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Inflammopharmacology
Published in: Inflammopharmacology 5/2017

01-10-2017 | Original Article

Quercetin inhibits gout arthritis in mice: induction of an opioid-dependent regulation of inflammasome

Authors: Kenji W. Ruiz-Miyazawa, Larissa Staurengo-Ferrari, Sandra S. Mizokami, Talita P. Domiciano, Fabiana T. M. C. Vicentini, Doumit Camilios-Neto, Wander R. Pavanelli, Phileno Pinge-Filho, Flávio A. Amaral, Mauro M. Teixeira, Rubia Casagrande, Waldiceu A. Verri Jr.

Published in: Inflammopharmacology | Issue 5/2017

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Abstract

We investigated the anti-inflammatory and analgesic effects of quercetin in monosodium urate crystals (MSU)-induced gout arthritis, and the sensitivity of quercetin effects to naloxone, an opioid receptor antagonist. Mice were treated with quercetin, and mechanical hyperalgesia was assessed at 1–24 h after MSU injection. In vivo, leukocyte recruitment, cytokine levels, oxidative stress, NFκB activation, and gp91phox and inflammasome components (NLRP3, ASC, Pro-caspase-1, and Pro-IL-1β) mRNA expression by qPCR were determined in the knee joints at 24 h after MSU injection. Inflammasome activation was determined, in vitro, in lipopolysaccharide-primed macrophages challenged with MSU. Quercetin inhibited MSU-induced mechanical hyperalgesia, leukocyte recruitment, TNFα and IL-1β production, superoxide anion production, inflammasome activation, decrease of antioxidants levels, NFκB activation, and inflammasome components mRNA expression. Naloxone pre-treatment prevented all the inhibitory effects of quercetin over MSU-induced gout arthritis. These results demonstrate that quercetin exerts analgesic and anti-inflammatory effect in the MSU-induced arthritis in a naloxone-sensitive manner.
Literature
Anjaneyulu M, Chopra K (2003a) Quercetin, a bioflavonoid, attenuates thermal hyperalgesia in a mouse model of diabetic neuropathic pain. Prog Neuropsychopharmacol Biol Psychiatry 27:1001–1005CrossRefPubMed
Anjaneyulu M, Chopra K (2003b) Reversal of lipopolysaccharide-induced thermal and behavioural hyperalgesia by quercetin. Drug Dev Res 58:248–252CrossRef
Borghi SM, Carvalho TT, Staurengo-Ferrari L et al (2013) Vitexin inhibits inflammatory pain in mice by targeting TRPV1, oxidative stress, and cytokines. J Nat Prod 76:1141–1149CrossRefPubMed
Borghi SM, Pinho-Ribeiro FA, Fattori V et al (2016) Quercetin inhibits peripheral and spinal cord nociceptive mechanisms to reduce intense acute swimming-induced muscle pain in mice. PLoS One 11:e0162267CrossRefPubMedPubMedCentral
Boumaza S, Belkebir A, Neggazi S et al (2016) Therapeutic role of resveratrol and quercetin on aortic fibroblasts of psammomys obesus after oxidative stress by hydrogen peroxide. Am J Ther 0:1–15
Bryan HK, Olayanju A, Goldring CE, Park BK (2013) The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. Biochem Pharmacol 85:705–717CrossRefPubMed
Cai W, Zhang Y, Li J, Wang J (2014) κ-opioid receptor agonist U50, 488H attenuates myocardial ischemia-reperfusionvia modulating Toll-like receptor 4/nuclear factor-κB signaling in rat. Zhonghua Xin Xue Guan Bing Za Zhi 42:866–872PubMed
Calixto-Campos C, Corrêa MP, Carvalho TT et al (2015) Quercetin reduces Ehrlich tumor-induced cancer pain in mice. Anal Cell Pathol 2015:1–18CrossRef
Cao S, Chao D, Zhou H et al (2015) A novel mechanism for cytoprotection against hypoxic injury: δ-opioid receptor-mediated increase in Nrf2 translocation. Br J Pharmacol 172:1869–1881CrossRefPubMedPubMedCentral
Chen J-C, Ho F-M, Chao Pei-Dawn Lee et al (2005) Inhibition of iNOS gene expression by quercetin is mediated by the inhibition of IkappaB kinase, nuclear factor-kappa B and STAT1, and depends on heme oxygenase-1 induction in mouse BV-2 microglia. Eur J Pharmacol 521:9–20CrossRefPubMed
