Authors
1 Department of Pharmacology and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
2 Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
Abstract
Background: Derivatives of pyridine-4-one act as iron chelators and possess various pharmacological effects such as antifungal, antimalarial, antiviral, anti-inflammatory, and analgesic effects. The aim of our study was to evaluate the anti-inflammatory effects of the three new derivatives of pyridine-4-one.
Materials and Methods: Carrageenan-induced paw edema in rats and croton oil-induced ear edema in mice were used to evaluate the anti-inflammatry effects of three 3-hydroxy-pyridine-4-one derivatives (compounds A, B, and C). Compound A (10, 20 mg/kg), compound B (200, 400 mg/kg), and compound C (100, 200 mg/kg), vehicle (1 mL/kg), and indomethacin as standard drug (10 mg/kg) were injected intraperitoneally 30 min prior to carrageenan injection and 4 h later, the paw volume was measured using a mercury plethysmograph. The maximum dose of each test compound was used in the croton oil-induced ear edema test.
Results: All compounds showed significant anti-inflammatory activity in both tests. On a molar basis, compound A had the greatest potency, which may be due to the presence of a benzyl group substitution on the pyridine ring.
Conclusions: Because cyclooxygenase and lipoxygenase as key enzymes of the inflammation pathway are heme-dependent, it seems that the anti-inflammatory effect of derivatives of pyridine-4-one may be related to their iron chelating properties. However, more investigations are needed to find out their exact mechanism of actions.
Keywords
1. | Muirden KD. Ferritin in synovial cells in patients with rheumatoid arthritis. Ann Rheum Dis 1966;25:387-401. [PUBMED] |
2. | Senator GB, Muirden KD. Concentration of iron in synovial membrane, synovial fluid and serum in rheumatoid arthritis and other joint diseases. Ann Rheum Dis 1968;27:49-53. [PUBMED] |
3. | Halliwell B. Superoxide dependent formation of hydroxyl radicals in the presence of iron salts. Its role in degradation of hyaluronic acid by a superoxide generating system. FEBS Lett 1978;96:238-44. [PUBMED] |
4. | Brunton LL, Lazo JS, Parker KL. Goodman and Gilman′s The Pharmacological Basis of Therapeutics. New York: McGraw-Hill; 2006. |
5. | Kulmacz RJ, Lands WE. Prostaglandin H synthase. Stoichiometry of heme cofactor. J Biol Chem 1984;259:6358-63. [PUBMED] |
6. | Sedgwick AD, Blake DR, Winwood P, Moore AR, Al-Duaij A, Willoughby DA. Studies into the effects of the iron chelator desferrioxamine on the inflammatory process. Eur J Rheumatol Inflamm 1984;7:87-94. [PUBMED] |
7. | Hewitt SD, Hider RC, Sarpong P, Morris C, Blake DR. Investigation of the anti-inflammatory properties of hydroxypyridinones. Ann Rheum Dis 1989;48:382-8. |
8. | Ozturk G, Erol DD, Uzbay T, Aytemir MD. Synthesis of 4 (1H)-pyridinone derivatives and investigation of analgesic and anti-inflammatory activities. Farmaco 2001;56:251-6. |
9. | Ozturk G, Erol DD, Aytemir MD, Uzbay T. New analgesic and antiinflammatory agents 4(H)-pyridinone derivatives. Eur J Med Chem 2002;37:829-34. |
10. | Aytemir MD, Uzbay T, Erol DD. New 4 (1H)-pyridinone derivatives as analgesic agents. Arzneimittelforschung 1999;49:250-4. |
11. | Hajhashemi V, Saghaei L, Fassihi A, Mojiri-Froshani H. A study on the analgesic effects of four new derivatives of 3-hydroxy pyridine-4-one. Res Pharm Sci 2012;7:37-42. |
12. | Nikazma A. Synthesis of 1-aryl-2-methyl-3-hydroxypyridine-4-one derivatives as iron chelators. School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, A PharmD Thesis, 2001. p. 33-6. |
