Abstract
Objective
The present study evaluates the anti-inflammatory effect of the quinoline alkaloid skimmianine (SKM), isolated from Ruta graveolens L., against carrageenan-induced acute inflammation.
Methods
SKM at a dose of 5.0 mg/kg body weight was found to be the minimal concentration for maximal edema inhibition. Carrageenan suspension was administered into the sub-plantar tissue of the right hind paw 1 h after SKM and diclofenac (20 mg/kg) administration (i.p.). Paw edema was determined 3 h after carrageenan administration. The rats were then killed and mRNA expressions of TNF-α and IL-6, levels of PGE2 and TBARS, activities of COX-2, 5-LOX, SOD, catalase, glutathione peroxidase (GPx) and myeloperoxidase (MPO) and the level of nitrite were measured.
Results
SKM treatment resulted in a decrease in the mRNA levels of TNF-α and IL-6, which are upstream events of the inflammatory cascade. The levels of PGE2 and NO and the activities of COX-2 and 5-LOX were also significantly reduced after SKM treatment. Neutrophil infiltration, lipid peroxidation and associated oxidative stress in the paw tissue were reduced following SKM treatment.
Conclusion
These results support the anti-inflammatory properties of skimmianine and its multi-targeted mechanism of action, suggesting its potential therapeutic efficacy in various inflammatory diseases.
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References
Serhan CN, Levy B. Success of prostaglandin E2 in structure-function is a challenge for structure-based therapeutics. Proc Natl Acad Sci USA. 2003;100:8609–11.
Goulet JL, Snouwaert JN, Latour AM, Coffman TM, Koller BH. Altered inflammatory responses in leukotriene-deficient mice. Proc Natl Acad Sci USA. 1994;91:12852–6.
Amin AR, Vyas P, Attur M, Leszczynska-Piziak J, Patel IR, Weissmann G, et al. The mode of action of aspirin-like drugs: effect on inducible nitric oxide synthase. Proc Natl Acad Sci USA. 1995;92:7926–30.
Marucha PT, Zeff RA, Kreutzer DL. Cytokine-induced IL-1 beta gene expression in the human polymorphonuclear leukocyte: transcriptional and post-transcriptional regulation by tumor necrosis factor and IL-1. J Immunol. 1991;147:2603–8.
Davies NM, Saleh JY, Skjodt NM. Detection and prevention of NSAID-induced enteropathy. J Pharm Pharm Sci. 2000;3:137–55.
James MW, Hawkey CJ. Assessment of non-steroidal anti-inflammatory drug (NSAID) damage in the human gastrointestinal tract. Br J Clin Pharmacol. 2003;56:146–55.
Wallace JL. Selective cyclooxygenase-2 inhibitors: after the smoke has cleared. Dig Liver Dis. 2002;34:89–94.
Bermond P. Analgesic and antiinflammatory properties of vitamins. Int J Vitam Nutr Res Suppl. 1989;30:153–60.
Ratnam DV, Ankola DD, Bhardwaj V, Sahana DK, Kumar MN. Role of antioxidants in prophylaxis and therapy: a pharmaceutical perspective. J Control Release. 2006;113:189–207.
Osadebe PO, Okoye FBC. Anti-inflammatory effects of crude methanolic extract and fractions of Alchornea cordifolia leaves. J Ethnopharmacol. 2003;89:19–24.
Conway GA, Slocumb JC. Plants used as abortifacients and emmenagogues by Spanish New Mexicans. J Ethnopharmacol. 1979;1:241–61.
Kuzovkina I, Al’terman I, Schneider B. Specific accumulation and revised structures of acridone alkaloid glucosides in the tips of transformed roots of Ruta graveolens. Phytochemistry. 2004;65:1095–100.
Ratheesh M, Shyni GL, Sindhu G, Helen A. Protective effects of isolated polyphenolic and alkaloid fractions of Ruta graveolens L. on acute and chronic models of inflammation. Inflammation. 2010;33:18–24.
Garcia-Argaez AN, Ramirez Apan TO, Parra Delgado H, Velazquez G, Martinez-Vazquez M. Anti-inflammatory activity of coumarins from Decatropis bicolor on TPA ear mice model. Planta Med. 2000;66:279–81.
Nugroho AE, Riyanto S, Sukari MA, Maeyama K. Effects of skimmianine, a quinoline alkaloid of Aegle marmelos correa roots, on the histamine release from rat mast cells. J Basic Appl Sci. 2010;6:141–8.