Cunha TM, Verri WA, Schivo IR et al (2008) Crucial role of neutrophils in the development of mechanical inflammatory hypernociception. J Leukoc Biol 83:824–832CrossRefPubMed
Cunha TM, Roman-Campos D, Lotufo CM et al (2010) Morphine peripheral analgesia depends on activation of the PI3K/AKT/nNOS/NO/KATP signaling pathway. Proc Natl Acad Sci 107:4442–4447CrossRefPubMedPubMedCentral
de Souza MR, de Paula CA, Pereira de Resende ML et al (2012) Pharmacological basis for use of Lychnophora trichocarpha in gouty arthritis: anti-hyperuricemic and anti-inflammatory effects of its extract, fraction and constituents. J Ethnopharmacol 142:845–850CrossRefPubMed
Desaulniers P, Fernandes M, Gilbert C et al (2001) Crystal-induced neutrophil activation. VII. Involvement of Syk in the responses to monosodium urate crystals. J Leukoc Biol 70:659–668PubMed
Dhanasekar C, Kalaiselvan S, Rasool M (2015) Morin, a bioflavonoid suppresses monosodium urate crystal-induced inflammatory immune response in RAW 264.7 macrophages through the inhibition of inflammatory mediators, intracellular ROS levels and NF-κB activation. PLoS One 10:e0145093CrossRefPubMedPubMedCentral
Domiciano TP, Wakita D, Jones HD et al (2017) Quercetin inhibits inflammasome activation by interfering with ASC oligomerization and prevents interleukin-1 mediated mouse vasculitis. Sci Rep 7:41539CrossRefPubMedPubMedCentral
Donato F, de Gomes MG, Goes ATR et al (2014) Hesperidin exerts antidepressant-like effects in acute and chronic treatments in mice: possible role of l-arginine-NO-cGMP pathway and BDNF levels. Brain Res Bull 104:19–26CrossRefPubMed
Dubchak N, Falasca GF (2010) New and improved strategies for the treatment of gout. Int J Nephrol Renovasc Dis 3:145–166PubMedPubMedCentral
Ellis A, Grace PM, Wieseler J et al (2016) Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury. Brain Behav Immun 58:348–356CrossRefPubMed
Franchi S, Moretti S, Castelli M et al (2012) Mu opioid receptor activation modulates Toll like receptor 4 in murine macrophages. Brain Behav Immun 26:480–488CrossRefPubMed
Gan L, Johnson JA (2014) Oxidative damage and the Nrf2-ARE pathway in neurodegenerative diseases. Biochim Biophys Acta 1842:1208–1218CrossRefPubMed
Gim H, Nam JH, Lee S et al (2015) Quercetin inhibits pacemaker potentials via nitric oxide/cGMP-dependent activation and TRPM7/ANO1 channels in cultured interstitial cells of cajal from mouse small intestine. Cell Physiol Biochem 35:2422–2436CrossRefPubMed
Guazelli CFS, Fattori V, Colombo BB et al (2013) Quercetin-loaded microcapsules ameliorate experimental colitis in mice by anti-inflammatory and antioxidant mechanisms. J Nat Prod 76:200–208CrossRefPubMed
Guerrero ATGG, Verri WA, Cunha TM et al (2006) Hypernociception elicited by tibio-tarsal joint flexion in mice: a novel experimental arthritis model for pharmacological screening. Pharmacol Biochem Behav 84:244–251CrossRefPubMed
Hu Q-H, Zhang X, Pan Y et al (2012) Allopurinol, quercetin and rutin ameliorate renal NLRP3 inflammasome activation and lipid accumulation in fructose-fed rats. Biochem Pharmacol 84:113–125CrossRefPubMed
Huang J, Zhu M, Tao Y et al (2012) Therapeutic properties of quercetin on monosodium urate crystal-induced inflammation in rat. J Pharm Pharmacol 64:1119–1127CrossRefPubMed
Jiang W, Huang Y, Han N et al (2016) Quercetin suppresses NLRP3 inflammasome activation and attenuates histopathology in a rat model of spinal cord injury. Spinal Cord 54:592–596CrossRefPubMed
Jung K-A, Kwak M-K (2010) The Nrf2 system as a potential target for the development of indirect antioxidants. Molecules 15:7266–7291CrossRefPubMed
