Journal of Gastroenterology

, Volume 45, Issue 5, pp 478–487 | Cite as

Rikkunshito, a traditional Japanese medicine, may relieve abdominal symptoms in rats with experimental esophagitis by improving the barrier function of epithelial cells in esophageal mucosa

  • Hiroto Miwa
  • Junichi Koseki
  • Tadayuki Oshima
  • Takashi Kondo
  • Toshihiko Tomita
  • Jiro Watari
  • Takayuki Matsumoto
  • Tomohisa Hattori
  • Kunitsugu Kubota
  • Seiichi Iizuka
Original Article—Alimentary Tract



A traditional Japanese medicine, rikkunshito, has been reported to relieve dyspepsia symptoms. We investigated the effect of rikkunshito on RE-induced abdominal dyspepsia, and performed experiments to elucidate the mechanism of that effect.


RE model rats were prepared using 8-week-old male Wistar rats, and rikkunshito was administered in drinking water. Voluntary movement was used as an index of RE-induced abdominal dyspepsia, which was monitored by an infrared sensor. On the tenth day after surgery, the total area of esophageal erosion was measured, and samples of nonerosive mucosa were collected. Using those samples, intercellular spaces of epithelial mucosa were examined by transmission electron microscopy, and the NP-40-soluble and -insoluble levels of the tight junction proteins claudin-1, -3 and -4 and their mRNAs were determined.


Rikkunshito did not reduce the average total area of erosive lesions in the esophageal mucosa of RE model rats. On day 10, voluntary movement was significantly decreased in the RE model rats and rikkunshito significantly increased it. Nonerosive esophageal mucosa from RE rats showed dilation of intercellular spaces in epithelium, and significantly decreased claudin-3 mRNA and protein levels. Rikkunshito significantly suppressed intercellular space dilation and significantly increased the level of NP-40-insoluble claudin-3, but it did not affect the mRNA level, suggesting that it promoted tight junction formation by facilitating the translocation of proteins.


Rikkunshito increased voluntary movement in RE model rats. This may have been because rikkunshito ameliorated the symptoms of RE by improving the barrier function of esophageal mucosa.


GERD Experimental esophagitis Tight junction Claudin Dilated intercellular spaces Animal model 


