Abstract
Background: Yeokwisan, a standardized herbal formula, has exhibited clinical benefit for patients suffering from refractory functional dyspepsia (FD) in Korea since 2016. However, data about the mechanism of action of this formula are yet not available.Aim of the study: To evaluate and explore the effects of Yeokwisan on gastric emptying, a major symptom of functional dyspepsia, and its underlying mechanisms of action using a mouse model.Materials and methods: BALB/C mice were pretreated with Yeokwisan (100, 200, and 400 mg/kg, po) or mosapride (3 mg/kg, po) for 5 days and then treated with loperamide (10 mg/kg, ip) after 20 h of fasting. A solution of 0.05% phenol red (500 μL) or diet of 5% charcoal (200 μL) was orally administered, followed by assessment of gastric emptying or intestinal transit. Plasma acyl-ghrelin (ELISA), C-kit (immunofluorescence and western blotting), nNOS (western blotting) and gastric contraction- and ghrelin-related gene/protein expression levels were examined in stomach and small intestine tissues.Results: Loperamide injection substantially delayed gastric emptying, while Yeokwisan pretreatment (especially 200 and 400 mg/kg Yeokwisan) significantly attenuated this peristaltic dysfunction, as evidenced by the quantity of phenol red retained in the stomach (p < 0.05 or 0.01) and stomach weight (p < 0.05 or 0.01). The levels of plasma acyl-ghrelin and expression of gastric ghrelin-related genes, such as growth hormone secretagogue receptor (GHSR), ghrelin-O-acyltransferase (GOAT), adrenergic receptor β1 (ADRB1) and somatostatin receptor (SSTR), were significantly normalized (p < 0.05 or 0.01) by Yeokwisan (400 mg/kg). Yeokwisan (400 mg/kg) significantly tempered the loperamide-induced alterations in the c-kit and nNOS levels (p < 0.01) as well as the expression of contraction- and ghrelin-related genes, such as 5-HT4 receptor (5-HT4R), anoctamin-1 (ANO1), ryanodine receptor 3 (RYR3) and smooth muscle myosin light chain kinase (smMLCK), in the stomach, but not in the small intestine.Conclusion: The present results showed the clinical relevance of Yeokwisan, in treating FD, especially in promoting gastric emptying but not small intestinal transit. The main mechanisms corresponding to these effects may involve the modulation of the ghrelin pathway and activation of interstitial cells of Cajal in stomach tissue.
Highlights
One-fifth of the general population complains of dyspeptic symptoms, such bloating, anorexia, early satiety, and epigastric discomfort (Ford et al, 2015)
Loperamide injection inhibited the passage of phenol red, leading to fullness of the stomach, and this effect was significantly attenuated by pretreatment with Yeokwisan (p < 0.05 for 200 mg/kg and p < 0.01 for 400 mg/kg), as observed by the naked eye (Figure 2A), measurement of stomach weight (Figure 2B), calculation of whole and forestomach area (Figures 2C,D), and quantification of the amount of phenol red retained in the stomach (Figure 2E)
Yeokwisan did not achieve a significant improvement of intestinal transit (p > 0.05 for all doses), even though it slightly accelerated the passage of the charcoal diet (Figures 3A,B)
Summary
One-fifth of the general population complains of dyspeptic symptoms, such bloating, anorexia, early satiety, and epigastric discomfort (Ford et al, 2015). Eighty percent of them cannot be explained either structurally or organically, and these symptoms are referred to as functional dyspepsia (FD) (Ford et al, 2020). FD is generally divided into three subtypes depending on the main symptoms: postprandial fullness and early satiety (postprandial distress syndrome, PDS), epigastric pain/burning symptoms (epigastric pain syndrome, EPS), and a combination of these symptoms (Asano et al, 2016). In Asia, the PDS subtype is known to be more prevalent than the EPS or combination type, especially in Korea and Japan (Lee and Chua, 2012). A standardized herbal formula, has exhibited clinical benefit for patients suffering from refractory functional dyspepsia (FD) in Korea since 2016. Data about the mechanism of action of this formula are yet not available
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