Advertisement

Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 385, Issue 4, pp 411–421 | Cite as

Adenosine A2A receptor contributes to the anti-inflammatory effect of the fixed herbal combination STW 5 (Iberogast®) in rat small intestinal preparations

  • Sebastian Michael
  • Heba Abdel-Aziz
  • Dieter Weiser
  • Christa E. Müller
  • Olaf Kelber
  • Karen NieberEmail author
Original Article

Abstract

STW 5 (Iberogast®), an established herbal combination, was effective in randomized, double blind clinical studies in functional dyspepsia and irritable bowel syndrome. Since STW 5 was found to influence intestinal motility and has anti-inflammatory properties, this study investigated the expression of adenosine receptors and characterized their role in the control of the anti-inflammatory action of STW 5 and its fresh plant component STW 6 in inflammation-disturbed rat small intestinal preparations. The inflammation was induced by intraluminal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS, 0.01 M). The effects of coincubation with selective receptor agonists and antagonists, STW 5, STW 6, or combinations of these compounds on acetylcholine (ACh)-evoked contraction of ileum/jejunum preparations were tested. Adenosine receptor mRNA expression was examined by reverse transcription-polymerase chain reaction (RT-PCR). In untreated preparations, RT-PCR revealed the presence of all adenosine receptor subtypes. Suppressed expression was detected for all subtypes in inflamed tissues, except for A2BR mRNA, which was unaffected. STW 5 reversed these effects and enhanced A2AR expression above control levels. Radioligand binding assays confirm the affinity of STW 5 to the A2AR, and the A2AR antagonist was able to prevent the effect of STW 5 on TNBS-induced attenuation of the ACh contraction. Our findings provide evidence that STW 5, but not STW 6 interacts with A2AR, which is involved in the anti-inflammatory action of STW 5. STW 6 did not contribute to adenosine A2AR-mediated anti-inflammatory effect of STW 5. Other signaling pathways could be involved in the mechanism of action of STW 6.

