Rikkunshito Research Articles

Rikkunshito improves anorexia through ghrelin- and orexin-dependent activation of the brain hypothalamus and mesolimbic dopaminergic pathway in rats.

Rikkunshito (RKT), a traditional Japanese medicine, can relieve epigastric discomfort and anorexia in patients with functional dyspepsia. RKT enhances the orexigenic hormone, ghrelin. Ghrelin regulates food motivation by stimulating the appetite control center in the hypothalamus and the brain mesolimbic dopaminergic pathway (MDPW). However, the effect of RKT on MDPW remains unclear. Here, we aimed to investigate the central neural mechanisms underlying the orexigenic effects of RKT, focusing on the MDPW. We examined the effects of RKT on food intake and neuronal c-Fos expression in restraint stress- and cholecystokinin octapeptide-induced anorexia in male rats. RKT treatment significantly restored stress- and cholecystokinin octapeptide-induced decreased food intake. RKT increased c-Fos expression in the ventral tegmental area (VTA), especially in tyrosine hydroxylase-immunoreactive neurons, and nucleus accumbens (NAc). The effects of RKT were suppressed by the ghrelin receptor antagonist [D-Lys3]-GHRP-6. RKT increased the number of c-Fos/orexin-double-positive neurons in the lateral hypothalamus (LH), which project to the VTA. The orexin receptor antagonist, SB334867, suppressed RKT-induced increase in food intake and c-Fos expression in the LH, VTA, and NAc. RKT increased c-Fos expression in the arcuate nucleus and nucleus of the solitary tract of the medulla, which was inhibited by [D-Lys3]-GHRP-6. RKT may restore appetite in subjects with anorexia through ghrelin- and orexin-dependent activation of neurons regulating the brain appetite control network, including the hypothalamus and MDPW.

A review of frequently used Kampo prescriptions. Part 5. Rikkunshito

AbstractBackgroundThe source of rikkunshito (RKT) is thought to be Yixuezhengzhuan by Yu Tuan. RKT was originally designed for many patients to treat gastrointestinal symptoms such as abdominal bloating, discomfort, nausea, and anorexia.Key FindingsRKT consists of eight types of crude drugs. Clinical studies including randomized clinical trials (RCT) for patients with non‐erosive reflux disease (NERD) refractory to proton‐pump inhibitor (PPI) have demonstrated that RKT improves not only acid‐related dysmotility symptoms, but also extra‐esophageal symptoms, and with RCT trial for functional dyspepsia (FD), RKT can simultaneously treat gastrointestinal and psychological symptoms. Moreover, RKT was recently applied to the day‐to‐day conditions, post‐operative management, and chemotherapy in cancer patients. Preclinical studies have also reported that various pharmacological functions of RKT such as its protective effect on mucosal injuries and its prokinetic effect on gastrointestinal tract motility have been elucidated. RKT was considered to increase plasma ghrelin levels by the inhibition of 5‐HT2B and 5‐HT2C receptor activities, enhanced ghrelin‐mediated signaling, inhibited degradation of acylated ghrelin to suppress decreases in plasma ghrelin levels by inhibiting the rate of degradation of acyl ghrelin to des‐acyl ghrelin, and inhibited PDE III activity. The incidence of adverse events associated with RKT was only 1.2%, and almost all adverse drug reactions were non‐serious reactions.ConclusionRKT is one of the very good candidates for beneficial medicines especially for patients presenting with intractable symptoms caused by gastrointestinal diseases such as disorders of gut–brain interaction or cancers.

Japanese Traditional Herbal Medicine, Rikkunshito, Partially Suppresses Inflammatory Responses in Myocardial Ischemia/Reperfusion Injury.

