Skip to main content
SpringerLink
Log in

Effect of a new De-N-acetyl-lysoglycosphingolipid on chemically-induced inflammatory bowel disease: possible mechanism of action

  • Original Articles
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Summary

A new, orally active de-N-acetylated lysoglycosphingolipid (WILD20) was evaluated as antiinflammatory agent using a model of chemically-induced inflammatory bowel disease (IBD) in the rat to mimic human ulcerative colitis and Chron's disease. IBD was induced by hapten trinitrobenzenesulphonic acid (TNB). WILD20, orally administered as preventive or curative, was demonstrated to be efficacious at daily dosages of 0.1–1 mg/kg for 4–5 days. Damage scores, body weight, spleen weight, colonic tissular levels of LTB4, myeloperoxidase (MPO) and malondialdehyde (MDA) are influenced and brought into parameters of normality.

Histological observation demonstrated quicker healing, better repair, reduced inflammation, and poor eosinophil degranulation.

The mechanisms underlying WILD20 antinflammatory effects were investigated: whereas WILD20 fails to show a direct effect on PKC, it reduces PKC translocation to the membrane; cellular PLA2 was consequently greatly reduced through this mechanism and thought to be responsible for WILD20 efficacy towards chemically-induced IBD.

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

Access this article

Log in via an institution

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

References

  • Ahnfelt-Ronne I, Hagen Nielson O (1987) The anti-inflammatory moiety of sulfasalazine, 5-aminosalicylic acid, is a free radical scavenger. Agents & Actions 21:191–194

    Google Scholar 

  • Bianco ID, Fidelio GD, Maggio B (1990) Effect of sulfatide and gangliosides on phospholipase C and phospholipase A2 activity. A monolayer study. Biochim Biophys Acta 1026:179–185

    Google Scholar 

  • Bianco ID, Fidelio GD, Yu RK, Maggio B (1991) Degradation of dilauroylphosphatidylcholine by phospholipase A2 in monolayers containing glycosphingolipids. Biochemistry 30:1709–1714

    Google Scholar 

  • Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37:911–915

    Google Scholar 

  • Boughton-Smith NK, Wallace JL, Whittle BJR (1985) Arachidonic acid metabolism and leukocyte infiltration as measured by myeloperoxidase activity in a model of IBD. Gut 26:A1148

    Google Scholar 

  • Boughton-Smith NK, Wallace JL, Whittle BJR (1988) Relationship between arachidonic acid metabolism, myeloperoxidase activity and leukocyte infiltration in a rat model of inflammatory bowel disease. Agents & Actions 25:1–2

    Google Scholar 

  • Bradley PP, Priebat DA, Christensen RD, Rothstein G (1982) Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 78:206–209

    Google Scholar 

  • Chang HW, Kudo I, Hara S, Karasawa K, Inoue K (1986) Extracellular phospholipase A2 activity in peritoneal cavity of casein-treated rats. J Biochem 100:1099–1101

    Google Scholar 

  • Correa SG, Bianco ID, Riera CM, Fidelio GD (1991) Anti-inflammatory effects of gangliosides in the rat hindpaw edema test. Eur J Pharmacol 199:93–98

    Google Scholar 

  • Craven PA, Pfansteil J, Saito R, Derubertis FR (1987) Actions of sulfasalazine and 5-aminosalicylic acid as reactive oxygen scavengers in the suppression of bile acid induced increases in colonic epithelial cell loss and proliferative activity. Gastroenterol 92:1998–2008

    Google Scholar 

  • Dennis EA (1987) Regulation of eicosanoid production: role of phospholipase and inhibitors. Biotechnology 5:1294

    Google Scholar 

  • Dew MJ, Herries AD, Evans N, Evans BK, Rhodes J (1983) Maintenance of remission in ulcerative colitis with 5-aminosalicylic acid in high doses by mouth. Br Med J 287:23–24

    Google Scholar 

  • Djuric SW, Gaginella TS, Fretland DJ, Jones PH (1989) Recent advances in the treatment of inflammatory bowel disease. Ann Rep Med Chem 24:167–175

