[en] OBJECTIVES: To determine the antioxidant activities of nonsteroidal anti-inflammatory drugs (NSAIDS), we examined by chemiluminescence (CL) and electron spin resonance (ESR) their scavenging properties towards lipid peroxides, hypochlorous acid and peroxynitrite. METHODS: The antioxidant properties of nimesulide (NIM), 4-hydroxynimesulide (4-HONIM), aceclofenac (ACLO), 4-hydroxyaceclofenac (4-HOA-CLO), diclofenac (DICLO) and indomethacin (INDO) were tested on four different reactive oxygen species (ROS) generating systems: (I) phorbol-myristate acetate (PMA)-activated neutrophils, (II) Fe2+/ascorbate-induced lipid peroxidation, (III) HOCl-induced light emission, (IV) the kinetics of ONOO- decomposition followed by spectrophotometry. ROS production was monitored by luminol-enhanced CL or by ESR using two different spin traps. RESULTS: At 10 microM, ACLO, NIM, 4-HONIM, 4-HOA-CLO, and DICLO decreased luminol-enhanced CL generated by PMA-activated neutrophils. Inversely, INDO increased the luminol enhanced CL. Interestingly, hydroxylated metabolites were more potent antioxidants than the parent drugs. Furthermore, all drugs tested, excepted ACLO, lowered lipid peroxidation induced by Fe2+/ascorbate system. ACLO and DICLO, even at the highest concentration tested (100 microM), did not significantly lower HOCl induced CL, whereas the other drugs were potent scavengers. Finally, all the NSAIDS accelerated decomposition of ONOO-, suggesting a potential capacity of the molecules to scavenge peroxynitrite. CONCLUSION: The NSAIDs possess variable degrees of antioxidant activities, linked to their ability to react with HOCl, lipid peroxides or ONOO-. These antioxidant activities could offer interesting targeted side-effects in the treatment of joint inflammatory diseases.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Mouithys-Mickalad, Ange ; Université de Liège - ULiège > Centre de l'oxygène : Recherche et développement (C.O.R.D.)
Zheng, S. X.
Dupont, Ginette ; Université de Liège - ULiège > Centres généraux > Centre de l'oxygène : Recherche et développement (C.O.R.D.)
Lamy, Maurice ; Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques
Reginster, Jean-Yves ; Université de Liège - ULiège > Département des sciences de la santé publique > Santé publique, Epidémiologie et Economie de la santé
Henrotin, Yves ; Université de Liège - ULiège > Département des sciences de la motricité > Unité de recherche sur l'os et le cartillage (U.R.O.C.)
Language :
English
Title :
In vitro study of the antioxidant properties of non steroidal anti-inflammatory drugs by chemiluminescence and electron spin resonance (ESR).
Henrotin Y.E., Labasse A.H., Simonis P.E., Zheng S.X., Deby G.P., Famaey J.-P., Crielaard J.-M.R., Reginster J.-Y.L. (1999) Effects of nimesulide and sodium diclofenac on interleukin-6, interleukin-8, proteoglycans and prostaglandin E2 production by human articular chondrocytes in vitro. Clinical and Experimental Rheumatology 17:151-160.
Pelletier J.-P., Mineau F., Fernandes J., Kiansa K., Ranger P., Martel-Pelletier J. (1997) Two NSAIDs, nimesulide and naproxen, can reduce the synthesis of urokinase and IL-6 while increasing PAI-1, in human OA synovia] fibroblasts. Clinical and Experimental Rheumatology 15:393-398.
Dreiser R.L., Benevelli D.C. (1993) Long term tolerability profile of nimesulide in the treatment of osteoarthritis. Drugs 46:270-274.
Famaey J.-P. (1996) In vitro and in vivo pharmacological evidence of selective cyclooxygenase-2 inhibition by nimesulide: An overview. Inflammation Research 46:437-446.
Mitchell J.A., Akarasereenont P., Thiemermann C., Flower R.J. (1994) Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proceedings of the National Academy of Sciences of the United States of America 90:11693-11697.
Wober W. (1999) Comparative efficacy and safety of nimesulide and diclofenac in patients with acute shoulder, and a meta-analysis of controlled studies with nimesulide. Rheumatology 38:33-38.
