Anti-Inflammatory Activity of 5-O-Demethylnobiletin, a Polymethoxyflavone Isolated from Sideritis tragoriganum

Abstract

We have studied the effect of 5-O-demethylnobiletin (1) on both the inflammation of mouse ears induced by repeated application of 12-O-tetradecanoylphorbol 13-acetate (TPA) and the acute mouse paw oedemas induced by carrageenan and phospholipase A₂ (PLA₂), and determined its activity on 5-lipoxygenase (5-LOX) and elastase release/activity. Compound 1 reduced the oedema formation, cell infiltration, and tissue damage in the inflammation induced by TPA in mouse ears, along with the acute oedema induced by carrageenan in mouse paws and the acute PLA₂-induced oedema in mouse paws. The flavone inhibited leukotriene B₄ formation in rat neutrophils and elastase release in human neutrophils, but did not reduce the expression of cyclooxygenase-2 (COX-2) in murine RAW 264.7 macrophages. These experimental results suggest that 1 may act through a direct inhibition of 5-LOX, without affecting the expression of COX-2.

Key words

5-O-Demethylnobiletin - 5-lipoxygenase - anti-inflammatory activity - Sideritis tragoriganum - Lamiaceae

References

• 1 Peris J B, Stübing G, Romo A. Plantas Medicinales de la Península Ibérica e Islas Baleares. Madrid; Ediciones Jaguar 2001: p. 422-3
• 2 Kawaii S, Tomono Y, Atase E, Ogawa K, Yano M, Koizumi M. et al . Quantitative study of flavonoids in leaves of Citrus plants.  J Agric Food Chem. 2000;  48 3865-71
• 3 Harborne J B, Mabry T J. The Flavonoids: Advances in Research. London; Chapman and Hall 1984: p. 200
• 4 Ishiwa J, Sato T, Mimaki Y, Sashida Y, Yano M, Ito A. A citrus flavonoid, nobiletin, suppresses production and gene expression of matrix metalloproteinase 9/gelatinase B in rabbit synovial fibroblasts.  J Rheumatol. 2000;  27 20-5
• 5 Mora A, Payá M, Ríos J L, Alcaraz M J. Structure-activity relationships of polymethoxyflavones and other flavonoids as inhibitors of non-enzymic lipid peroxidation.  Biochem Pharmacol. 1990;  40 793-7
• 6 Huguet A I, Máñez S, Alcaraz M J. Superoxide sacavenging properties of flavonoids in a non-enzymic system.  Z Naturforsch [c]. 1990;  45 19-24
• 7 Lasure A, Van Poel B, Cimanga K, Pieters L, Vanden Berghe D, Vlietinck A J. Modulation of the complement system by flavonoids.  Pharm Pharmacol Lett. 1994;  4 32-5
• 8 Malterud K E, Rydland K M. Inhibitors of 15-lipoxygenase from orange peel.  J Agric Food Chem. 2000;  48 5576-80
• 9 Murakami A, Nakamura Y, Torikai K, Tanaka T, Koshiba T, Koshimizu K. et al . Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice.  Cancer Res. 2000;  60 5059-66
• 10 Murakami A, Nakamura Y, Ohto Y, Yano M, Koshiba T, Koshimizu K. et al . Suppressive effects of citrus fruits on free radical generation and nobiletin, an anti-inflammatory polymethoxyflavonoid.  Biofactors. 2000;  12 187-92
• 11 Murakami A, Matsumoto K, Koshimizu K, Ohigashi H. Effects of selected food factors with chemopreventive properties on combined lipopolysaccharide- and interferon-γ-induced IκB degradation in RAW264.7 macrophages.  Cancer Lett. 2003;  195 17-25
• 12 Sasaki K, Yoshizaki F. Nobiletin as a tyrosinase inhibitor from the peel of Citrus fruit.  Biol Pharm Bull. 2002;  25 806-8
• 13 Villar A, Máñez S, Zafra-Polo M C, Ríos J L, Barberán F AT. Identificación de 5-hidroxi-6,7,8,4′-tetrametoxiflavona en Sideritis mugronensis Borja (Labiatae).  Pharm Mediterranea. 1984;  14(3) 243-6
• 14 Giner R M, Villalba M L, Recio M C, Máñez S, Cerdá-Nicolás M, Ríos J L. Anti-inflammatory glycoterpenoids from Scrophularia auriculata .  Eur J Pharmacol. 2000;  389 243-52
• 15 Giner-Larza E M, Máñez S, Recio M C, Giner R M, Prieto J M, Cerdá-Nicolás M. et al . Oleanonic acid, a 3-oxotriterpene from Pistacia, inhibits leukotriene synthesis and has anti-inflammatory activity.  Eur J Pharmacol. 2001;  428 137-43