    Google Scholar 

  • Eliakim R, Karmeli F, Rachmilewitz D (1987) Pathogenesis of active ulcerative colitis: enhanced synthesis of platelet-activating factor and its inhibition by prednisolone, 5-aminosalicylic acid and salazopyrine. Israel J Med Sci 23:1173 (abstr)

    Google Scholar 

  • Emerit J, Droy-Lefaix MT, Likforman J, Diemert MC (1989 a) Oxygen free radicals and inflammatory diseases of intestines. J Chir Paris 126:287–293

    Google Scholar 

  • Emerit J, Pelletier S, Tosoni Verlingue D, Mollet M (1989 b) Phase II trial of copper zinc superoxide dismutase (CuZnSOD) in treatment of Crohn's disease. Free Rad Biol Med 7:145–149

    Google Scholar 

  • Goswami SK, Kinsella JE (1981) Separation of prostaglandins A, B, D, E, F, thromboxane and 6-cheto prostaglandin F-1 (alpha) by thin layer chromatography. J Chromatogr 209/2:334–336

    Google Scholar 

  • Grisham MB, Gaginella TS, von Ritter C, Tamai H, Be RM, Granger DN (1990) Effects of neutrophil-derived oxidants on intestinal permeability, electrolyte transport, and epithelial cell viability. Inflammation 14:531–542

    Google Scholar 

  • Hanai N, Dohi T, Nores GA, Hakomori S (1988) A novel ganglioside, de-N-acetyl-GM3 (II3NeuNH2LacCer), acting as a strong promoter for epidermal growth factor receptor kinase and as a stimulator for cell growth. J Biol Chem 263:6296–6301

    Google Scholar 

  • Hannun YA, Bell RM (1987) Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses. Science 235:670–674

    Google Scholar 

  • Hannun YA, Bell RM (1989) Functions of sphingolipids and sphingolipid breakdown products in cellular regulation. Science 243: 500–507

    Google Scholar 

  • Hawkey CJ, Truelove SC (1981) Effect of prednisolone on prostaglandin synthesis by rectal mucosa in ulcerative colitis' investigation by laminar flow bioassay and radioimmunoassay. Gut 22:190–193

    Google Scholar 

  • Hawkey CJ, Boughton-Smith NK, Whittle BJR (1985) Modulation of human colonic arachidonic acid metabolism by sulfasalazine. Digest Dis Sci 130:1161–1165

    Google Scholar 

  • Heller R, Bussolino F, Ghigo D, Garbarino G, Pescarmona G, Till U, Bosia A (1991) Stimulation of platelet-activating factor synthesis in human endothelial cells by activation of the de novo pathway. Phorbol 12-myristate 13-acetate activates 1-alkyl-2-lyso-sn-glycero-3-phosphate:acetyl-CoA acetyltransferase and dithiothreitol-insensitive 1-alkyl-2-acetyl-sn-glycerol: CDP-choline cholinephosphotransferase. J Biol Chem 266:21358–21361

    Google Scholar 

  • Janero DR (1990) Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Rad Biol Med 9:515–540

    Google Scholar 

  • Kettle AJ, Winterbourn CC (1991) Mechanism of inhibition of myeloperoxidase by anti-inflammatory drugs. Biochem Pharmacol 41:1485–1492

    Google Scholar 

  • Kirk AP, Lennard-Jones JE (1982) Controlled trial of azathioprine in chronic ulcerative colitis. Br Med J 84:1291–1292

    Google Scholar 

  • Kobayashi T, Goto I, Yamanaka T, Suzuki Y, Nakano T, Suzuli K (1988) Infantile and fetal globoid cell leukodystrophy: analysis of galactosylceramide and galactosylsphingosine. Ann Neurol 24:517–522

    Google Scholar 

  • Krawisc JE, Sharon P, Stenson WF (1984) Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Gastroenterology 87:1344–1350

