexigenic action of ghrelin through several different mechanisms. In addition, several lines of evidence obtained from both animal and human studies indicate that rikkunshito can be an attractive and promising therapeutic option for the anorectic conditions including cisplatin-induced dyspepsia, anorexia of aging, stress-induced hypophagia, and cancer cachexia-anorexia syndrome. In this chapter, we highlight the orexigenic effect of rikkunshito with a special focus on its interaction with ghrelin signaling system.

Rikkunshito and Ghrelin Secretion

Rikkunshito is a kampo herbal medicine which is widely used in Japan for the treatment of the upper gastrointestinal symptoms of patients with functional dyspepsia (FD), gastroesophageal reflux disease (GERD), dyspeptic symptoms of postgastrointestinal surgery patients, and chemotherapy-induced dyspepsia in cancer patients. Recently, very unique characteristics of rikkunshito have been unveiled; oral administration of rikkunshito potentiates orexigenic action of ghrelin through several different mechanisms. In addition, several lines of evidence obtained from both animal and human studies indicate that rikkunshito can be an attractive and promising therapeutic option for the anorectic conditions including cisplatin-induced dyspepsia, anorexia of aging, stress-induced hypophagia, cancer cachexia-anorexia syndrome. In this review, we will highlight what is known about the orexigenic effect of rikkunshito with a special focus on an interaction with ghrelin signaling system.

Serotonin 2C receptor antagonism ameliorates novelty-induced hypophagia in aged mice.

This study was conducted to clarify the role of serotonin (5-hydroxytryptamine, 5-HT) 2C receptor (5-HT2CR) signaling during novelty-induced hypophagia in aged mice. Male C57BL/6J mice [6-week-old (young) and 79-80-week-old (aged) mice] were exposed to a novel environment, and its effects on feeding behavior, stress hormones, and appetite-related factors were examined. Exposure of aged mice to a novel environment suppressed food intake and increased corticosterone secretion. These responses were marked compared with those in young mice. The expression in hypothalamic corticotropin-releasing factor (CRF), pituitary CRF1R and proopiomelanocortin mRNA in aged mice exposed to a novel environment was increased or tended to increase, compared to control mice. 5-HT2CR antagonist, SB242084 or rikkunshito administration attenuated the decrease in food intake and increased stress hormone levels in aged mice exposed to the environmental change. The 5-HT2CR mRNA expression in paraventricular nucleus was significantly enhanced, when aged mice was exposure to the novel environment. Thus, novelty-induced hypophagia in aged mice resulted, at least in part, from up-regulated hypothalamic 5-HT2CR function. In conclusion, 5-HT2CR signaling enhancement and the subsequent activation of the CRF neuron were involved in novelty-induced hypophagia in aged mice, and the 5-HT2CR antagonists offer a promising therapeutic option for depression.

Rikkunshito, a Japanese Kampo Medicine, Ameliorates Decreased Feeding Behavior via Ghrelin and Serotonin 2B Receptor Signaling in a Novelty Stress Murine Model

We investigated the effects of rikkunshito (RKT), a ghrelin signal enhancer, on the decrease in food intake after exposure to novelty stress in mice. RKT administration (500 mg/kg, per os) improved the decrease in 6 h cumulative food intake. In control mice, the plasma acylated ghrelin levels significantly increased by 24 h fasting. In contrast, the acylated ghrelin levels did not increase by fasting in mice exposed to the novelty stress. RKT administration to the novelty stress mice showed a significant increase in the acylated ghrelin levels compared with that in the distilled-water-treated control mice. Food intake after administering serotonin 2B (5-HT2B) receptor antagonists was evaluated to clarify the role of 5-HT2B receptor activation in the decrease in feeding behavior after novelty stress. SB215505 and SB204741, 5-HT2B receptor antagonists, significantly improved the decrease in food intake after exposure to novelty stress. A component of RKT, isoliquiritigenin, prevented the decrease in 6 h cumulative food intake. Isoliquiritigenin showed 5-HT2B receptor antagonistic activity in vitro. In conclusion, the results suggested that RKT improves the decrease in food intake after novelty stress probably via 5-HT2B receptor antagonism of isoliquiritigenin contained in RKT.

Optimal Dose Period for Indisetron Tablets for Preventing Chemotherapy-Induced Nausea and Vomiting with Modified FOLFOX6: A Randomized Pilot Study

Background: Indisetron is a serotonin (5-hydroxytryptamine type 3) receptor antagonist that also antagonizes 5-hydroxytryptamine type 4 receptors. We designed a pilot study in order to explore the optimal dosing period for indisetron during modified FOLFOX6 (mFOLFOX6). Patients and Methods: Forty-two chemotherapy-naive patients with advanced colorectal cancer scheduled to receive mFOLFOX6 were randomly assigned to either a 1- or 3-day indisetron regimen arm. The primary endpoint was complete protection from vomiting. Results: Proportions of patients with complete protection from vomiting were 85.7% [95% confidence interval (CI) 63.7–97.0] with the 3-day regimen and 81.0% (95% CI 58.1–94.6) with the 1-day regimen. Proportions of patients with complete protection from nausea were 47.6% in each arm (95% CI 25.7–70.2). No rescue therapy rates were 66.7% (95% CI 43.0–85.4) versus 57.1% (95% CI 34.0–78.2). No severe adverse events were observed in either arm. Conclusion: Both 1- and 3-day indisetron regimens were feasible for preventing nausea and vomiting induced by mFOLFOX6.

Multicenter observational study on functional bowel disorders diagnosed using Rome III diagnostic criteria in Japan

BackgroundThe Rome III diagnostic criteria had been used to diagnose functional gastrointestinal disorders (FGIDs) world wide, and functional bowel disorders (FBDs) including irritable bowel syndrome (IBS) have recently attracted the attention of Japanese physicians. However, there have been few reports on the prevalence of FBDs diagnosed by the Rome III diagnostic criteria.AimsThe aim of this study was to determine the prevalence of FBDs diagnosed according to the diagnostic criteria of Rome III in Japan.Patients and methodsAll patients who were booked for colonoscopy were enrolled from eight institutions in Japan. This study was a prospective observational study in the period from April 2013 to December 2013. Patients filled out FGID questionnaires of Rome III when they were waiting for colonoscopy.ResultsData for 1200 patients who underwent colonoscopy were analyzed. A total of 547 patients (45.6%) were diagnosed with FBDs. Out of those patients, 9.1% had IBS. According to the Rome III diagnostic criteria, 134 patients (11.2%) had functional bloating (FB), 73 (6.1%) had functional constipation (FC), 40 (3.3%) had functional diarrhea (FD), and 191 (15.9%) had unspecified functional bowel disorder (UFBD). Patients with FBDs had significantly higher rates of almost all symptoms (abdominal pain, hard or lumpy stools, loose or watery stools, and bloating) than those in the controls.ConclusionsIn Japan, the prevalence of FBDs and IBS is high, similar to that in the US. Many patients with FBDs have multiple symptoms.