Skip to main content
Log in

Rolipram, a Specific Type IV Phosphodiesterase Inhibitor, Ameliorates Aspirin-Induced Gastric Mucosal Injury in Rats

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Inhibition of type IV phosphodiesterase (PDE IV) activity reduces the production of various proinflammatory cytokine and suppresses neutrophil activation. Nonsteroidal anti-inflammatory drugs such as aspirin induce gastric mucosal lesions. In the pathogenesis of aspirin-induced gastric mucosal lesion, the contributions, of activated inflammatory cells and proinflammatory cytokine production are critical. The specific PDE IV inhibitor rolipram is known to be a potent inhibitor of inflammation by increasing intracellular cyclic AMP in leukocytes. The aim of the present study was to determine whether rolipram can ameliorate aspirin-induced gastric mucosal lesions in rats and whether the agent can inhibit the inrease in neutrophil accumulation and the production of proinflammatory cytokines. Gastric lesions were produced by administration of aspirin (200 mg/kg) and HCl (0.15 N; 8.0 ml/kg). Rolipram was injected 30 min before aspirin administration. The tissue myeloperoxidase concentration in gastric mucosa was measured as an indicat or of neutrophil infiltration. The gastric mucosal concentrations of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were determined by ELISA. The intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. Gastric mucosal lesions induced by aspirin were significantly inhibited by treatment with rolipram. The mucosal myeloperoxidase concentration was also suppressed by rolipram. Increases in the gastric content of TNF-α and IL-1β after aspirin administration were inhibited by pretreatment with rolipram. We demonstrated that the specific type IV PDE inhibitor, rolipram, could have a potent antiulcer effect, presumably mediated by its anti-inflammatory properties.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Refrences

  1. Eric V, Pierre M, Pierre L, Michel R: In vitro effect of nonsteroidal anti-inflammatory drugs on proteoglycanase and collagenase activity in human osteoarthritic cartilage. Arth Rheum 34:1332–1335, 1991

    Article  Google Scholar 

  2. Jane H, Eric FM, Sami M, Morry Z, Les P, Nicolas JG, Peter JM, O’Hare JP: Effects of nonsteroidal anti-inflammatory drugs and water immersion. Arth Rheum 37:1132–1137, 1994

    Article  Google Scholar 

  3. Rashad S, Revell P, Hemingway A, Low F, Rainaford K, Walker F: Effect of nonsteroidal anti-inflammatory drugs on the course of osteoarthritis. Lancet 2(8662):519–522, 1989

    Article  CAS  PubMed  Google Scholar 

  4. Paul LB, Ramnik X, Naifang LU, Nanthakumar NN, Mary D, Daniel KP, Brian S: Mechanism of NSAIDs-induced gastrointestinal injury defined using mutant mice. Gastroenterology 119:699–705, 2000

    Article  Google Scholar 

  5. Yoshikawa T, Naito Y, Kishi A, Tomii T, Kaneko T, Iinuma S, Ichikawa H, Yasuda M, Takahashi S, Kondo M: Role of active oxygen, lipid peroxidation, and antioxidants in the pathogenesis of gastric mucosal injury induced by indomethacin in rats. Gut 34:732–737, 1993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Takeuchi K, Ueshima K, Hironaka Y, Fujioka Y, Matsumoto J, Okabe S: Oxygen free radicals and lipid peroxidation in the pathogensis of gastric mucosal lesions induced by indomethacin in rats. Relation to gastric hypermotility. Digestion 49:175–184, 1991

    CAS  PubMed  Google Scholar 

  7. Andrews FJ, Malcontenti-Wilson C, O’Brien PE: Effect of nonsteroidal anti-inflammatory drugs on LFA-1 and ICAM-1 expression in gastric mucosa. Am J Physiol 266:G657–G664, 1994

    CAS  PubMed  Google Scholar 

  8. John LW, Catherine MK, Granger DN: Gastric ulceration induced by nonsteroidal anti-inflammatory drugs is a neutrophil-dependent process. Am J Physiol 259:G462–G467, 1990

    Article  Google Scholar 

  9. Yoshida N, Yoshikawa T, Nakamura Y, Arai M, Matsuyama K, Iinuma S, Yagi N, Naito Y, Miyasaka M, Kondo M: Role of neutrophil-mediated inflammation in aspirin-induced gastric mucosal injury. Dig Dis Sci 40:2300–2304. 1995

