Ghrelin enhancer, rikkunshito, improves postprandial gastric motor dysfunction in an experimental stress model

Abstract

BackgroundFunctional dyspepsia (FD) is one of the most common disorders of gastrointestinal (GI) diseases. However, no curable treatment is available for FD because the detailed mechanism of GI dysfunction in stressed conditions remains unclear. We aimed to clarify the association between endogenous acylated ghrelin signaling and gastric motor dysfunction and explore the possibility of a drug with ghrelin signal‐enhancing action for FD treatment.MethodsSolid gastric emptying (GE) and plasma acylated ghrelin levels were evaluated in an urocortin1 (UCN1) ‐induced stress model. To clarify the role of acylated ghrelin on GI dysfunction in the model, exogenous acylated ghrelin, an endogenous ghrelin enhancer, rikkunshito, or an α 2‐adrenergic receptor (AR) antagonist was administered. Postprandial motor function was investigated using a strain gauge force transducer in a free‐moving condition.Key ResultsExogenous acylated ghrelin supplementation restored UCN1‐induced delayed GE. Alpha2‐AR antagonist and rikkunshito inhibited the reduction in plasma acylated ghrelin and GE in the stress model. The action of rikkunshito on delayed GE was blocked by co‐administration of the ghrelin receptor antagonist. UCN1 decreased the amplitude of contraction in the antrum while increasing it in the duodenum. The motility index of the antrum but not the duodenum was significantly reduced by UCN1 treatment, which was improved by acylated ghrelin or rikkunshito.Conclusions & InferencesThe UCN1‐induced gastric motility dysfunction was mediated by abnormal acylated ghrelin dynamics. Supplementation of exogenous acylated ghrelin or enhancement of endogenous acylated ghrelin secretion by rikkunshito may be effective in treating functional GI disorders.

Usefulness of a Kampo Medicine on Stress‐Induced Delayed Gastric Emptying in Mice

“…Adrenergic α2 antagonism can relieve delayed gastric emptying induced by the urocortin 1-CRF2 pathway [48]. Considering that 6-shogaol, 8-shogaol, and 10-gingerol derived from ginger and synephrine derived from Citrus unshiu peel reportedly showed adrenergic α2 antagonistic activities [49], these compounds might be involved in the restorative effect of BGH in CRF-induced delayed gastric emptying model, which was observed in this study. Magnolol, honokiol [50], and ginger extract [51] can accelerate gastric emptying, although their precise mechanisms remain unclear.…”

Management of functional dyspepsia: state of the art and emerging therapies

“…72 Harada and colleagues reported Rikkunshito improved acylated ghrelin levels and impaired gastric emptying in the urocortin 1-induced stress models. 73 They suggested supplementation of exogenous acylated ghrelin or enhancement of endogenous acylated ghrelin secretion by the treatment of Rikkunshito will be effective for amelioration of functional dyspepsia symptoms because acylated ghrelin has a strong efficiency of GI motility. In addition, Clinical symptoms assessed by visual analogue scale (VAS scale: 0-10; 0 = absent, and 10 = maximal) acotiamide and rabeprazole combination therapy versus rabeprazole monotherapy.…”

Complementary and alternative treatment in functional dyspepsia

“…35 In animal models, rikkunshito seems to accelerate gastric emptying by increasing ghrelin plasma concentration, but human studies are inconclusive. [36][37][38][39] However, a barostat study researching gastric response to environmental stress showed that rikkunshito improved gastric volume thresholds for generation of first sensation and epigastric discomfort, suggesting a potential modulation of visceral afferents. 38 A recent multicenter RCT has been run in Asia on 247 FD patients (Rome III) to compare the efficacy of rikkunshito or placebo for eight weeks.…”

“…Traditional Chinese and Japanese medicine have been used for centuries to treat a number of symptoms, but only recently, the Kampo therapy has been systematically evaluated 35 . The ailment most studied is the rikkunshito treatment, which has been studied in Japanese scientific literature since 1500 36 . Rikkunshito is a complex herbal remedy composed of eight constituents.…”

“…However, recent deeper chromatographic analysis showed that the rikkunshito formula was even more complex, revealing several additional ingredients 35 . In animal models, rikkunshito seems to accelerate gastric emptying by increasing ghrelin plasma concentration, but human studies are inconclusive 36–39 . However, a barostat study researching gastric response to environmental stress showed that rikkunshito improved gastric volume thresholds for generation of first sensation and epigastric discomfort, suggesting a potential modulation of visceral afferents 38 .…”