Keywords

Iberogast Inflammation Adenosine receptors TNFα Isometric contraction TNBS 

References

  1. Abraham C, Cho JH (2009) Inflammatory bowel disease. N Engl J Med 361(21):2066–2078PubMedCrossRefGoogle Scholar
  2. Akkari R, Burbiel JC, Hockemeyer J, Muller CE (2006) Recent progress in the development of adenosine receptor ligands as antiinflammatory drugs. Curr Top Med Chem 6(13):1375–1399PubMedGoogle Scholar
  3. Ammon HPT, Kelber O, Okpynyi SN (2006) Spasmolytic and tonic effect of Iberogast® (STW 5) in intestinal smooth muscle. Phytomedicine 13(SV):67PubMedCrossRefGoogle Scholar
  4. Antonioli L, Fornai M, Colucci R, Ghisu N, Blandizzi C, Del Tacca M (2006) A2a receptors mediate inhibitory effects of adenosine on colonic motility in the presence of experimental colitis. Inflamm Bowel Dis 12(2):117–122PubMedCrossRefGoogle Scholar
  5. Antonioli L, Fornai M, Colucci R, Ghisu N, Da Settimo F, Natale G, Kastsiuchenka O, Duranti E, Virdis A, Vassalle C, La Motta C, Mugnaini L, Breschi MC, Blandizzi C, Del Taca M (2007) Inhibition of adenosine deaminase attenuates inflammation in experimental colitis. J Pharmacol Exp Ther 322(2):435–442PubMedCrossRefGoogle Scholar
  6. Antonioli L, Fornai M, Colucci R, Ghisu N, Tuccori M, Del Tacca M, Blandizzi C (2008) Regulation of enteric functions by adenosine: pathophysiological and pharmacological implications. Pharmacol Ther 120(3):233–253PubMedCrossRefGoogle Scholar
  7. Antonioli L, Fornai M, Colucci R, Awwad O, Ghisu N, Tuccori M, Del Tacca M, Blandizzi C (2011a) Differential recruitment of high affinity A1 and A2A adenosine receptors in the control of colonic neuromuscular function in experimental colitis. Eur J Pharmacol 650(2–3):639–649PubMedCrossRefGoogle Scholar
  8. Antonioli L, Fornai M, Colucci R, Tuccori M, Blandizzi C (2011b) Pharmacological modulation of adenosine receptor pathways and inflammatory disorders: the way towards novel therapeutics? Expert Opin Investig Drugs 20(6):717–721PubMedCrossRefGoogle Scholar
  9. Ardizzone S, Bianchi Porro G (2005) Biologic therapy for inflammatory bowel disease. Drugs 65(16):2253–2286PubMedCrossRefGoogle Scholar
  10. Bamias G, Sugawara K, Pagnini C, Cominelli F (2003) The Th1 immune pathway as a therapeutic target in Crohn’s disease. Curr Opin Investig Drugs 4(11):1279–1286PubMedGoogle Scholar
  11. Bilkei-Gorzo A, Abo-Salem OM, Hayallah AM, Michel K, Muller CE, Zimmer A (2008) Adenosine receptor subtype-selective antagonists in inflammation and hyperalgesia. Naunyn Schmiedebergs Arch Pharmacol 377(1):65–76PubMedCrossRefGoogle Scholar
  12. Buira SP, Albasanz JL, Dentesano G, Moreno J, Martin M, Ferrer I, Barrachina M (2010) DNA methylation regulates adenosine A(2A) receptor cell surface expression levels. J Neurochem 112(5):127–1285CrossRefGoogle Scholar
  13. Chen Y, Epperson S, Makhsudova L, Ito B, Suarez J, Dillmann W, Villarreal F (2004) Functional effects of enhancing or silencing adenosine A2b receptors in cardiac fibroblasts. Am J Physiol Heart Circ Physiol 287(6):H2478–H2486PubMedCrossRefGoogle Scholar
  14. Christofi FL, Zhang H, Yu JG, Guzman J, Xue J, Kim M, Wang YZ, Cooke HJ (2001) Differential gene expression of adenosine A1, A2a, A2b, and A3 receptors in the human enteric nervous system. J Comp Neurol 439(1):46–64PubMedCrossRefGoogle Scholar
  15. Cronstein BN, Montesinos MC, Weissmann G (1999) Salicylates and sulfasalazine, but not glucocorticoids, inhibit leukocyte accumulation by an adenosine-dependent mechanism that is independent of inhibition of prostaglandin synthesis and p105 of NFkappaB. Proc Natl Acad Sci U S A 96(11):6377–6381PubMedCrossRefGoogle Scholar
  16. Eckle T, Krahn T, Grenz A, Kohler D, Mittelbronn M, Ledent C, Jacobson MA, Osswald H, Thompson LF, Unertl K, Eltzschig HK (2007) Cardioprotection by ecto-5′-nucleotidase (CD73) and A2B adenosine receptors. Circulation 115(12):1581–1590PubMedCrossRefGoogle Scholar
  17. Elson CO, Sartor RB, Tennyson GS, Riddell RH (1995) Experimental models of inflammatory bowel disease. Gastroenterology 109(4):1344–1367PubMedCrossRefGoogle Scholar