Maffei F.R., Caranini M., Aldini G., Saibene L., Macciocchi A. (1993) Antioxidant profile of nimesulide, indomethacin and diclofenac in phosphatidylcholine liposomes (PLC) as membrane model. International Journal of Tissue Reactions 15:225-234.
Cappecchi P.L., Ceccatelli L., Beermann U., Laghi P.L., Di Perri T. (1993) Inhibition of neutrophil function in vitro by nimesulide. Preliminary evidence of an adenosine-mediated mechanism. Arzneimittel-Forschung 43:992-996.
Ribeiro C.A., Figeuiredo A., Tavares P., Poiares-Baptista A., Teixeria F. (1992) Tiaprofenic acid-induced photohemolysis in vitro is inhibited by nimesulide. Drug Metabolism and Drug Interactions 10:293-305.
Bevilacqua M., Vago T., Baldi G., Renesto E., Dallegri F., Norblato G. (1994) Nimesulide decreases superoxide production by inhibiting phosphodiesterase type IV. European Journal of Pharmacology 268:415-423.
Dallegri F., Patrone F., Ballestrero A., Ottonello L., Ferrando F., Sacchetti C. (1990) Inactivation of neutrophil-derived hypochlorous acid by nimesulide: A potential mechanism for the tissue protection during inflammation. International Journal of Tissue Reactions 12:107-111.
Maffei-Facino R., Carini M., Aldini G. (1993) Anti-oxidant activity of nimesulide and its main metabolites. Drugs 46(SUPPL. 1):15-21.
Maffei F.C., Carini M., Aldini G., Saibene L., Morelli M. (1995) Differential inhibition of superoxide, hydroxyl and peroxyl radicals by nimesulide and its main metabolite 4-hydroxynimesulide. Arzneimittel-Forschung 45:1102-1109.
Guillen C., McInnes I.B., Kruger H., Brock J.H. (1998) Iron, lactoferrin and iron regulatory protein activity in the synovium; relative importance of iron loading and the inflammatory response. Annals of the Rheumatic Diseases 57:309-314.
Guillen C., McInnes I.B., Brock J.H. (1997) Iron in synovial fluid: Removal by lactoferrin, and relationship to iron regulatory protein (IRP) activity. Biochemical Society Transactions 25.
Dabbagh A.J., Trenam C.W., Morris C.J., Blake D.R. (1993) Iron in joint inflammation. Annals of the Rheumatic Diseases 52:67-73.
Rister M., Bauermeister K., Gravert U., Gladtke E. (1978) Superoxide-dismutase deficiency in rheumatoid arthritis. Lancet 1:1094.
Aaseth J., Haugen M., Forre O. (1998) Rheumatoid arthritis and metal compounds - Perspectives on the role of oxygen radical detoxification. Analyst 123:3-6.
Beckman J.S., Beckman T.W., Chen J., Marshall P.A., Freeman B.A. (1990) Apparent hydroxyl radical production of peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proceedings of the National Academy of Sciences of the United States of America 87:1620-1624.
Oh M., Fukuda K., Asada S., Yasuda Y., Tanaka S. (1998) Concurrent generation of nitric oxide and superoxide inhibits proteoglycan synthesis in bovine articular chondrocytes: Involvement of peroxynitrite. Journal of Rheumatology 25:2169-2174.
Jang D., Murrell G.A.C. (1998) Nitric oxide in arthritis. Free Radical Biology and Medicine 24:1511-1519.
Whiteman M., Kaur H., Halliwell B. (1996) Protection against peroxynitrite dependent tyrosine nitration and alpha 1-antiproteinase inactivation by some antiinflammatory drugs and by the antibiotic tetracycline. Annals of Rheumatologic Disesases 55:383-387.
Ottonello L., Dapino P., Scirocco M.C., Balbi A., Bevilacqua M., Dallegri P. (1995) Sulphonamides as anti-inflammatory agents: Old drugs for new therapeutic strategies in neutrophilic inflammation?. Clinical Science 88:331-336.
Schiller J., Arnhold J., Schwinn J., Sprinz H., Brede O., Arnold K. (1998) Reactivity of cartilage and selected carbohydrates with hydroxyl radicals. An NMR study to detect degradation products. Free Radical Research 28:215-228.
