EN PL
PRACA ORYGINALNA
Esculetin reduces leukotriene B4 level in plasma of rats with adjuvant-induced arthritis
 
Więcej
Ukryj
 
Data publikacji online: 05-10-2016
 
 
Reumatologia 2016;54(4):161-164
 
SŁOWA KLUCZOWE
STRESZCZENIE
Objectives: Esculetin (6,7-dihydroxycoumarin) is a natural coumarin with anti-oxidant, anti-inflammatory and anti-nociceptive activity. It acts as a potent inhibitor of lipoxygenases (5-LOX and 12-LOX) and decreases the production of matrix metalloproteinases (MMP-1, MMP-3 and MMP-9). Because both inhibition of lipoxygenases and inhibition of matrix metalloproteinases are effective strategies in the treatment of rheumatoid arthritis, we investigated whether esculetin may be effective in adjuvant-induced arthritis in rats.
Material and methods: The study was performed on male Lewis rats, in the adjuvant-induced arthritis model. Rats were divided into two groups: control (treated with 1% methylcellulose) and experimental (treated with esculetin – 10 mg/kg ip.). The tested compound was administered for 5 consecutive days starting on the 21st day after induction of arthritis. Each group consisted of 7 animals. After 5 days of treatment, rats were anesthetized. The concentration of leukotriene B4 (LTB4) in plasma was determined by a competitive enzyme immunoassay.
Results: The LTB4 level in plasma of rats with adjuvant-induced arthritis is increased in comparison to rats without inflammation (362 ±34 vs. 274 ±15 pg/ml, p < 0.01, respectively). Five-day treatment with esculetin in adjuvant-induced arthritis rats decreases the LTB4 level to a level comparable with rats without inflammation (284 ±23 pg/ml, p < 0.01).
Conclusions: LTB4 is the most potent chemotactic agent influencing neutrophil migration into the joint. It is known that its level in serum of patients with active rheumatoid arthritis is increased and correlates with disease severity. Some other lipoxygenase inhibitors have already been tested as potential drug candidates in clinical and preclinical trials for rheumatoid arthritis (Zileuton, PF-4191834). Because esculetin decreases the LTB4 level in plasma of rats in adjuvant-induced arthritis, it may also be considered as an attractive drug candidate for patients with rheumatoid arthritis.
 
REFERENCJE (22)
1.
Martin-Aragon S, Benedi JM, Villar AM. Effects of the antioxidant (6,7-dihydroxycoumarin) esculetin on the glutathione system and lipid peroxidation in mice. Gerontology 1998; 44: 21-25.
 
2.
Witaicenis A, Seito LN, Di Stasi LC. Intestinal anti-inflammatory activity of esculetin and 4-methylesculetin in the trinitrobenzenesulphonic acid model of rat colitis. Chem Biol Interact 2010; 186: 211-218.
 
3.
Rzodkiewicz P, Gasinska E, Maśliński S, et al. Antinociceptive properties of esculetin in non-inflammatory and inflammatory models of pain in rats. Clin Exp Pharmacol Physiol 2015; 42: 213-219.
 
4.
Du L, Zhang Z, Luo X, et al. Binding investigation of human 5-lipoxygenase with its inhibitors by SPR technology correlating with molecular docking simulation. J Biochem 2006; 139: 715-723.
 
5.
Yokota S, Oda T, Fahimi HD. The role of 15-lipoxygenase in disruption of the peroxisomal membrane and in programmed degradation of peroxisomes in normal rat liver. J Histochem Cytochem 2001; 49: 613-622.
 
6.
Yamada H, Watanabe K, Saito T, et al. Esculetin (dihydroxycoumarin) inhibits the production of matrix metalloproteinases in cartilage explants, and oral administration of its prodrug, CPA-926, suppresses cartilage destruction in rabbit experimental osteoarthritis. J Rheumatol 1999; 26: 654-662.
 
7.
Nagakura Y, Okada M, Kohara A, et al. Allodynia and hyperalgesia in adjuvant-induced arthritic rats: time course of progression and efficacy of analgesics. J Pharmacol Exp Ther 2003; 306: 490-497.
 
8.
Watanabe K, Ito A, Sato T, et al. Esculetin suppresses proteoglycan metabolism by inhibiting the production of matrix metalloproteinases in rabbit chondrocytes. Eur J Pharmacol 1999; 370: 297-305.
 
9.
Elliott S, Rowan AD, Carrere S, et al. Esculetin inhibits cartilage resorption induced by interleukin 1alpha in combination with oncostatin M. Ann Rheum Dis 2001; 60: 158-165.
 
10.
Gajewski M, Rzodkiewicz P, Maśliński S. Aktualne poglądy na znaczenie neutrofilów w reumatoidalnym zapaleniu stawów. Wciąż neutrofile czy może już mikrofagi? Reumatologia 2011; 49: 344-350.
 
11.
Leppert D, Hauser SL, Kishiyama JL, et al. Stimulation of matrix metalloproteinase-dependent migration of T cells by eicosanoids. FASEB J 1995; 9: 1473-1481.
 
12.
Ahluwalia N, Lin AY, Tager AM, et al. Inhibited aortic aneurysm formation in BLT1-deficient mice. J Immunol 2007; 179: 691-697.
 
13.
Guerrero AT, Verri WA Jr., Cunha TM, et al. Involvement of LTB4 in zymosan-induced joint nociception in mice: participation of neutrophils and PGE2. J Leukoc Biol 2008; 83: 122-130.
 
14.
Grespan R, Fukada SY, Lemos HP, et al. CXCR2-specific chemokines mediate leukotriene B4-dependent recruitment of neutrophils to inflamed joints in mice with antigen-induced arthritis. Arthritis Rheum 2008; 58: 2030-2040.
 
15.
Henderson WR, Jr. The role of leukotrienes in inflammation. Ann Intern Med 1994; 121: 684-697.
 
16.
Uberti AF, Olivera-Severo D, Wassermann GE, et al. Pro-inflammatory properties and neutrophil activation by Helicobacter pylori urease. Toxicon 2013; 69: 240-249.
 
17.
Ahmadzadeh N, Shingu M, Nobunaga M, et al. Relationship between leukotriene B4 and immunological parameters in rheumatoid synovial fluids. Inflammation 1991; 15: 497-503.
 
18.
Gursel T. Firat S, Ercan ZS. Increased serum leukotriene B4 level in the active stage of rheumatoid arthritis in children. Prostaglandins Leukot Essent Fatty Acids 1997; 56: 205-207.
 
19.
Chen M, Lam BK, Kanaoka Y, et al. Neutrophil-derived leukotriene B4 is required for inflammatory arthritis. J Exp Med 2006; 203: 837-842.
 
20.
Lin HC, Lin TH, Wu MY, et al. 5-Lipoxygenase inhibitors attenuate TNF-αlpha-induced inflammation in human synovial fibroblasts. PLoS One 2014; 9: e107890.
 
21.
Weinblatt ME, Kremer JM, Coblyn JS, et al. Zileuton, a 5-lipoxygenase inhibitor in rheumatoid arthritis. J Rheumatol 1992; 19: 1537-1541.
 
22.
Masferrer JL, Zweifel BS, Hardy M, et al. Pharmacology of PF-4191834, a novel, selective non-redox 5-lipoxygenase inhibitor effective in inflammation and pain. J Pharmacol Exp Ther 2010; 334: 294-301.
 
Copyright: © Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie. This is an Open Access journal, all articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (https://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
eISSN:2084-9834
ISSN:0034-6233
Journals System - logo
Scroll to top