Khabbazi S, Goumon Y, Parat M-O (2015) Morphine modulates interleukin-4- or breast cancer cell-induced pro-metastatic activation of macrophages. Sci Rep 5:11389CrossRefPubMedPubMedCentral
Khanna D, Fitzgerald JD, Khanna PP et al (2012) 2012 American College of Rheumatology guidelines for management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) 64:1431–1446CrossRef
Kim Y-J, Park W (2016) Anti-inflammatory effect of quercetin on RAW 264.7 mouse macrophages induced with polyinosinic-polycytidylic acid. Molecules 21:450CrossRefPubMed
Liang Y, Chu H, Jiang Y, Yuan L (2016) Morphine enhances IL-1β release through toll-like receptor 4-mediated endocytic pathway in microglia. Purinergic Signal 12:637–645CrossRefPubMedPubMedCentral
Liu C-M, Ma J-Q, Xie W-R et al (2015) Quercetin protects mouse liver against nickel-induced DNA methylation and inflammation associated with the Nrf2/HO-1 and p38/STAT1/NF-κB pathway. Food Chem Toxicol 82:19–26CrossRefPubMed
Liu D, Cao G, Han L et al (2016) Flavonoids from Radix Tetrastigmae inhibit TLR4/MD-2 mediated JNK and NF-κB pathway with anti-inflammatory properties. Cytokine 84:29–36CrossRefPubMed
Lu F, Liu L, Yu D et al (2014) Therapeutic effect of Rhizoma Dioscoreae Nipponicae on gouty arthritis based on the SDF-1/CXCR 4 and p38 MAPK pathway: an in vivo and in vitro study. Phyther Res 28:280–288CrossRef
Maioli NAA, Zarpelon ACC, Mizokami SSS et al (2015) The superoxide anion donor, potassium superoxide, induces pain and inflammation in mice through production of reactive oxygen species and cyclooxygenase-2. Braz J Med Biol Res 48:321–331CrossRefPubMedPubMedCentral
Manchope MF, Calixto-Campos C, Coelho-Silva L et al (2016) Naringenin inhibits superoxide anion-induced inflammatory pain: role of oxidative stress, cytokines, Nrf-2 and the NO–cGMP–PKG–KATPChannel signaling pathway. PLoS One 11:e0153015CrossRefPubMedPubMedCentral
Martin WJ, Walton M, Harper J (2009) Resident macrophages initiating and driving inflammation in a monosodium urate monohydrate crystal-induced murine peritoneal model of acute gout. Arthritis Rheum 60:281–289CrossRefPubMed
Martin JL, Koodie L, Krishnan AG et al (2010) Chronic morphine administration delays wound healing by inhibiting immune cell recruitment to the wound site. Am J Pathol 176:786–799CrossRefPubMedPubMedCentral
Martinez RM, Pinho-Ribeiro FA, Steffen VS et al (2015a) Hesperidin methyl chalcone inhibits oxidative stress and inflammation in a mouse model of ultraviolet B irradiation-induced skin damage. J Photochem Photobiol B Biol 148:145–153CrossRef
Martinez RM, Pinho-Ribeiro FA, Steffen VS et al (2015b) Naringenin inhibits UVB irradiation-induced inflammation and oxidative stress in the skin of hairless mice. J Nat Prod 78:1647–1655CrossRefPubMed
Martinon F, Pétrilli V, Mayor A et al (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237–241CrossRefPubMed
Meotti FC (2005) Analysis of the antinociceptive effect of the flavonoid myricitrin: evidence for a role of the l-arginine-nitric oxide and protein kinase C pathways. J Pharmacol Exp Ther 316:789–796CrossRefPubMed
Muthusamy VR, Kannan S, Sadhaasivam K et al (2012) Acute exercise stress activates Nrf2/ARE signaling and promotes antioxidant mechanisms in the myocardium. Free Radic Biol Med 52:366–376CrossRefPubMed
Neuschäfer-Rube F, Pathe-Neuschäfer-Rube A, Hippenstiel S et al (2013) NF-κB-dependent IL-8 induction by prostaglandin E2 receptors EP1 and EP4. Br J Pharmacol 168:704–717CrossRefPubMedPubMedCentral
Nishimura A, Akahoshi T, Takahashi M et al (1997) Attenuation of monosodium urate crystal-induced arthritis in rabbits by a neutralizing antibody against interleukin-8. J Leukoc Biol 62:444–449PubMed
Okamoto T (2005) Safety of quercetin for clinical application (review). Int J Mol Med 16:275–278PubMed