  1. 1.
    Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101(8):1900–20.CrossRefPubMedGoogle Scholar
  2. 2.
    Dimenäs E. Methodological aspects of evaluation of quality of life in upper gastrointestinal diseases. Scand J Gastroenterol Suppl. 1993;119:18–21.CrossRefGoogle Scholar
  3. 3.
    Dimenäs E, Carlsson G, Glise H, Israelsson B, Wiklund I. Relevance of norm values as part of the documentation of quality of life instruments for use in upper gastrointestinal disease. Scand J Gastroenterol Suppl. 1996;221:8–13.CrossRefPubMedGoogle Scholar
  4. 4.
    Venables TL, Newland RD, Patel AC, Hole J, Wilcock C, Turbitt ML. Omeprazole 10 milligrams once daily, omeprazole 20 milligrams once daily, or ranitidine 150 milligrams twice daily, evaluated as initial therapy for the relief of symptoms of gastro-oesophageal reflux disease in general practice. Scand J Gastroenterol. 1997;32:965–73.CrossRefPubMedGoogle Scholar
  5. 5.
    Fujiwara Y, Arakawa T. Epidemiology and clinical characteristics of GERD in the Japanese population. J Gastroenterol. 2009;44:518–34.CrossRefPubMedGoogle Scholar
  6. 6.
    Dean BB, Gano AD Jr, Knight K, Ofmann JJ, Fass R. Effectiveness of proton pump inhibitors in nonerosive reflux disease. Clin Gastroenterol Hepatol. 2004;2:656–64.CrossRefPubMedGoogle Scholar
  7. 7.
    Miwa H, Sasaki M, Furuta T, Koike T, Habu Y, Ito M, et al. Efficacy of rabeprazole on heartburn symptom resolution in patients with non-erosive and erosive gastro-oesophageal reflux disease: a multicenter study from Japan. Aliment Pharmacol Ther. 2007;26:69–77.CrossRefPubMedGoogle Scholar
  8. 8.
    Koide A, Yamaguchi T, Koyama H, Koyama H, Tsuyuguchi T, Kitahara H, et al. Effect and role of TJ-43: Rikkun-shi-to from the aspects of endoscopic findings and QOL improvement in GERD patients. Gastroenterology. 2005;128:A-530.Google Scholar
  9. 9.
    Kawahara H, Kubota A, Hasegawa T, Okuyama H, Ueno T, Ida S, et al. Effects of rikkunshito on the clinical symptoms and esophageal acid exposure in children with symptomatic gastroesophageal reflux. Pediatr Surg Int. 2007;23:1001–5.CrossRefPubMedGoogle Scholar
  10. 10.
    Omura N, Kashiwagi H, Chen G, Suzuki Y, Yano F, Aoki T. Establishment of surgically induced chronic acid reflux esophagitis in rats. Scand J Gastroenterol. 1999;34:948–53.CrossRefPubMedGoogle Scholar
  11. 11.
    Miwa H, Oshima T, Sakurai J, Tomita T, Matsumoto T, Iizuka S, et al. Experimental oesophagitis in the rat is associated with decreased voluntary movement. Neurogastroenterol Motil. 2009;21:296–303.CrossRefPubMedGoogle Scholar
  12. 12.
    Sakakibara A, Furuse M, Saitou M, Ando-Akatsuka Y, Tsukita S. Possible involvement of phosphorylation of occludin in tight junction formation. J Cell Biol. 1997;137:1393–401.CrossRefPubMedGoogle Scholar
  13. 13.
    Tatsuta M, Iishi H. Effect of treatment with liu-jun-zi-tang (TJ-43) on gastric emptying and gastrointestinal symptoms in dyspeptic patients. Aliment Pharmacol Ther. 1993;7:459–62.PubMedCrossRefGoogle Scholar
  14. 14.
    Tomono H, Ito Y, Watanabe T. Successful antiemetic treatment of TSUMURA Rikkunshi-to extract granules for ethical use in addition to other antiemetic agents in neoadjuvant chemotherapy for an advanced breast cancer patient. Jpn J Cancer Chemother. 2006;33:1129–31.Google Scholar
  15. 15.
    Oka T, Tamagawa Y, Hayashida S, Kaneda Y, Kodama N, Tsuji S. Rikkunshi-to attenuates adverse gastrointestinal symptoms induced by fluvoxamine. Biopsychosoc Med. 2007;15:21–6.CrossRefGoogle Scholar
  16. 16.
    Hayakawa T, Arakawa T, Kase Y, Akiyama S, Ishige A, Takeda S, et al. Liu-Jun-Zi-Tang, a kampo medicine, promotes adaptive relaxation in isolated guinea pig stomachs. Drugs Exp Clin Res. 1999;25:211–8.PubMedGoogle Scholar
  17. 17.
    Kido T, Nakai Y, Kase Y, Sakakibara I, Nomura M, Takeda S, et al. Effects of rikkunshi-to, a traditional Japanese medicine, on the delay of gastric emptying induced by N(G)-nitro-l-arginine. J Pharmacol Sci. 2005;98:161–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Takeda H, Sadakane C, Hattori T, Katsurada T, Ohkawara T, Nagai K, et al. Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology. 2008;134:2004–13.CrossRefPubMedGoogle Scholar
  19. 19.
    Fujitsuka N, Asakawa A, Hayashi M, Sameshima M, Amitani H, Kojima S, et al. Selective serotonin reuptake inhibitors modify physiological gastrointestinal motor activities via 5-HT2c receptor and acyl ghrelin. Biol Psychiatr. 2009;65:748–59.CrossRefGoogle Scholar
  20. 20.
    Hiyama T, Yoshihara M, Tanaka S, Haruma K, Chayama K. Strategy for treatment of nonerosive reflux disease in Asia. World J Gastroenterol. 2008;28:3123–8.CrossRefGoogle Scholar