  18. Estrela AB, Abraham WR (2011) Adenosine in the inflamed gut: a Janus faced compound. Curr Med Chem 18(18):2791–2815PubMedCrossRefGoogle Scholar
  19. Ferré S, Quiroz C, Orru M, Guitart X, Navarro G, Cortés A, Casadó V, Canela EI, Lluis C, Franco R (2011) Adenosine A(2A) receptors and A(2A) receptor heteromers as key players in striatal function. Front Neuroanat 5:36–44PubMedCrossRefGoogle Scholar
  20. Guieu R, Dussol B, Devaux C, Sampol J, Brunet P, Rochat H, Bechis G, Berland YF (1998) Interactions between cyclosporine A and adenosine in kidney transplant recipients. Kidney Int 53(1):200–204PubMedCrossRefGoogle Scholar
  21. Gundermann KJ, Godehardt E, Ulbrich M (2003) Efficacy of a herbal preparation in patients with functional dyspepsia: a meta-analysis of double-blind, randomized, clinical trials. Adv Ther 20:43–49PubMedCrossRefGoogle Scholar
  22. Hasko G, Cronstein BN (2004) Adenosine: an endogenous regulator of innate immunity. Trends Immunol 25(1):33–39PubMedCrossRefGoogle Scholar
  23. Hasko G, Kuhel DG, Chen JF, Schwarzschild MA, Deitch EA, Mabley JG, Marton A, Szabo C (2000) Adenosine inhibits IL-12 and TNF-[alpha] production via adenosine A2a receptor-dependent and independent mechanisms. FASEB J 14(13):2065–2074PubMedCrossRefGoogle Scholar
  24. Heinle H, Hagelauer D, Pascht U, Kelber O, Weiser D (2006) Intestinal spasmolytic effects of STW5 (Iberogast®) and its components. Phytomedicine 13(SV):75–79PubMedCrossRefGoogle Scholar
  25. Hohenester B, Ruhl A, Kelber O, Schemann M (2004) The herbal preparation STW5 (lberogast) has potent and region-specific effects on gastric motility. Neurogastroenterol Motil 16(6):765–773PubMedCrossRefGoogle Scholar
  26. Jacobson KA, Gao ZG (2006) Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 5(3):247–264PubMedCrossRefGoogle Scholar
  27. Kelber O, Wittwer A, Lapke C, Kroll U, Weiser D, Okpanyi SN, Heilmann J (2006) Ex vivo/in vitro absorption of STW 5 (Iberogast) and its extract components. Phytomedicine 13(Suppl 5):107–113PubMedCrossRefGoogle Scholar
  28. Kirfel A, Schwabenländer F, Müller CE (1997) Crystal structure of 1-propyl-8-(4-sulfophenyl)-7H-imidazo[4, 5-d]pyrimidin-2,6(1H, 3H)-dione dihydrate, C14H14N4O5S⋅2H2O. Z Kristallographie-New Cryst Struct 3:447–448Google Scholar
  29. Klotz KN, Lohse MJ, Schwabe U, Cristalli G, Vittori S, Grifantini M (1989) 2-Chloro-N6-[3H]cyclopentyladenosine ([3H]CCPA)—a high affinity agonist radioligand for A1 adenosine receptors. Naunyn Schmiedebergs Arch Pharmacol 340(6):679–683PubMedCrossRefGoogle Scholar
  30. Kolachala V, Asamoah V, Wang L, Obertone TS, Ziegler TR, Merlin D, Sitaraman SV (2005) TNF-alpha upregulates adenosine 2b (A2b) receptor expression and signaling in intestinal epithelial cells: a basis for A2bR overexpression in colitis. Cell Mol Life Sci 62(22):2647–2657PubMedCrossRefGoogle Scholar
  31. Kolachala V, Ruble B, Vijay-Kumar M, Wang L, Mwangi S, Figler H, Figler R, Srinivasan S, Gewirtz A, Linden J, Merlin D, Sitaraman S (2008) Blockade of adenosine A2B receptors ameliorates murine colitis. Br J Pharmacol 155(1):127–137PubMedCrossRefGoogle Scholar
  32. Kong T, Westerman KA, Faigle M, Eltzschig HK, Colgan SP (2006) HIF-dependent induction of adenosine A2B receptor in hypoxia. FASEB J 20(13):2242–2250PubMedCrossRefGoogle Scholar
  33. Kuno M, Seki N, Tsujimoto S, Nakanishi I, Kinoshita T, Nakamura K, Terasaka T, Nishio N, Sato A, Fujii T (2006) Anti-inflammatory activity of non-nucleoside adenosine deaminase inhibitor FR234938. Eur J Pharmacol 534(1–3):241–249PubMedCrossRefGoogle Scholar
  34. Link AA, Kino T, Worth JA, McGuire JL, Crane ML, Chrousos GP, Wilder RL, Elenkov IJ (2000) Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes. J Immunol 164(1):436–442PubMedGoogle Scholar
  35. Lomax AE, Fernandez E, Sharkey KA (2005) Plasticity of the enteric nervous system during intestinal inflammation. Neurogastroenterol Motil 17(1):4–15PubMedCrossRefGoogle Scholar
  36. Madisch A, Holtmann G, Mayr G, Vinson B, Hotz J (2004a) Treatment of functional dyspepsia with a herbal preparation. A double-blind, randomized, placebo-controlled, multicenter trial. Digestion 69(1):45–52PubMedCrossRefGoogle Scholar