Myocardial ischemia/reperfusion (I/R) injury can cause additional damage to an ischemic myocardium, even after successful reperfusion therapy. Inflammation is a mechanism that exacerbates myocardial damage after I/R injury. Rikkunshito(RKT) is a traditional Japanese herbal medicine widely used to treat gastrointestinal symptoms. It attenuates inflammation and fibrosis in some diseases of the heart; however, it remains unclear whether RKT exerts cardioprotective effects against myocardial I/R injury. To elucidate this, we evaluated the effects of RKT pre-treatment by oral administration on the myocardium in a mouse model of in vivo I/R injury. Mice were randomly assigned to a group receiving distilled water (DW) or one receiving RKT (1000 mg/kg/day) for 14 days orally. For each of the RKT and DW groups, a sham group, an I/R 2 h group, and an I/R 24 h group were created. On day 15, myocardial I/R surgery was performed. The left anterior descending coronary artery (LAD) was ligated for 30 min, and reperfusion time was set at 2 h or 24 h. The myocardial infarct size (IS) was measured after 2 h of reperfusion, and cardiac cytokine mRNA expression levels were evaluated by quantitative reverse transcription polymerase chain reaction (RT-PCR) after 2 h and 24 h of reperfusion. RKT pre-treatment significantly suppressed the cardiac mRNA expression level of interleukin-1β in the RKT-I/R 2 h group compared to the DW-I/R 2 h group (P < 0.05). Additionally, RKT significantly suppressed the mRNA expression levels of transforming growth factor-β compared to DW; the same result was obtained for the expression levels of interleukin-6. However, RKT did not reduce the IS or mRNA expression levels of the cardiac congestive markers natriuretic peptide a(NPPA) and natriuretic peptide b (NPPB). In addition, RKT did not alter the plasma concentration of ghrelin and sirtuin 1 (Sirt1), which have been reported to be stimulated by RKT. This study showed that pre-treatment of RKT for myocardial I/R injury partially suppressed inflammation-related cytokines. However, further studies are needed on the effect of RKT on the reduction of myocardial infarction size.

Effect of the Japanese herbal drug rikkunshito for the treatment of malnutrition in patients with chronic heart failure

AbstractAimAlthough malnutrition is an important prognostic factor in patients with chronic heart failure (CHF), no effective treatment for malnutrition has been established. Rikkunshito (RKT) is a Japanese herbal drug that has been used in daily practice for patients with loss of appetite. However, no data have demonstrated whether or not RKT can improve the body composition in patients with CHF. The aim of this study was to elucidate the effect of RKT on the nutritional status of patients with CHF.MethodsThis single‐center retrospective observational study included 14 patients with CHF and loss of appetite who were treated with RKT. Body mass index (BMI) and body composition including fat‐free mass index (FFMI), skeletal muscle mass index (SMI) and fat mass index (FMI) were measured by the bioimpedance method. Body composition was measured at baseline and 12 weeks later. The primary endpoint was the change of BMI and body composition.ResultsBMI was significantly improved from 23.7 (20.0–26.1) kg/m2 to 24.2 (20.3–27.3) kg/m2 (p = 0.0494). FFMI was significantly improved from 13.7 (11.3–14.9) kg/m2 to 14.2 (12.0–15.7) kg/m2 (p = 0.0002). SMI was also improved from 5.0 (3.0–6.2) kg/m2 to 5.3 (3.3–6.8) kg/m2 (p = 0.0085). On the other hand, FMI was not significantly changed (9.4 (7.2–12.0) kg/m2 to 10.3 (7.9–12.0) kg/m2, p = 0.8552).ConclusionThe Japanese herbal drug RKT was effective in improving the nutritional status of patients with CHF.

Effects of Rikkunshi-To on the donepezil-induced gastrointestinal symptoms in mice

Donepezil is used for treatment of Alzheimer&apos;s disease, but it is associated with increased risk for gastrointestinal (GI) symptoms, such as anorexia, nausea, and vomiting. Their insufficient control affects the ability to continue the donepezil therapy. Rikkunshi-To (RKT), a traditional herbal Japanese medicine, has been prescribed for patients with various GI symptoms because it improves the GI function via the potentiation of ghrelin signaling pathway. In this study, we investigated the effects of RKT on the prevention of donepezil-induced anorexia, nausea, and vomiting in mice and the involvement of ghrelin in its therapeutic effect. We have reported that donepezil (5mg/kg, i.p.) induced anorexia and pica, kaolin ingestion behavior, could be used to evaluate nausea and vomiting in mice fed the normal diet. Mice fed the diet supplemented with RKT (1%) did not show donepezil-induced anorexia and pica, and this therapeutic effect was antagonized by pretreatment with the ghrelin receptor antagonist. Donepezil significantly suppressed the intestinal motility in mice fed the normal diet; however, RKT recovered the motility delay. Furthermore, the ghrelin receptor antagonist reduced the effect of RKT to improve the intestinal motility. These findings suggest that RKT is a candidate for the treatment of donepezil induced anorexia, nausea, and vomiting in human patients, and that the enhancement of ghrelin signaling is involved in its therapeutic effect.