Chen JJ, Wang TY, Hwang TL. Neolignans, a coumarinolignan, lignan derivatives, and a chromene: anti-inflammatory constituents from Zanthoxylum avicennae. J Nat Prod. 2008;71:212–7.
Robertson AV. The proton magnetic resonance of furoquinoline alkaloids and related compounds. Aust J Chem Soc. 1963;16:451–8.
Riyanto S, Sukari MA, Rahmani M, Ee GCL, Yap YHT, Aimi N, et al. Alkaloids from Aegle marmelos (Rutaceae). Malays J Anal Sci. 2001;7:463–5.
Winter CA, Risley EA, Nuss GW. Carrageenin-induced edema in hind paw of the rat as an assay for antiinflammatory drugs. Proc Soc Exp Biol Med. 1962;111:544–7.
Shyni GL, Ratheesh M, Sindhu G, Helen A. Anti-inflammatory and antioxidant effects of Jeevaneeya Rasayana: an ayurvedic polyherbal formulation on acute and chronic models of inflammation. Immunopharmacol Immunotoxicol. 2010;32:569–75.
Bradley PP, Priebat DA, Chrisrensen RD, Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol. 1982;78:206–9.
Kakkar P, Das B, Viswanathan PN. A modified spectrophotometric assay of superoxide dismutase. Indian J Biochem Biophys. 1984;21:130–2.
Aebi H. Catalase in vitro. Methods Enzymol. 1984;105:121–6.
Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967;70:158–69.
Draper HH, Hadley M. Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol. 1990;186:421–31.
Radhika A, Jacob SS, Sudhakaran PR. Influence of oxidatively modified LDL on monocyte-macrophage differentiation. Mol Cell Biochem. 2007;305:133–43.
Axelrod B, Cheesebrough TM, Laakso S, Axelrod B, Cheesebrough TM, Laakso S. Lipoxygenase from soybean. Methods Enzymol. 1981;71:441–5.
Grisham MB, Johnson GG, Lancaster JR Jr. Quantitation of nitrate and nitrite in extracellular fluids. Methods Enzymol. 1996;268:237–46.
Vane J, Botting R. Inflammation and the mechanism of action of anti-inflammatory drugs. FASEB J. 1987;1:89–96.
Tomlinson A, Appleton I, Moore AR, Gilroy DW, Willis D, Mitchell JA, et al. Cyclooxygenase and nitric oxide synthase isoforms in rat carrageenin-induced pleurisy. Br J Pharmacol. 1994;113:693–8.
Cuzzocrea S, Nocentini G, Di Paola R, Agostini M, Mazzon E, Ronchetti S, et al. Proinflammatory role of glucocorticoid-induced TNF receptor-related gene in acute lung inflammation. J Immunol. 2006;177:631–41.
Mazzon E, Esposito E, Di Paola R, Muia C, Crisafulli C, Genovese T, et al. Effect of tumour necrosis factor-alpha receptor 1 genetic deletion on carrageenan-induced acute inflammation: a comparison with etanercept. Clin Exp Immunol. 2008;153:136–49.
Dawson J, Sedgwick AD, Edwards JC, Lees P. A comparative study of the cellular, exudative and histological responses to carrageenan, dextran and zymosan in the mouse. Int J Tissue React. 1991;13:171–85.
Janero DR. Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med. 1990;9:515–40.
Tracey WR, Nakane M, Kuk J, Budzik G, Klinghofer V, Harris R, et al. The nitric oxide synthase inhibitor, l-NG-monomethylarginine, reduces carrageenan-induced pleurisy in the rat. J Pharmacol Exp Ther. 1995;273:1295–9.
Salvemini D, Wang ZQ, Bourdon DM, Stern MK, Currie MG, Manning PT. Evidence of peroxynitrite involvement in the carrageenan-induced rat paw edema. Eur J Pharmacol. 1996;303:217–20.
Baeuerle PA, Baltimore D. NF-kappa B: ten years after. Cell. 1996;87:13–20.
Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–79.
Dayer JM, Beutler B, Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med. 1985;162:2163–8.
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Ratheesh, M., Sindhu, G. & Helen, A. Anti-inflammatory effect of quinoline alkaloid skimmianine isolated from Ruta graveolens L.. Inflamm. Res. 62, 367–376 (2013). https://doi.org/10.1007/s00011-013-0588-1
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DOI: https://doi.org/10.1007/s00011-013-0588-1