Pal A, Fontanilla D, Gopalakrishnan A et al (2012) The sigma-1 receptor protects against cellular oxidative stress and activates antioxidant response elements. Eur J Pharmacol 682:12–20CrossRefPubMedPubMedCentral
Pinho-Ribeiro FA, Hohmann MSNN, Borghi SM et al (2015) Protective effects of the flavonoid hesperidin methyl chalcone in inflammation and pain in mice: role of TRPV1, oxidative stress, cytokines and NF-κB. Chem Biol Interact 228:88–99CrossRefPubMed
Pinho-Ribeiro FA, Zarpelon AC, Fattori V et al (2016) Naringenin reduces inflammatory pain in mice. Neuropharmacology 105:508–519CrossRefPubMed
Rasool M, Varalakshmi P (2006) Suppressive effect of Withania somnifera root powder on experimental gouty arthritis: an in vivo and in vitro study. Chem Biol Interact 164:174–180CrossRefPubMed
Ribeiro KA, Chaves HV, Filho SMP et al (2016) Αlpha-2 adrenergic and opioids receptors participation in mice gastroprotection of Abelmoschus esculentus lectin. Curr Pharm Des 22:4736–4742CrossRefPubMed
Rosales MAB, Silva KC, Duarte DA et al (2014) Endocytosis of tight junctions caveolin nitrosylation dependent is improved by cocoa via opioid receptor on RPE cells in diabetic conditions. Investig Opthalmol Vis Sci 55:6090CrossRef
Rukdee N, Rojsanga P, Phechkrajang CM (2015) Development and validation of LC-MS/MS method for quantitative determination of adenosine, guanosine, xanthine and uric acid in widely consumed vegetables in Thailand. Nat Prod Commun 10:1435–1437PubMed
Sabina EP, Nagar S, Rasool M (2011) A role of piperine on monosodium urate crystal-induced inflammation—an experimental model of gouty arthritis. Inflammation 34:184–192CrossRefPubMed
Sazonova EN, Samarina EY, Lebed’ko OA et al (2016) Cytoprotective effect of peptide sedatin, an agonist of μ/δ-opioid receptors, on primary culture of pulmonary fibroblasts of albino rats under conditions of oxidative stress. Bull Exp Biol Med 161:41–44CrossRefPubMed
Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 25:192–205CrossRefPubMed
Souto FO, Zarpelon AC, Staurengo-Ferrari L et al (2011) Quercetin reduces neutrophil recruitment induced by CXCL8, LTB 4, and fMLP: inhibition of actin polymerization. J Nat Prod 74:113–118CrossRefPubMed
Staurengo-Ferrari L, Mizokami SS, Fattori V et al (2014) The ruthenium nitric oxide donor, [Ru(HEDTA)NO], inhibits acute nociception in mice by modulating oxidative stress, cytokine production and activating the cGMP/PKG/ATP-sensitive potassium channel signaling pathway. Naunyn Schmiedebergs Arch Pharmacol 387:1053–1068CrossRefPubMed
Sun GY, Chen Z, Jasmer KJ et al (2015a) Quercetin attenuates inflammatory responses in BV-2 microglial cells: role of MAPKs on the Nrf2 pathway and induction of heme oxygenase-1. PLoS One 10:e0141509CrossRefPubMedPubMedCentral
Sun X, Yamasaki M, Katsube T, Shiwaku K (2015b) Effects of quercetin derivatives from mulberry leaves: improved gene expression related hepatic lipid and glucose metabolism in short-term high-fat fed mice. Nutr Res Pract 9:137CrossRefPubMed
Sun G-W, Qiu Z-D, Wang W-N et al (2016) Flavonoids extraction from propolis attenuates pathological cardiac hypertrophy through PI3K/AKT signaling pathway. Evid Based Complement Altern Med 2016:1–11
Umamaheswari M, Asokkumar K, Sivashanmugam AT et al (2009) In vitro xanthine oxidase inhibitory activity of the fractions of Erythrina stricta Roxb. J Ethnopharmacol 124:646–648CrossRefPubMed
Valério DA, Georgetti SR, Magro DA et al (2009) Quercetin reduces inflammatory pain: inhibition of oxidative stress and cytokine production. J Nat Prod 72:1975–1979CrossRefPubMed
Verri WA, Cunha TM, Parada CA et al (2006) Hypernociceptive role of cytokines and chemokines: targets for analgesic drug development? Pharmacol Ther 112:116–138CrossRefPubMed