Kampo medicines Rikkunshito and Hangeshashinto prevent cisplatin-induced intestinal mucosal injury in rats

Background/PurposeWe examined the effects and mechanisms of rikkunshito (RKT) and hangeshashinto (HST) on cisplatin-induced mucosal injuries in the rat small bowel. MethodsJuvenile rats were divided into 6 groups: sham control, cisplatin injection without kampo medicines, and cisplatin injection with oral administration of low and high doses of RKT (1000 mg/kg and 2000 mg/kg) and HST (500 mg/kg and 1000 mg/kg). Fecal condition, intestinal morphological changes, enterocyte proliferation, and enterocyte apoptosis were assessed. ResultsDiarrhea and atrophy of ileal villi observed in the cisplatin group were significantly improved in all kampo groups. Injury scores of the jejunum were significantly lower with RKT (2000 mg/kg) and HST (500 and 1000 mg/kg) than with cisplatin, and those of the ileum were significantly lower with HST (500 and 1000 mg/kg) than with cisplatin. Enterocyte proliferation of the jejunum was significantly increased with RKT (2000 mg/kg) and HST (500 mg/kg) compared with cisplatin, and those of the ileum were significantly increased in all kampo groups compared with the cisplatin group. Jejunal and ileal apoptosis following cisplatin administration was significantly inhibited by HST. ConclusionsRKT and HST prevented cisplatin-induced intestinal mucosal injury with increasing proliferation of intestinal epithelial cells. HST also attenuated cisplatin-induced crypt cell apoptosis.

Effects of the herbal medicine Rikkunshito, for functional dyspepsia: A systematic review and meta-analysis.

Background and AimFunctional dyspepsia (FD) is characterized by chronic and unexplained indigestion at upper abdomen. Because of unsatisfactory effect of conventional treatments, demand is growing for complementary and alternative medicine. Rikkunshito (RKT) is a herbal medicine, which has been widely used for FD in Asia; however, the evidence is lacking. We carried out systematic review and meta‐analysis to evaluate the effect and safety of RKT in the treatment of FD.MethodsElectronic databases were searched in April 2019, including PUBMED, EMBASE, and Cochrane Library. All eligible studies should be randomized controlled trials (RCTs) comparing RKT or combination therapy (RKT and western medicine) group to western medicine group. The primary outcome measure was the total clinical efficacy rate (TCE). The secondary outcomes were total dyspepsia symptom scale, gastric emptying rate, gastrin, motilin, recurrence 6 months after treatment, and Hamilton depression rating scale.ResultsFifty‐two RCTs with 5475 patients were involved in this systematic review and meta‐analysis. Compared with western medicine, RKT showed significant better result, with higher TCE (relative risk = 1.21, 95% confidence interval 1.17 to 1.25, P < 0.001). RKT presented higher reduction of total dyspepsia symptom scale, more improved gastric emptying rate, and lower recurrence 6 months after treatment compared with western medicine. However, there was no significant difference in Hamilton depression rating scale between RKT and western medicine group. Combination therapy brought significant symptom improvement with TCE compared with western medicine alone.ConclusionsRikkunshito and combination therapy might be considered an effective alternative treatment for FD. Further rigorously designed and high‐quality RCTs are needed.

Alternatives to Acid Suppression Treatment for Laryngopharyngeal Reflux.