  37. Madisch A, Holtmann G, Plein K, Hotz J (2004b) Treatment of irritable bowel syndrome with herbal preparations: results of a double-blind, randomized, placebo-controlled, multi-centre trial. Aliment Pharmacol Ther 19(3):271–279PubMedCrossRefGoogle Scholar
  38. Michael S, Kelber O, Hauschildt S, Spanel-Borowski K, Nieber K (2009) Inhibition of inflammation-induced alterations in rat small intestine by the herbal preparations STW 5 and STW 6. Phytomedicine 16(2–3):161–171PubMedCrossRefGoogle Scholar
  39. Michael S, Warstat C, Michel F, Yan L, Muller CE, Nieber K (2010) Adenosine A(2A) agonist and A(2B) antagonist mediate an inhibition of inflammation-induced contractile disturbance of a rat gastrointestinal preparation. Purinergic Signal 6(1):117–124PubMedCrossRefGoogle Scholar
  40. Montesinos MC, Desai A, Cronstein BN (2006) Suppression of inflammation by low-dose methotrexate is mediated by adenosine A2A receptor but not A3 receptor activation in thioglycollate-induced peritonitis. Arthritis Res Ther 8(2):R53PubMedCrossRefGoogle Scholar
  41. Müller CE (2000) Adenosine receptor ligands—recent developments part I. Agonists. Curr Med Chem 7(12):1269–1288PubMedGoogle Scholar
  42. Müller CE, Shi D, Manning M Jr, Daly JW (1993) Synthesis of paraxanthine analogs (1,7-disubstituted xanthines) and other xanthines unsubstituted at the 3-position: structure–activity relationships at adenosine receptors. J Med Chem 36(22):3341–3349PubMedCrossRefGoogle Scholar
  43. Müller CE, Thorand M, Qurishi R, Diekmann M, Jacobson KA, Padgett WL, Daly JW (2002) Imidazo[2,1-i]purin-5-ones and related tricyclic water-soluble purine derivatives: potent A(2A)- and A(3)-adenosine receptor antagonists. J Med Chem 45(16):3440–3450PubMedCrossRefGoogle Scholar
  44. Odashima M, Bamias G, Rivera-Nieves J, Linden J, Nast CC, Moskaluk CA, Marini M, Sugawara K, Kozaiwa K, Otaka M, Watanabe S, Cominelli F (2005) Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease. Gastroenterology 129(1):26–33PubMedCrossRefGoogle Scholar
  45. Odashima M, Otaka M, Jin M, Horikawa Y, Matsuhashi T, Ohba R, Linden J, Watanabe S (2006) A selective adenosine A2A receptor agonist, ATL-146e, prevents concanavalin A-induced acute liver injury in mice. Biochem Biophys Res Commun 347(4):949–954PubMedCrossRefGoogle Scholar
  46. Ohman L, Simren M (2010) Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions. Nat Rev Gastroenterol Hepatol 7(3):163–173PubMedCrossRefGoogle Scholar
  47. Palmer TM, Trevethick MA (2008) Suppression of inflammatory and immune responses by the A(2A) adenosine receptor: an introduction. Br J Pharmacol 153(Suppl 1):S27–S34PubMedGoogle Scholar
  48. Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30(9):e36PubMedCrossRefGoogle Scholar
  49. Pizarro TT, De La Rue SA, Cominelli F (2006) Role of interleukin 6 in a murine model of Crohn’s ileitis: are cytokine/anticytokine strategies the future for IBD therapies? Gut 55(9):1226–1227PubMedCrossRefGoogle Scholar
  50. Puffinbarger NK, Hansen KR, Resta R, Laurent AB, Knudsen TB, Madara JL, Thompson LF (1995) Production and characterization of multiple antigenic peptide antibodies to the adenosine A2b receptor. Mol Pharmacol 47(6):1126–1132PubMedGoogle Scholar
  51. Rogachev B, Ziv NY, Mazar J, Nakav S, Chaimovitz C, Zlotnik M, Douvdevani A (2006) Adenosine is upregulated during peritonitis and is involved in downregulation of inflammation. Kidney Int 70(4):675–681PubMedCrossRefGoogle Scholar
  52. Rosch W, Vinson B, Sassin I (2002) A randomised clinical trial comparing the efficacy of a herbal preparation STW 5 with the prokinetic drug cisapride in patients with dysmotility type of functional dyspepsia. Z Gastroenterol 40(6):401–408PubMedCrossRefGoogle Scholar
  53. Rosch W, Liebregts T, Gundermann KJ, Vinson B, Holtmann G (2006) Phytotherapy for functional dyspepsia: a review of the clinical evidence for the herbal preparation STW 5. Phytomedicine 13(Suppl 5):114–121PubMedCrossRefGoogle Scholar
