Evaluation of the Anti-inflammatory Activity of Luteolin in Experimental Animal Models

Abstract

Luteolin, a flavonoid abundant in plants worldwide, demonstrates a spectrum of biological activities. This study is aimed at evaluating its inhibiting effects on inflammatory responses in vivo. We investigated the anti-inflammatory activity of luteolin in acute and chronic models in mice. We found that oral administration of luteolin (10 and 50 mg/kg) efficiently suppressed paw edema when induced by injecting carrageenan, and a similar tendency was also observed in the cotton pellet granuloma test. In the air pouch test, luteolin markedly reduced the number of infiltrated leukocytes and the elevated level of 6-keto-prostaglandin F_1α (6-keto-PGF_1α) in the exudate. The results derived from the whole blood assay for cyclooxygenase (COX) and from the reverse transcription-polymerase chain reaction (RT-PCR) assay indicate that luteolin may be a potent selective inhibitor of cyclooxygenase-2 (COX-2) and that the inhibition is attributable to its down-regulation of the mRNA expression of COX-2 in inflammatory responses.

Key words

Luteolin - anti-inflammatory - cyclooxygenase - prostacyclin - mice

References

• 1 Paris R. Presence of a luteolin glucoside in wele (Reseda luteola).  Ann Pharm Fr. 1955;  13 485-7.
• 2 Kim S J, Park H, Kim H P. Inhibition of nitric oxide production from LPS-treated Raw 264.7 cells by synthetic flavones: Structure-activity relationship and action mechanism.  Arch Pharm Res. 2004;  27 937-43.
• 3 Kim J A, Kim D K, Kang O H, Choi Y A, Park H J, Choi S C. et al . Inhibitory effect of luteolin on TNF-alpha-induced IL-8 production in human colon epithelial cells.  Int Immunopharmacol. 2005;  5 209-17.
• 4 Hirano T, Higa S, Arimitsu J, Naka T, Shima Y, Ohshima S. et al . Flavonoids such as luteolin, fisetin and apigenin are inhibitors of interleukin-4 and interlukin13 production by activated human basophils.  Int Arch Allergy Immunol. 2004;  134 135-8.
• 5 Chen C C, Chow M P, Huang W C, Lin Y C, Chang Y J. Flavonoids inhibit tumor necrosis factor-alpha-induced up-regulation of intercellular adhesion molecule-1 (ICAM-1) in respiratory epithelial cells through activator protein-1 and nuclear factor-kappa B: structure-activity relationships.  Mol Pharmacol. 2004;  66 683-93.
• 6 Wu M J, Wang L, Ding H Y, Weng C Y, Yen J H. Glossogyne tenuifolia acts to inhibit inflammatory mediator production in a macrophage cell line by downregulating LPS-induced NF-kappa B.  J Biomed Sci. 2004;  11 186-99.
• 7 Suleyman H, Buyukokuroqlu M E. The effects of newly synthesized pyrazole derivatives on formaldehyde-, carrageenan-, and dextran-induced acute paw edema in rats.  Biol Pharm Bull. 2001;  24 1133-6.
• 8 Kim J Y, Hwang Y P, Kim D H, Han E H, Chung Y C, Roh S H. et al . Inhibitory effect of the saponins derived from roots of Platycodon grandiflorum on carrageenan-induced inflammation.  Biosci Biotechnol Biochem. 2006;  70 858-64.
• 9 Brideau C, Kargman S, Liu S, Dallob A L, Enrich E W, Rodger I W. et al . A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors.  Inflamm Res. 1996;  45 68-74.
• 10 Vineger R, Schreiber W, Hugo R. Biphasic development of carrageenan edema in rats.  J Pharmacol Exp Ther. 1969;  166 96-103.
• 11 Sedgwick A D, Moore A R, A1-Duaij A Y, Edwards J C, Willoughby D A. Studies into the influence of carrageenan-induced inflammation on articular cartilage degradation using implantation into air pouches.  Br J Exp Pathol. 1985;  66 445-53.
• 12 Gamache D A, Povlishock J T, Ellis E F. Carageenan-induce brain inflammation. Characterization of the model.  J Neurosurg. 1986;  65 675-85.
• 13 Seibert T K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W. et al . Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain.  Proc Natl Acad Sci USA. 1994;  91 12 013-7.
• 14 Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N, Nagai H. Effects of luteolin, quercetin and baicalein on immunologbulin E-mediated release from human cultured mast cells.  Clin Exp Allergy. 2000;  30 501-8.
• 15 Kimata M, Inagaki N, Nagai H. Effects of luteolin and other flavonoids on IgE-mediated allergic reactions.  Planta Med. 2000;  66 25-9.
• 16 Patrignani P, Panara M R, Greco A, Fusco O, Natoli C, Iacobelli S. et al . Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases.  J Pharmacol Exp Ther. 1994;  271 1705-12.
• 17 Warner T D, Giuliano F, Vojnovic I, Bukasa A, Mitchell J A, Vane J R. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: A full in vitro analysis.  Proc Natl Acad Sci USA. 1999;  96 7563-8.
• 18 Mancini J A, Riendeau D, Falgueyret J P, Vickers P J, O’Neill G P. Arginine 120 of prostaglandin G/H synthase-1 is required for the inhibition by nonsteroidal anti-inflammatory drugs containing a carboxylic acid moiety.  J Biol Chem. 1995;  270 29 372-7.
• 19 Harris G K, Qian Y, Leonard S S, Sbarra D C, Shi X. Luteolin and chrysin differentially inhibit cyclooxygenase-2 expression and scavenge reactive oxygen species but similarly inhibit prostaglandin-E₂ formation in RAW 264.7 cells.  J Nutr. 2006;  136 1517-21.
• 20 Hu C, Kitts D D. Luteolin and luteolin-7-O-glucoside from dandelion flower suppress iNOS and COX-2 in RAW264.7 cells.  Mol Cell Biochem. 2004;  265 107-13.