Laryngopharyngeal reflux (LPR) and associated symptoms can be refractory to treatment with acid suppressing medication. We investigated the role and evidence for complementary and alternative medicine (CAM) for LPR in this systematic review. Complementary and alternative treatment was defined in this systematic review as any non-acid suppressing medication, treatment, or therapy. A literature search was performed by two authors in consultation with a medical librarian using controlled vocabulary for "complementary and alternative medicine" and "laryngopharyngeal reflux" in the databases PubMed and EMBASE, with supplemental searches with Google Scholar. Twenty articles were included in this review for the modalities: alginate, diet modification, prokinetics, respiratory retraining, voice therapy, rikkunshito (RKT), hypnotherapy, and sleep positioning. The studies were analyzed for bias based on the Cochrane criteria for RCTs and Methodological Index for non-RCT (MINORS) criteria for all other studies. For each modality a level of evidence was assigned to the current body of evidence using the GRADE approach. There is mixed evidence with a high degree of bias and heterogeneity between studies for the modalities presented in the paper. Based on this review, an anti-reflux diet is recommended for all patients and there is some low-quality evidence to support alkaline water. For patients with predominant vocal symptoms there is evidence that supports voice therapy. There is insufficient evidence to recommend prokinetics at this time. For patients with predominant globus symptoms, alginate, RKT, and relaxation strategies may be used in conjunction with acid suppressing medications for symptom relief.

Effects of Rikkunshito treatment on renal fibrosis/inflammation and body weight reduction in a unilateral ureteral obstruction model in mice

Chronic kidney disease (CKD) progresses to end-stage renal failure via renal tubulointerstitial fibrosis. Malnutrition, inflammation, and arteriosclerosis interact to exacerbate the poor prognosis of CKD, and their effective management is thus essential. The traditional Japanese medicine Rikkunshito (RKT) exerts appetite-stimulating effects via ghrelin, which attenuates inflammation and fibrosis. We evaluated the therapeutic effect of RKT in unilateral ureter obstruction (UUO)-induced renal fibrosis/inflammation and body weight loss in mice. UUO and sham-operated mice were fed a standard diet or diet containing 3.0% RKT. Renal fibrosis was investigated by histopathology and macrophage infiltration was determined by immunohistochemistry. Expression levels of genes associated with fibrosis, inflammation, ghrelin, and mitochondrial function were determined by quantitative reverse transcription-polymerase chain reaction and western blot analyses. RKT treatment partially prevented UUO-induced weight loss but failed to attenuate renal fibrosis and inflammation. Renal expression of sirtuin 1, a ghrelin-downstream signalling molecule, and gene expression of peroxisome proliferator-activated receptor-γ coactivator 1α and Bcl-2/adenovirus E1B interacting protein 3 were unaffected by RKT. These results indicate that RKT inhibits weight loss but does not improve renal fibrosis or inflammation in a rapidly progressive renal fibrosis mouse model. RKT may have a protective effect on weight loss associated with CKD.

Prospective, randomized, cross-over pilot study of the effects of Rikkunshito, a Japanese traditional herbal medicine, on anorexia and plasma-acylated ghrelin levels in lung cancer patients undergoing cisplatin-based chemotherapy.

Purpose Anorexia induced by cytotoxic chemotherapy on delayed phase is a highly frequent adverse event. We aimed to determine the effects of rikkunshito (RKT) on chemotherapy-induced anorexia (CIA) in patients with lung cancer. Methods This prospective, randomized, cross-over pilot trial included 40 lung cancer patients scheduled to undergo cisplatin-based chemotherapy and randomized to either a group given RKT 7.5g/day for 14days (Group A, N = 20) or not (Group B, N = 20), then the treatments were switched. All patients received dexamethasone, palonosetron hydrochloride and aprepitant regardless of group assignment. Rescue drugs were allowed as required. The primary and key secondary endpoints were changes in caloric intake and in plasma acylated ghrelin (AG) levels, respectively. Average daily caloric intake during days 3 to 5 was compared with that on day 1 of each course. Results The primary and key secondary endpoints were analyzed in 31 patients (per protocol population) completing the study. Reduction rate of caloric intake was lower in RKT, than in control courses (18% vs. 25%, P = 0.025). Plasma AG levels significantly declined between days 1 and 3 in RKT (12.3 vs. 7.5 fmol/mL, P < 0.001) and control (10.8 vs. 8.6 fmol/mL, P < 0.001) courses. However, those obviously increased to 8.5 fmol/mL (P = 0.025) by day 5 in RKT course but not in control course (7.7 fmol/mL, P = 0.28). Conclusions Rikkunshito could mitigate CIA and ameliorate plasma AG levels during the delayed phase of CDDP-based chemotherapy in lung cancer patients. Clinical trial registration numbers: UMIN000010748.