13. | Winter CA, Risely EA, Nuss GW. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc Soc Exp Biol Med 1962;111:544-7. |
14. | Koshihara Y, Fujimoto Y, Inoue H. A new 5-lipoxygenase selective inhibitor derived from Artocarpus communis strongly inhibits arachidonic acid-induced ear edema. Biochem Pharmacol 1988;37:2161-5. |
15. | Tubaro A, Dri P, Delbello G, Zilli C, Logia RD. The croton oil ear test revisited. Agents Actions 1985;17:347-9. |
16. | Sawadago WR, Boly R, Lompo M, Some N. Anti inflammatory, analgesic and antipyretic activities of Dicliptera verticallata. J Pharmacol 2006;2:435-8. |
17. | Jedinak A, Dudhgaonkar S, Wu QL, Simon J, Sliva D. Anti-inflammatory activity of edible oyster mushroom is mediated through the inhibition of NF-kB and AP-1 signaling. Nutr J 2011;10:52-62. |
18. | Okusada K, Nakamoto K, Nishida M, Fujita-Hamabe W, Kamiya K, Mizushina Y, et al. The antinociceptive and anti-inflammatory action of the CHCl3-soluble phase and its main active component, damnacanthal, isolated from the root of Morinda citrifolia. Biol Pharm Bull 2011;1:103-7. |
19. | Santos EN, Lima JC, Noldin VF, Cechinel-Filho V, Rao VS, Lima EF, et al. Anti-inflammatory, antinociceptive, and antipyric effects of methanol extract of Cariniana rubra stem bark in animal models. An Acad Bras Ciênc 2011;2:557-66. |
20. | Besra SE, Sharma RM, Gomes A. Anti-inflammatory effect of petroleum ether extract of leaves of Litchi chinensis Gaertn (Sapindaceae). J Ethnopharmacol 1996;54:1-6. |
21. | Botting RM. Vane's discovery of the mechanism of action of aspirin changed our understanding of its clinical pharmacology. Pharmacol Rep 2010;62:518-25. |
22. | Capone ML, Tacconelli S, Rodriguez LG, Patrignani P. NSAIDs and cardiovascular disease: Transducing human pharmacology results into clinical read-outs in the general population. Pharmacol Rep 2010;62:518-25. |
23. | Harris SG, Padilla J, Koumas L, Ray D, Phipps RP. Prostaglandins as modulators of immunity. Trends Immunol 2002;3:144-50. |
24. | Charles AW, Edwin AR, George WN. Carrageenin induced edema in hind paw of the rat as an assay for anti-inflammatory drugs. Proc Soc Biol Med 1962;1:544-7. |
25. | Matsuda R, Tanihata S. Suppressive effect of sialic acid on the prostaglandin E2-mediated oedema in carrageenininduced inflammation of rat hind paws (Japanese). Nippon Yakurigaku Zasshi 1992;99:363-72. |
26. | Gabor M. Models of acute inflammation in the ear. Methods Mol Biol 2003;225:129-37. |
27. | Saraiva RA, Araruna MK, Oliveira RC, Menezes KD, Leite GO, Kerntopf MR, et al. Topical anti-inflammatory effect of Caryocar coriaceum Wittm. (Caryocaraceae) fruit pulp fixed oil on mice ear edema induced by different irritant agents. J Ethnopharmacol 2011;136:504-10. |
28. | Rao TS, Currie JL, Shaffer AF, Isakson PC. Comparative evaluation of arachidonic acid (AA)- and tetradecanoylphorbol acetate (TPA)-induced dermal inflammation. Inflammation 1993;17:723-41. |
29. | Furstenberger G, Csuk-Glanzer BI, Marks F, Keppler D. Phorbol ester-induced leukotriene biosynthesis and tumor promotion in mouse epidermis. Carcinogenesis 1994;15:2823-7. |
30. | Abeysinghe RD, Roberts PJ, Cooper CE, MacLean KH, Hider RC, Porter JB. The environment of the lipoxygenase iron binding site explored with novel hydroxypyridinone iron chelators. J Biol Chem 1996;271:7965-72. |
31. | Aruoma OI, Grootveld M, Bahorun T. Free radicals in biology and medicine: From inflammation to biotechnology. Biofactors 2006;27:1-3. |