Verri WA, Guerrero ATG, Fukada SY et al (2008) IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice. Proc Natl Acad Sci USA 105:2723–2728CrossRefPubMedPubMedCentral
Verri WA, Souto FO, Vieira SM et al (2010) IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy. Ann Rheum Dis 69:1697–1703CrossRefPubMed
Verri WA, Vicentini FTMC, Baracat MM et al (2012) Flavonoids as anti-inflammatory and analgesic drugs: mechanisms of action and perspectives in the development of pharmaceutical forms. In: Rahman A (ed) Studies in natural products chemistry. Elsevier, Amsterdam, pp 297–330
Vicentini FTMC, He T, Shao Y et al (2011) Quercetin inhibits UV irradiation-induced inflammatory cytokine production in primary human keratinocytes by suppressing NFkB pathway. J Dermatol Sci 61:162–168CrossRefPubMed
Wang J, Barke RA, Charboneau R, Roy S (2005) Morphine impairs host innate immune response and increases susceptibility to Streptococcus pneumoniae lung infection. J Immunol 174:426–434CrossRefPubMed
Wang C, Pan Y, Zhang Q-Y et al (2012) Quercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasome activation and lipid accumulation. PLoS One 7:e38285CrossRefPubMedPubMedCentral
Wang J, Shanmugam A, Markand S et al (2015) Sigma 1 receptor regulates the oxidative stress response in primary retinal Müller glial cells via NRF2 signaling and system xc−, the Na+-independent glutamate–cystine exchanger. Free Radic Biol Med 86:25–36CrossRefPubMedPubMedCentral
Wu Z, Li L, Zheng L-T et al (2015) Allosteric modulation of sigma-1 receptors by SKF83959 inhibits microglia-mediated inflammation. J Neurochem 134:904–914CrossRefPubMed
Xu L, Liu S, Guan M, Xue Y (2016) Comparison of prednisolone, etoricoxib, and indomethacin in treatment of acute gouty arthritis: an open-label, randomized, controlled trial. Med Sci Monit 22:810–817CrossRefPubMedPubMedCentral
Yao P, Nussler A, Liu L et al (2007) Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways. J Hepatol 47:253–261CrossRefPubMed
Yin H, Cai H-Z, Wang S-K et al (2015) Wheat peptides reduce oxidative stress and inhibit NO production through modulating μ-opioid receptor in a rat NSAID-induced stomach damage model. Chin J Nat Med 13:22–29PubMed
Zarpelon AC, Cunha TMT, Alves-Filho JC et al (2013) IL-33/ST2 signalling contributes to carrageenin-induced innate inflammation and inflammatory pain: role of cytokines, endothelin-1 and prostaglandin E2. Br J Pharmacol 169:90–101CrossRefPubMedPubMedCentral
Zhang X, Zhang J-H, Chen X-Y et al (2015) Reactive oxygen species-induced TXNIP drives fructose-mediated hepatic inflammation and lipid accumulation through NLRP3 inflammasome activation. Antioxid Redox Signal 22:848–870CrossRefPubMedPubMedCentral
Zhao J, Huang Y (2015) Salivary uric acid as a noninvasive biomarker for monitoring the efficacy of urate-lowering therapy in a patient with chronic gouty arthropathy. Clin Chim Acta 450:115–120CrossRefPubMed
Zhou R, Tardivel A, Thorens B et al (2010) Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 11:136–140CrossRefPubMed
Zimmermann M (1983) Ethical guidelines for investigations of experimental pain in conscious animals. Pain 16:109–110CrossRefPubMed
Metadata
Title
Quercetin inhibits gout arthritis in mice: induction of an opioid-dependent regulation of inflammasome
Authors
Kenji W. Ruiz-Miyazawa
Larissa Staurengo-Ferrari
Sandra S. Mizokami
Talita P. Domiciano
Fabiana T. M. C. Vicentini
Doumit Camilios-Neto
Wander R. Pavanelli
Phileno Pinge-Filho
Flávio A. Amaral
Mauro M. Teixeira
Rubia Casagrande
Waldiceu A. Verri Jr.
Publication date
01-10-2017
Publisher
Springer International Publishing
Published in
Inflammopharmacology / Issue 5/2017
Print ISSN: 0925-4692
Electronic ISSN: 1568-5608
DOI
https://doi.org/10.1007/s10787-017-0356-x

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