  54. Ryzhov S, Goldstein AE, Matafonov A, Zeng D, Biaggioni I, Feoktistov I (2004) Adenosine-activated mast cells induce IgE synthesis by B lymphocytes: an A2B-mediated process involving Th2 cytokines IL-4 and IL-13 with implications for asthma. J Immunol 172(12):7726–7733PubMedGoogle Scholar
  55. Ryzhov S, Solenkova NV, Goldstein AE, Lamparter M, Fleenor T, Young PP, Greelish JP, Byrne JG, Vaughan DE, Biaggioni I, Hatzopoulos AK, Feoktistov I (2008) Adenosine receptor-mediated adhesion of endothelial progenitors to cardiac microvascular endothelial cells. Circ Res 102(3):356–363PubMedCrossRefGoogle Scholar
  56. Sandborn WJ, Targan SR (2002) Biologic therapy of inflammatory bowel disease. Gastroenterology 122(6):1592–1608PubMedCrossRefGoogle Scholar
  57. Sands WA, Martin AF, Strong EW, Palmer TM (2004) Specific inhibition of nuclear factor-kappaB-dependent inflammatory responses by cell type-specific mechanisms upon A2A adenosine receptor gene transfer. Mol Pharmacol 66(5):1147–1159PubMedCrossRefGoogle Scholar
  58. Sitkovsky M, Lukashev D (2005) Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors. Nat Rev Immunol 5(9):712–721PubMedCrossRefGoogle Scholar
  59. Stein RB, Hanauer SB (1999) Medical therapy for inflammatory bowel disease. Gastroenterol Clin North Am 28(2):297–321PubMedCrossRefGoogle Scholar
  60. Sullivan GW (2003) Adenosine A2A receptor agonists as anti-inflammatory agents. Curr Opin Investig Drugs 4(11):1313–1319PubMedGoogle Scholar
  61. Sundaram U, Hassanain H, Suntres Z, Yu JG, Cooke HJ, Guzman J, Christofi FL (2003) Rabbit chronic ileitis leads to up-regulation of adenosine A1/A3 gene products, oxidative stress, and immune modulation. Biochem Pharmacol 65(9):1529–1538PubMedCrossRefGoogle Scholar
  62. von Arnim U, Peitz U, Vinson B, Gundermann KJ, Malfertheiner P (2007) STW 5, a phytopharmacon for patients with functional dyspepsia: results of a multicenter, placebo-controlled double-blind study. Am J Gastroenterol 102(6):1268–1275CrossRefGoogle Scholar
  63. Voß U, Michael S, Kelber O, Weiser D, Nieber K (2011) Effects of STW 5 and STW 6 on rat ileal and colonic preparations: a comparative study. 383 (S1) 24/P045Google Scholar
  64. Wegener T, Wagner H (2006) The active components and the pharmacological multi-target principle of STW 5 (Iberogast). Phytomedicine 13(Suppl 5):20–35PubMedCrossRefGoogle Scholar
  65. Wood JD (2004) Enteric neuroimmunophysiology and pathophysiology. Gastroenterology 127(2):635–657PubMedCrossRefGoogle Scholar
  66. Yan L, Müller CE (2004) Preparation, properties, reactions, and adenosine receptor affinities of sulfophenylxanthine nitrophenyl esters: toward the development of sulfonic acid prodrugs with peroral bioavailability. J Med Chem 47(4):1031–1043PubMedCrossRefGoogle Scholar
  67. Yang D, Zhang Y, Nguyen HG, Koupenova M, Chauhan AK, Makitalo M, Jones MR, St Hilaire C, Seldin DC, Toselli P, Lamperti E, Schreiber BM, Gavras H, Wagner DD, Ravid K (2006) The A2B adenosine receptor protects against inflammation and excessive vascular adhesion. J Clin Invest 116(7):1913–1923PubMedCrossRefGoogle Scholar
  68. Zhong H, Belardinelli L, Maa T, Feoktistov I, Biaggioni I, Zeng D (2004) A(2B) adenosine receptors increase cytokine release by bronchial smooth muscle cells. Am J Respir Cell Mol Biol 30(1):118–125PubMedCrossRefGoogle Scholar
  69. Zhong H, Belardinelli L, Maa T, Zeng D (2005) Synergy between A2B adenosine receptors and hypoxia in activating human lung fibroblasts. Am J Respir Cell Mol Biol 32(1):2–8PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Sebastian Michael
    • 1
  • Heba Abdel-Aziz
    • 2
  • Dieter Weiser
    • 2
  • Christa E. Müller
    • 3
  • Olaf Kelber
    • 2
  • Karen Nieber
    • 4
    Email author
  1. 1.Löwen-ApothekeWaldheimGermany
  2. 2.Scientific DepartmentSteigerwald Arzneimittelwerk GmbHDarmstadtGermany
  3. 3.PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry IUniversity of BonnBonnGermany
  4. 4.Institute of Pharmacy, Pharmacology for Natural SciencesUniversity of LeipzigLeipzigGermany

Personalised recommendations