Green M.J., Hill H.A. (1984) Oxygen Radicals in Biological Systems. Methods in Enzymology 105:3-22.
Borgeat P., Samuelsson B. (1979) Arachidonic acid metabolism in polymorphonuclear leukocytes: Effects of ionophore A23187. Proceedings of the National Academy of Sciences of the United States of America 76:2148-2152.
Uppu R.M., Squadrito G.L., Cueto R., Pryor W.A. (1996) Selecting the most appropriate synthesis of peroxynitrite. Methods in Enzymology 269:311-321.
Kissner R., Nauser T., Bugnon P., Lye P.G., Koppenol W.H. (1997) Formation and properties of peroxynitrite as studied by laser flash photolysis, high-pressure stopped-flow technique, and pulse radiolysis. Chemical Research in Toxicology 10:1285-1292.
Davis R., Brogden R.N. (1994) Nimesulide. An update of its pharmacodynamic and pharmacokinetic efficacy. Drugs 48:431-454.
Areenwald G.R., Moxx W.W. (1979) Inhibition of collagen gelation by action of superoxide radical. Arthritis and Rheumatism 22:251-259.
Imlay J.A., Linn S. (1988) DNA damage and oxygen radical toxicity. Science 240:1302-1304.
Burkhardt H., Schwingel M., Menninger H., Macartney H.W., Tschesche H. (1986) Oxygen radicals as effectors of cartilage degradation. Arthritis and Rheumatism 29:379-387.
Carp H., Janoff A. (1980) Potential mediator of inflammation: Phagocyte derived oxidants suppress the elastase inhibitory capacity of α1-proteinase inhibitor in vitro. Journal of Clinical Investigation 66:987-995.
Eiserich J.P., Hristova M., Cross C.E., Jones A.D., Freeman B.A., Halliwell B., Van der Vliet A. (1998) Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 391:393-397.
Dallegri F., Ottenello L., Dapino P., Sacchetti C. (1992) Effect of nonsteroidal antiinflammatory drugs on the neutrophil promoted inactivation of alpha-l-proteinase inhibitor. Journal of Rheumatology 19:419-423.
Ottonello L., Dapino P., Pastorino G., Montagnani G., Gatti F., Guidi G., Dallegri F. (1993) Nimesulide as a downregulator of the activity of the neutrophil myeloperoxidase pathway. Drugs 46(SUPPL. 1):29-33.
Zheng S.X., Mouithys-Mickalad A., Deby-Dupont G., Deby C., Maroulis A., Labasse A., Lamy M., Crielaard J.-M., Reginster J.-Y., Henrotin Y. (2000) In vitro study of the antioxidant properties of nimesulide and 4-HO nimesulide: Effects on HRP-and luminol-dependent chemiluminescence produced by human chondrocytes. Osteoarthritis and Cartilage, in press; .
Bevilacqua M., Eagni M. (1993) Recent contribution to knowledge of the mechanism of action of nimesulide. Drugs 46(SUPPL. 1):40-47.
Nandgaonkar B., Rotschild T., Yu K., Higgins R. (1999) Indomethacin improves oxygen-induced retinopathy in the mouse. Pediatric Research 46:184-188.
Carreras C.M., Pargament G.A., Catz S.D., Poderoso J.J., Boveris A. (1994) Kinetics of nitric oxide and hydrogen peroxide production and formation of peroxynitrite during the respiratory burst of human neutrophils. FEBS Letters 341:65-68.
Gagnon C., Leblond F.A., Filep J.G. (1998) Peroxynitrite production by human neutrophils, monocytes and lymphocytes challenged with lipopolysaccharide. FEBS Letters 431:107-110.
Deby-Dupont G., Deby C., Lamy M. (1999) Neutrophil myeloperoxidase revisited: It's role in health and disease. Intensivmedizin 36:500-513.
Winterbourn C.C., Brennan S.O. (1997) Characterization of the oxidation products of the reaction between reduced glutathione and hypochlorous acid. Biochemical Journal 326:87-92.
Pryor W.A., Squadrito G.L. (1995) The chemistry of peroxynitrite: A product from the reaction of nitric oxide with superoxide. American Journal of Physiology 268.
Arteel G.E., Briviba K., Sies H. (1999) Protection against peroxynitrite. FEBS Letters 45:226-230.