    Google Scholar 

  • Kremer JM, Esker MW, Pathmamanoharan C, Wiersema PH (1977) Vescicoles of variable diameter prepared by a modified injection method. Biochemistry 16:3932–3935

    Google Scholar 

  • Kudo JI, Chang HW, Hara S, Murakami M, Inoue K (1989) Characteristics and pathophysiological roles of extracellular phospholipase A2 in inflamed sites. Dermatological 179:72

    Google Scholar 

  • Lanni C, Becker EL (1983) Release of phospholipase A2 activity from rabbit peritoneal neutrophils by f-Met-Leu-Phe. Am J Pathol 113:90–94

    Google Scholar 

  • Lilius EM, Laakso SA (1982) A sensitive lipoxygenase assay based on chemiluminescence. Ann Biochem 119:135–141

    Google Scholar 

  • Lederer Jr, Riley DL, Demer S (1983) Rapid extraction of arachidonic acid metabolites utilizing octadecyl reversed-phase columns. J Chromatogr 273/2:402–409

    Google Scholar 

  • Mallet AI, Cunningham FM (1985) Structural identification of platelet activating factor in psoriatic scale. Biochem Biophys Res Commun 126:192–198

    Google Scholar 

  • McCord JM (1985) Oxygen derived free radicals in postischemic tissue injury. N Engl J Med 312:159–163

    Google Scholar 

  • Mita H, Yasueda H, Hayakawa T, Shida T (1989) Quantitation of platelet-activating factor by high-performance liquid chromatography with fluorescent detection. Anal Biochem 180:131–135

    Google Scholar 

  • Miyachi Y, Yoshioka A, Imamura S, Niwa Y (1987) Effect of sulfasalazine and its metabolites on the generation of reactive oxygen species. Gut 28:190–195

    Google Scholar 

  • Morris GP, Rebeiro L, Herridge MM, Szewezuk M, Depew W (1984) An animal model of chronic granulomatous inflammation of the stomach and colon. Gastroenterology 86:A1188

    Google Scholar 

  • Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL (1989) Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology 96:795–803

    Google Scholar 

  • Nores GA, Hanai N, Levery SB, Eaton HL, Salyan MEK, Hakomori S (1988) Synthesis and characterization of lyso-GM3 (II3Neu5Ac lactosyl sphingosine), de-N-acetyl-GM3 (II3NeuNH2 lactosyl Cer), and related compounds. Carbohyd Red 179:393–410

    Google Scholar 

  • Parente I, Flower RJ (1985) Hydrocortisone and macrocortin inhibit the zimosan-induced release of lyso-PAF from rat peritoneal leucocytes. Life Sci 36:1225–1231

    Google Scholar 

  • Ohkawa H, Ohishis N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Google Scholar 

  • Pelosin JM, Keramidas M, Chambaz EM (1991) Production of platelet-activating factor is a component of the angiotensin II-protein kinase C activation pathway in bovine adrenocortical cells. Biochem J 278:29–34

    Google Scholar 

  • Pereira JL, Hughes IE, Young HL (1987) Spleen size in patients with inflammatory bowel disease. Dis Colon Rectum 30:403–409

    Google Scholar 

  • Pruzanski W, Vadas P (1991) Phospholipase A2 a mediator between proximal and distal effectors of inflammation. Immunol Today 12:1143–1146

    Google Scholar 

  • Rhodes J, Beck P, Bainton D, Campbell H (1971) Controlled trial of azathioprine in Crohn's disease. Lancet 2:1273–1276

    Google Scholar 

  • Roediger W, Schapel G, Lawson M, Radcliffe B, Nance S (1986) Effect of 5-aminosalicylic acid (5-ASA) and other salicylates on short-chain fat metabolism in the colonic mucosa. Pharmacological implications for ulcerative colitis. Biochem Pharmacol 35:221–225

    Google Scholar 

  • Rosenberg JL, Levin B, Wall AJ (1975 a) A controlled trial of azathioprine in Crohn's disease. Am J Digest Dis 20:721–726