Traditional Japanese herbal medicine rikkunshito increases food intake and plasma acylated ghrelin levels in patients with esophageal cancer treated by cisplatin-based chemotherapy

Cisplatin (CDDP) is an important chemotherapeutic drug for treating esophageal cancer that often induces nausea and vomiting. Rikkunshito (RKT), a traditional Japanese herbal medicine, can increase levels of plasma ghrelin, which is an orexigenic gut hormone that can alleviate chemotherapy-induced nausea and vomiting (CINV) and anorexia. This prospective randomized crossover study included 20 patients with esophageal cancer who were administered with CDDP-based chemotherapy. Ten of them were assigned to group A [1st course: with RKT 7.5 g/day on days 1-14; 2nd course: without RKT (control)] and 10 were assigned to group B [1st course: without RKT (control); 2nd course: with RKT 7.5 g/day on days 22-35]. Food intake and levels of plasma acylated ghrelin (AG) were compared between the control and RKT courses. Data from 18 patients were included in this analysis, as chemotherapy was immediately stopped due to deteriorating renal function in one patient and intracerebral bleeding in another. The median rate at which food intake decreased between days 4 and 6 was considerably lower in the course with, than without RKT (2% vs. 30%; P=0.02). Median levels of AG significantly increased from days 3 to 8 in patients in both courses with and without RKT (9.6 to 15.7 fmol/mL, P<0.0001; control, 10.2 to 17.8, P=0.0002). The rate at which median plasma AG levels increased from days 3 to 8 tend to be higher in the RKT, than in the control course (68% vs. 48%, P=0.08). RKT can improve CDDP-induced, delayed-onset anorexia and increase plasma AG levels among patients with esophageal cancer who undergo highly emetogenic chemotherapy (HEC).

Metabolites as mediator for alleviating adverse effects in chemotherapy: A new finding from a recent study of Japanese traditional Kampo medicine, rikkunshito (RKT).

e18292 Background: In Japan, RKT is used for chemotherapy-induced anorexia. There is considerable variation in the therapeutic response to RKT. We assessed the efficacy of RKT on anorexia induced by cisplatin (CDDP) therapy in lung cancer patients (pts) from the clinical and the plasma metabolomics perspectives. Methods: The study was a double-blind, randomized trial evaluating pts with age ≥20 y with lung cancer assigned to receive regimen including CDDP, ECOG PS 0 to 1. Pts were administered RKT or placebo from the beginning of 1st course of chemotherapy (Day1) until just before starting the 2nd course (21 or 28 consecutive days). The clinical endpoints were the change in mean dietary intake in hospital (MDIH), QOL and nutritional indices. Plasma samples were collected at Day1, Day7 and Day22 (22nd or 29th day) for metabolome analyses. Results: 60 pts were enrolled between Nov 2014 and Aug 2017. 29 were allocated to RKT and 31 to placebo. The ANCOVA estimate of treatment effect in MDIH (baseline adjusted RKT-Placebo difference) was not significant (-6.7; 95% C.I. -61.1 to 47.8). Regarding QOL, there was no significant results in changes of QLQ-C30 Global Health Status. Among the related subscales, Pain in Day22 in PPS analysis was the only significant item (-17.0; -29.7 to -4.2). Regarding QLQ-LC13 , Alopecia in Day22 was the only significant item (-21.3; -36.9 to -5.8). The changes in nutritional indices did not show any significant difference, either. In metabolome analysis, CDDP drastically influenced metabolites, such as essential amino acids. RKT did not significantly change them compared to the placebo. In contrast, the changes of acetylglycine and arabinose in plasma strongly correlated with those in dietary intake and pain only in the RKT. Conclusions: In this exploratory study, no significant difference was observed in the MDIH. Although, pain and alopecia observed in QOL were significantly improved in the RKT. Some plasma metabolites were found to correlate with improvement in dietary intake or QOL. This is the first suggestive evidence that the efficacy of RKT would be variable depend on the metabolic profile. Clinical trial information: JAPIC CTI-142747.