    Article  CAS  PubMed  Google Scholar 

  10. Yoshida N, Takemura T, Granger DN, Anderso DC, Wolf RE, Mclntire LV, Kvietys PK: Molecular determinations of aspirin-induced neutrophil adherence to endothelial cells. Gastroenterology 105:715–724, 1993

    Article  CAS  PubMed  Google Scholar 

  11. Naito Y, Yoshikawa T, Yagi N, Matshuyama K, Yoshida N, Seto K, Yoneta T: Effects of polaprezinc on lipid peroxidation, neutrophil accumulation, and TNF-α expression in ratswith aspirin-induced gastric mucosal injury. Dig Dis Sci 46:845–851, 2001

    Article  CAS  PubMed  Google Scholar 

  12. Peter K, Hayley JH, Mauro P: Effect of rolipram in a murine model of acute inflammation: comparison with the corticoid dexamethasone. Eur J Pharmacol 281:69–74, 1995

    Article  Google Scholar 

  13. Mary SB, Joan O’ LB, Miriam B, Siegfried BC, Lenora BC, Klaus ME, Uma SP, Julia AR, Theodore JT: Association of the anti-inflammatory activity of phosphodiesterase 4(PDE4) inhibitors with either inhibition of PDE4 catalytic activity or competition for [3H] rolipram binding. Biochem Pharmacol 51:949–956, 1996

    Article  Google Scholar 

  14. Chitta SK, Carrie LS, Michael PD, Daniel WC: Regulation of IL-15-stimulated TNF-α production by rolipram. J Immunol 163:2836–2843, 1999

    Google Scholar 

  15. Mark DO, Joel L, Liping H, Diane LR, David FS, Gail S: Enhanced protection from renal ischemia: Reperfusion injury with A2A-adenosine receptor activation and PDE4 inhibition. Kidney Int 59:2114–2125, 2001

    Article  Google Scholar 

  16. Sekut L, Yarnall D, Stimpson SA, Noel LS, Bateman-Fite R, Clark RL, Brackeen MF, Menius JA, Jr, Connolly KM: Anti-inflammatory activity of phosphodiesterase (PDE)-IV inhibitors in acute and chronic models of inflammation. Clin Exp Immunol 100:126–132, 1995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nakamura C, Otaka M, Odashima M, Jin M, Konishi N, Horikawa Y, Matsuhashi T, Watanabe S: Rolipram, a specific type IV phosphodiesterase inhibitor, ameliorates indomethacin-induced gastric mucosal injury in rats. Pathophysiology 9:195–200, 2003

    Article  CAS  PubMed  Google Scholar 

  18. Brodie DA, Hanson HW: A study of the factors involved in the production of gastric ulcers by restraint technique. Gastroenterology 38:353–361, 1960

    CAS  PubMed  Google Scholar 

  19. Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254, 1976

    Article  CAS  PubMed  Google Scholar 

  20. Trevethic MA, Clayton NM, Strong P, Harman IW: Do infiltrating neutrophils contribute to the pathogenesis of indomethacin induced ulceration of the gastric antrum. Gut 34:156–160, 1993

    Article  Google Scholar 

  21. Toroudi HP, Rahgozar M, Bakhtiarian A, Djahanguiri B: Potassium channel modulatora and indomethaxin-induce gastric ulceration in rats. Scand J Gastroenterol 34:962–966, 1999

    Article  CAS  PubMed  Google Scholar 

  22. Santucci L, Fiorucci M, Giansanti M, Brunori PM, Di Matteo FM, Morelli A: Role of tumor necrosis factor α release and leukocyte margination in indomethaxin-induced gastric injury in rats. Gastroenterology 108:393–401, 1995

    Article  CAS  PubMed  Google Scholar 

  23. Stephen JB, Morise Z, Sven T, Laureen M, Granger DN, Matthew BG: Role of the proteasome in rat indomethacin-induced gastropathy. Gastroenterology 116:865–873, 1999

    Article  Google Scholar 

  24. Jeffrey LL, Michael VP, Lee EG, Christopher RS: The toxicity of repeated exposures to rolipram, a Type IV phosphodiesterase inhibitor, in rats. Pharmacol Toxicol 78:44–49, 1996