  21. 21.
    Tobey NA, Carson JL, Alkiek RA, Orlando RC. Dilated intercellular spaces: a morphological feature of acid reflux-damaged human esophageal epithelium. Gastroenterology. 1996;111:1200–5.CrossRefPubMedGoogle Scholar
  22. 22.
    Caviglia R, Ribolsi M, Maggiano N, Gabbrielli AM, Emerenziani S, Guarino MP, et al. Dilated intercellular spaces of esophageal epithelium in nonerosive reflux disease patients with physiological esophageal acid exposure. Am J Gastroenterol. 2005;100:543–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Furuse M, Hata M, Furuse K, Yoshida Y, Haratake A, Sugitani Y, et al. Claudin-based tight junctions are crucial for the mammalian epithermal barrier: a lesson from claudin-1-deficient mice. J Cell Biol. 2002;156:1099–111.CrossRefPubMedGoogle Scholar
  24. 24.
    Okuyama M, Fujiwara Y, Tanigawa T, Watanabe K, Shiba M, Tominaga K, et al. Roles of ZO-1 and epidermal growth factor in esophageal epithelial defense against acid. Digestion. 2007;75:135–41.PubMedGoogle Scholar
  25. 25.
    Hashimoto K, Oshima T, Tomita T, Kim Y, Matsumoto T, Joh T, et al. Oxidative stress induces gastric epithelial permeability through claudin-3. Biochem Biophys Res Commun. 2008;376:154–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Lu CL, Pasricha PJ, Hsieh JC. Changes of the neuropeptides content and gene expression in spinal cord and dorsal root ganglion after noxious colorectal distention. Regul Pept. 2005;131:66–73.CrossRefPubMedGoogle Scholar
  27. 27.
    Donaldson LF, Harmar AJ, McQueen DS, Seckl JR. Increased expression of preprotachykinin, calcitonin gene-related peptide, but not vasoactive intestinal peptide messenger RNA in dorsal root ganglia during the development of adjuvant monoarthritis in the rat. Brain Res Mol Brain Res. 1992;16:143–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Banerjee B, Meadda BK, Lazarova Z, Bansal N, Shaker R, Sengupta JN. Effect of reflux-induced inflammation on transient receptor potential vanilloid one (TRPV1) expression in primary sensory neurons innervating the oesophagus of rats. Neurogastroenterol Motil. 2007;19:681–91.CrossRefPubMedGoogle Scholar
  29. 29.
    Omura N, Kashiwagi H, Chen G, Yano F, Suzuki Y, Aoki T. Effects of ecabet sodium on experimentally induced reflux esophagitis. J Gastroenterol. 2000;35(7):504–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Barlow WJ, Orlando RC. The pathogenesis of heartburn in nonerosive reflux disease: a unifying hypothesis. Gastroenterology. 2005;128:771–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Asaoka D, Miwa H, Hirai S, Ohkawa A, Kurosawa A, Kawabe M. Altered localization and expression of tight-junction proteins in a rat model with chronic acid reflux esophagitis. J Gastroenterol. 2005;40:781–90.CrossRefPubMedGoogle Scholar
  32. 32.
    Stevenson BR, Goodenough DA. Zonulae occludentes in junctional complex—enriched fractions from mouse liver: preliminary morphological and biochemical characterization. J Cell Biol. 1984;98:1209–21.CrossRefPubMedGoogle Scholar
  33. 33.
    Kawahara H, Kubota A, Hasegawa T, et al. Effects of rikkunshito on the clinical symptoms and esophageal acid exposure in children with symptomatic gastroesophageal reflux. Pediatr Surg Int. 2007;23(10):1001–5.CrossRefPubMedGoogle Scholar
  34. 34.
    Suzuki H, Inadomi JM, Hibi T. Japanese herbal medicine in functional gastrointestinal disorders. Neurogastroenterol Motil. 2009;21(7):688–96.CrossRefPubMedGoogle Scholar
  35. 35.
    Kawahara H, Mitani Y, Nomura M, et al. Impact of rikkunshito, an herbal medicine, on delayed gastric emptying in profoundly handicapped patients. Pediatr Surg Int. 2009;25(11):987–90.CrossRefPubMedGoogle Scholar
  36. 36.
    Hayakawa T, Arakawa T, Kase Y, et al. Liu-Jun-Zi-Tang, a kampo medicine, promotes adaptive relation in isolated guinea pig stomachs. Drug Exp Clin Res. 1999;25:211–8.Google Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Hiroto Miwa
    • 1
  • Junichi Koseki
    • 1
    • 3
  • Tadayuki Oshima
    • 1
  • Takashi Kondo
    • 1
  • Toshihiko Tomita
    • 1
  • Jiro Watari
    • 1
  • Takayuki Matsumoto
    • 2
  • Tomohisa Hattori
    • 3
  • Kunitsugu Kubota
    • 3
  • Seiichi Iizuka
    • 3
  1. 1.Division of Upper Gastroenterology, Department of Internal MedicineHyogo College of MedicineNishinomiyaJapan
  2. 2.Division of Lower Gastroenterology, Department of Internal MedicineHyogo College of MedicineNishinomiyaJapan
  3. 3.Tsumura Research Laboratories, Tsumura & Co.IbarakiJapan

Personalised recommendations