    Google Scholar 

  • Rosenberg JL, Wall AJ, Levin B, Binder HJ, Kirsner JB (1975 b) A controlled trial of azathioprine in the management of chronic ulcerative colitis. Gastroenterology 69:96–99

    Google Scholar 

  • Sharon P, Stenson WF (1984) Enhanced synthesis of leukotriene B4 by colonic mucosa in inflammatory bowel disease. Gastroenterology 86:453–460

    Google Scholar 

  • Sohal PS, Cornell RB (1990) Sphingosine inhibits the activity of rat liver CTP: phosphocholine cytidyltransferase. J Biol Chem 265: 11746–11750

    Google Scholar 

  • Stendohl O, Coble BI, Dahlgen C, Hed J, Molin L (1984) Myeloperoxidase modulates the phagocytic activity of polymorphonuclear leukocytes. Studies with cells from a myeloperoxidase deficient patient. J Clin Invest 73:366–373

    Google Scholar 

  • Toda K, Kobayashi T, Goto I, Kurokawa T, Ogomori K (1989) Accumulation of lysosulfatide (sulfagalactosylsphingosine) in tissues of a boy with metachromatic leukodystrophy. Biochem Biophys Res Commun 159(2):605–611

    Google Scholar 

  • Tubaro E, Croce C, Cavallo G, Belogi L, Guida G, Santiangeli C, Cifone MG, Santoni A, Mainiero F (1993) Effect of a new glycosphingolipid on some parameters of neutrophil-mediated inflammatory events (in press)

  • Tubaro E, Belogi L, Croce C, Cavallo G, Guida G, Borelli G (1993) Antiplatelet effects of a new de-N-acetyl-lysoglycosphingolipid. Eur J Pharmacol 248:175–183

    Google Scholar 

  • Vadas P, Hay JB (1980) The release of phospholipase A2 from aggregated platelets and stimulated macrophages of sheep. Life Sci 26:1721–1729

    Google Scholar 

  • Vadas P, Pruzanski W (1986) Biology of disease: role of secretory phospholipases A2 in the pathobiology of disease. Lab Invest 55:391–404

    Google Scholar 

  • Wallace JL, Morris GP, McNaughton WK (1988) Evaluation of the role of leukotrienes as mediators of colonic inflammation and ulceration in an animal model. In: McDermott RP (ed) Inflammatory bowel disease: current status and future approach. Elsevier, (Biomedical Division), pp 279–284

  • Wallace JL, Braquet P, Ibbotson GC, McNaughton WK, Cirino G (1988 a) Assessment of the role of platelet-activating factor in an animal model of inflammatory bowel disease. J. Lipid Mediat (pre-issue): 13–23

  • Wallace JL, McNaughton WK, Morris GP, Beck PL (1988 b) Inhibition of leukotriene synthesis markedly accelerates healing in a rat model of inflammatory bowel disease. Gastroenterology 4:22–29

    Google Scholar 

  • Willoughby JMT, Beckett J, Kumar P, Dawsaon AM (1971) Controlled trial of azathioprine in Crohn's disease. Lancet 2:944–946

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Wellcome Italia Research Laboratories, Via del Mare, 36, I-00040, Pomezia (Rome), Italy

    E. Tubaro, C. Santiangeli, G. Cavallo, L. Belogi, G. Guida & C. Croce

  2. Institute of Human Pathology and Social Medicine, “G. D'Annunzio” University, Chieti, Italy

    A. Modesti

Authors
  1. E. Tubaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Santiangeli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. Cavallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. Belogi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. Guida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. Croce
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Modesti
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Correspondence to: E. Tubaro at the above address

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tubaro, E., Santiangeli, C., Cavallo, G. et al. Effect of a new De-N-acetyl-lysoglycosphingolipid on chemically-induced inflammatory bowel disease: possible mechanism of action. Naunyn-Schmiedeberg's Arch Pharmacol 348, 670–678 (1993). https://doi.org/10.1007/BF00167246

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00167246

Key words

Search

Navigation