    Article  Google Scholar 

  25. Theudore JT: Phosphodiesterase isozymes. Am J Respir Crit Care Med 157:351–370, 1998

    Article  Google Scholar 

  26. Joseph AB: Cyclic nucleotide phosphodiesterases: Functional implications of multiple isoforms. Physiol Rev 75:725–748, 1995

    Article  Google Scholar 

  27. Torphy TJ: Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 157:351–370, 1998

    Article  CAS  PubMed  Google Scholar 

  28. Moore AR, Willoughby DA: The role of cAMP regulation in controlling inflammation. Clin Exp Immunol 101:387–389, 1995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bourne HR, Lichtenstein LM, Melmon KL, Henney CS, Weinstein Y, Shearer GM: Modulation of inflammation and immunity by cyclic AMP. Science 184:19–28, 1974

    Article  CAS  PubMed  Google Scholar 

  30. Sekut L, Yarnall D, Stimpson SA, Noel LS, Bateman-Fite R, Clark RL, Brackeen MF, Menius JR JA, Connolly KM: Anti-inflammatory activity of phosphodiesterase(PDE)-IV inhibitors in acute and chronic models of inflammation. Clin Exp Immunol 100:126–132, 1995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Reuter BK, Wallence JL: Phosphodiesterase inhibitors prevent NSAID enteropathy independent of effects on TNF-α release. Am J Physiol 277:G847–G854, 1999

    CAS  PubMed  Google Scholar 

  32. Semmler J, Wachtel H, Endres S: The specific type IV phosphodiesterase inhibitor rolipram suppresses tumor necrosis factor-alpha production by human mononuclear cells. Int J Immunopharmacol 15:409–413, 1993

    Article  CAS  PubMed  Google Scholar 

  33. Santucci L, Fiorucci M, Giansanti M, Brunori PM, Di Matteo FM, Morelli A: Pentoxifylline prevents indomethacin induced acute gastric mucosal damage in rats: role of tumor necrosis factor alpha. Gut 35:909–915, 1994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yoshikawa T, Takano H, Naito Y, Oyamada H, Ueda S, Kondo M: Augmentative effects of tumor necrosis factor-alpha (human, natural type) on polymorphonuclear leukocyte-derived superoxide generation induced by various stimulants. Int J Immunopharmacol 14:1391–1398, 1992

    Article  CAS  PubMed  Google Scholar 

  35. Kokura S, Wolf RE, Yoshikawa T, Granger DN, Aw TY: T-Lymphocyte-derived tumor necrosis factor exacerbates anoxia-reoxygenation-induced neutrophil-endothelial cell adhesion. Circ Res 86:205–213, 2000

    Article  CAS  PubMed  Google Scholar 

  36. Kahky MP, Daniel CO, Cruz AB, Gaskill HV 3rd: Portal infusion of tumor necrosis factor increases mortality in rats. J Surg Res 49:138–145, 1990

    Article  CAS  PubMed  Google Scholar 

  37. Spatafora M, Chiappara G, D’Amico D, Volpes D, Melis M, Pace E, Merendino A: Effect of indomethacin on the kinetics of tumour necrosis factor alpha release and tumour necrosis factor alpha gene expression by human blood monocytes. Pharmacol Res 23:247–257, 1991

    Article  CAS  PubMed  Google Scholar 

  38. Martich GD, Parker MM, Cunnion RE, Suffredini AF: Effects of ibuprofen and pentoxifylline on the cardiovascular response of normal humans to endotoxin. J Appl Physiol 73:925–931, 1992

    Article  CAS  PubMed  Google Scholar 

  39. Yasumoto K, Okamoto S, Mukaida N, Murakami S, Mai M, Matsushima K: Tumor necrosis factor alpha and interferon gamma synergistically induce interleukin 8 production in a human gastric cancer cell line through acting concurrently on AP-1 and NF-kB-like binding sites of the interleukin 8 gene. J Biol Chem 267:22506–22511, 1992

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michiro Otaka MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Odashima, M., Otaka, M., Jin, M. et al. Rolipram, a Specific Type IV Phosphodiesterase Inhibitor, Ameliorates Aspirin-Induced Gastric Mucosal Injury in Rats. Dig Dis Sci 50, 1097–1102 (2005). https://doi.org/10.1007/s10620-005-2711-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-005-2711-9

Key Words

Navigation