Effects of rikkunshito on renal fibrosis and inflammation in angiotensin II-infused mice

The underlying pathogenesis of chronic kidney disease involves an activated renin-angiotensin system and systemic inflammation which ultimately develop renal injury. Rikkunshito (RKT) has been reported to exert anti-fibrotic and anti-inflammatory effects through enhancement of ghrelin signaling pathway. In this study, we investigated the effects of RKT on renal fibrosis and inflammation in angiotensin II (Ang II)-induced renal injury model. Ang II-infused mice exhibited hypertension, cardiac hypertrophy, increases in blood urea nitrogen and serum creatinine, moderate albuminuria and renal pathological changes such as mild urinary cast, interstitial macrophage infiltration and modest interstitial fibrosis. RKT had no evident effects on the Ang II-induced renal functional insufficiency and fibrosis, but attenuated renal interstitial macrophage infiltration. In addition, RKT significantly restored the Ang II-induced alteration in the expression of renal fibrosis- and inflammation-related genes such as type 3 collagen, transforming growth factor-β, monocyte chemoattractant protein-1 and interleukin-6. Furthermore, although RKT did not affect the expression of renal ghrelin receptor, an Ang II-induced decrease in renal sirtuin 1 expression, a critical down-stream pathway of the ghrelin receptor, was restored by RKT. These findings suggest that RKT potentially has a renal anti-inflammatory effect in the development of renal injury, and this effect could be mediated by the ghrelin signaling pathway.

Role of Bitter Taste Receptors in Regulating Gastric Accommodation in Guinea Pigs.

Taste stimulants play important roles in triggering digestion and absorption of nutrients and in toxin detection, under the control of the gut-brain axis. Bitter compounds regulate gut hormone secretion and gastrointestinal motility through bitter taste receptors (TAS2Rs) located in the taste buds on the tongue and in the enteroendocrine cells. Gastric accommodation (GA) is an important physiologic function. However, the role of TAS2R agonists in regulating GA remains unclear. To clarify whether GA is influenced by bitter stimulants, we examined the effect of TAS2R agonist denatonium benzoate (DB), administered intraorally and intragastrically, by measuring the consequent intrabag pressure in the proximal stomach of guinea pigs. Effects of the Kampo medicine rikkunshito (RKT) and its bitter components liquiritigenin and naringenin on GA were also examined. Intraoral DB (0.2 nmol/ml) administration enhanced GA. Intragastric DB administration (0.1 and 1 nmol/kg) promoted GA, whereas higher DB doses (30 μmol/kg) inhibited it. Similar changes in GA were observed with intragastric (1000 mg/kg) and intraoral (200 mg/ml) RKT administration. Liquiritigenin and naringenin also promoted GA. These findings suggest that GA is affected by the stimulation of TAS2Rs in the oral cavity or gut in guinea pigs.

Use of a Caco-2 permeability assay to evaluate the effects of several Kampo medicines on the drug transporter P-glycoprotein

In modern medical care in which Kampo and Western drugs are often combined, it is extremely important to clarify drug–drug interaction (DDI) to ensure safety and efficacy. However, there is little evidence of DDI in Kampo medicines. Therefore, as part of our studies to clarify the DDI risk for Kampo medicines, we evaluated the effects of five Kampo medicines [yokukansan (YKS), rikkunshito (RKT), shakuyakukanzoto (SKT), hangeshashinto (HST), and goshajinkigan (GJG)] that are widely used in Japan, on drug transporter P-glycoprotein (P-gp) using a Caco-2 permeability assay. These Kampo medicines inhibited the P-gp transport of digoxin through a Caco-2 cell monolayer. The IC50 values were 1.94–10.80 mg/ml. Of the five Kampo medicines, YKS showed the strongest inhibition (IC50 = 1.94 mg/ml), which was attributed to Uncariae Uncis Cum Ramulus. Unfortunately, we could not find the active ingredients responsible for its action. Finally, the Igut/IC50 values for the five Kampo medicines were calculated, and the DDI risk was objectively evaluated according to the criteria in the DDI guidance issued by the Japanese Ministry of Health, Labor, and Welfare and the US Food and Drug Administration. The Igut/IC50 values for the five Kampo medicines were ≤3.4. As these values were <10, they were evaluated as having a weak P-gp inhibitory effect that does not require further verification in humans, suggesting that the DDI risk due to P-gp inhibition for these Kampo medicines is low. The results should provide useful clinical information on the safety and efficacy of the combined use of Kampo and Western medicines.

Enhancement of ghrelin-signaling system by Rikkunshi-To attenuates teriparatide-induced pica in rats

Teriparatide is clinically used for the treatment of osteoporosis; however, nausea is often observed in patients. Its insufficient control affects the ability to continue teriparatide therapy. Rikkunshi-To (RKT), a traditional Japanese herbal medicine, improves the gastrointestinal function via activation of the ghrelin-signaling system. We investigated the therapeutic effects of RKT on teriparatide-induced nausea in rats and the involvement of ghrelin in these effects. We previously reported that ovariectomized rats showed pica (kaolin ingestion), a behavior that can be used to assess nausea in rats, after the subcutaneous administration of teriparatide; thus, the behavior was used as an index of nausea. Ovariectomized rats were fed diets with or without RKT (1%) for 2 weeks, and then they received the subcutaneous injection of teriparatide (400 μg/kg). Teriparatide significantly increased the incidence of pica, while suppressing intestinal motility and plasma ghrelin levels in rats fed normal diets; however, rats fed diets with RKT showed improvements in all of the teriparatide-induced adverse reactions. These therapeutic effects were antagonized by a ghrelin receptor antagonist ([D-Lys3]-GHRP-6; 200 nmol/rat). These findings suggest that the enhancement of ghrelin-signaling is involved in RKT's therapeutic effect, and that RKT is a potentially useful treatment for teriparatide-induced nausea.

Psychological stress in aged female mice causes acute hypophagia independent of central serotonin 2C receptor activation.

Sex differences exist in the activation of the hypothalamic–pituitary–adrenal axis following exposure to stress, and the stress response is further affected by aging. This study was conducted to elucidate the mechanism of hypophagia in aged female mice exposed to stress. Immediately after a stress load, aged female mice exhibited acute hypophagia and a rise in plasma corticosterone levels. The administration of a serotonin 2C receptor (5-HT2CR) antagonist suppressed plasma corticosterone but did not affect the reduction in food intake. In contrast, an endogenous ghrelin enhancer, rikkunshito (RKT), significantly inhibited the reduction in food intake. An increase in peripheral acylated ghrelin levels during fasting, which occurs in young mice, was not observed in aged female mice. Moreover, in these mice, significantly increased levels of ghrelin and gastric preproghrelin mRNA expression were observed in the fed status. Moreover, plasma ghrelin levels were elevated by RKT and not by the 5-HT2CR antagonist. In female mice, the hypothalamic non-edited (INI) and partially edited mRNA 5-HT2CR isoforms (VNV, VNI, VSV or VSI) decreased with age, while in male mice, the editing isoform was unchanged by aging or stress. Estrogen receptor α (ERα)-positive cell counts in the arcuate nucleus of young male mice exposed to stress and control aged male mice were increased compared with those in young control mice. In aged male mice exposed to stress, the number of ERα-expressing cells in the paraventricular nucleus were significantly increased compared with those in aged control mice; in female mice, there was no increase in the number of ERα-positive cells. Hypophagia in aged female mice exposed to stress may be independent of 5-HT2CR activation. It seems likely that the mechanisms may be caused by sex dependent, differential regulation in 5-HT2CR mRNA expression, peripheral acylated ghrelin secretion and/or hypothalamic ERα expression.

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.

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.

Rikkunshito prevents paclitaxel-induced peripheral neuropathy through the suppression of the nuclear factor kappa B (NFκB) phosphorylation in spinal cord of mice.

Peripheral neuropathy is the major side effect caused by paclitaxel, a microtubule-binding antineoplastic drug. Paclitaxel-induced peripheral neuropathy causes a long-term negative impact on the patient's quality of life. However, the mechanism underlying paclitaxel-induced peripheral neuropathy is still unknown, and there is no established treatment. Ghrelin is known to attenuate thermal hyperalgesia and mechanical allodynia in chronic constriction injury of the sciatic nerve, and inhibit the activation of nuclear factor kappa B (NFκB) in the spinal dorsal horn. Rikkunshito (RKT), a kampo medicine, increases the secretion of ghrelin in rodents and humans. Thus, RKT may attenuate paclitaxel-induced peripheral neuropathy by inhibiting phosphorylated NFκB (pNFκB) in the spinal cord. We found that paclitaxel dose-dependently induced mechanical hyperalgesia in mice. Paclitaxel increased the protein levels of spinal pNFκB, but not those of spinal NFκB. NFκB inhibitor attenuated paclitaxel-induced mechanical hyperalgesia suggesting that the activation of NFκB mediates paclitaxel-induced hyperalgesia. RKT dose-dependently attenuated paclitaxel-induced mechanical hyperalgesia. Ghrelin receptor antagonist reversed the RKT-induced attenuation of paclitaxel-induced mechanical hyperalgesia. RKT inhibited the paclitaxel-induced increase in the protein levels of spinal pNFκB. Taken together, the present study indicates that RKT exerts an antihyperalgesic effect in paclitaxel-induced neuropathic pain by suppressing the activation of spinal NFκB.

Prospective randomized crossover study of effects of traditional Japanese herbal medicine rikkunshito on food intake and plasma acylated ghrelin levels in patients with esophageal cancer administered with cisplatin-based chemotherapy.

133 Background: Cisplatin (CDDP) is an important chemotherapeutic drug for treating esophageal cancer that often induces chemotherapy-induced nausea and vomiting (CINV). Acylated ghrelin (AG) is an orexigenic gut hormone that can alleviate CINV. We evaluated whether rikkunshito (RKT), a traditional Japanese herbal medicine with an orexigenic effect, can improve CINV-induced anorexia and increase levels of plasma AG in patients with esophageal cancer administered with CDDP-based chemotherapy. Methods: This prospective randomized crossover study included 20 patients with esophageal cancer who were administered with CDDP-based chemotherapy between July 2013 and March 2016. Tenof them were assigned to group A (1st course with 7.5 g/day RKT on days 1 - 14; 2nd course without RKT [control]) and 10 were assigned to group B (1st course without RKT [control]; 2nd course with RKT). Food intake and levels of plasma AG (fmol/mL) were compared between the control and RKT courses. Results: Data from 18 of the patients were included in this analysis, as chemotherapy was immediately stopped due to deteriorating renal function in one patients and intracerebral bleeding in another. The median rate at which food intake decreased between days 4 and 6, which is associated with delayed-onset CINV, was considerably lower in the groups given RKT than in the control (2% vs. 30%; p = 0.07). Median levels of AG significantly decreased between days 1 to 3 in the group given RKT (15.1 to 9.6 fmol/mL, p = 0.001) and the control (14.1 to 10.2, p = 0.003), and then obviously increased from days 3 to 8 in patients with both courses (RKT: 9.6 to 15.7 fmol/mL, p &lt; 0.0001; control: 10.2 to 17.8, p = 0.0002). However, the rate at which median plasm AG levels increased from days 3 to 8 tend to be higher in the RKT, than in the control group (68% vs. 48%, p = 0.08). Conclusions: RKT might improve delayed-onset CINV as well as CINV-induced anorexia and increases in plasma AG levels among patients with esophageal cancer who undergo highly emetogenic CDDP-based chemotherapy. Clinical trial information: UMIN000010747.