The Sesquiterpene Lactone, Budlein A, Inhibits Antigen-Induced Arthritis in Mice: Role of NF-κB and Cytokines
- 384 Downloads
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by debilitating pain, cartilage destruction, and loss of joint function. Management of RA includes drugs that target NF-κB and downstream cytokine production. Therefore, molecules that act by inhibiting this signaling pathway without the severe side effects of, for instance, corticoids would be suitable therapeutic strategies. Budlein A is a sesquiterpene lactone with antinociceptive and anti-inflammatory properties related to the inhibition of pro-inflammatory cytokines and neutrophil recruitment. In this study, the effect of budlein A was evaluated in antigen-induced arthritis (AIA) in mice. At the 26th day, leukocyte recruitment to the knee joint, knee contents of proteoglycans, blood levels of ALT and AST, stomach tissue myeloperoxidase activity, and RT-qPCR for pro-inflammatory gene mRNA expression in knee joint samples was performed. NF-κB luciferase activity was evaluated in RAW 264.7 macrophages. Budlein A treatment dose-dependently inhibited AIA-induced mechanical hyperalgesia, edema, total leukocytes and neutrophil recruitment, and proteoglycan degradation. Budlein A did not induce gastric or liver damage. Budlein also inhibited AIA-induced Il-33, Tnf, Il-1β, preproET-1, and Cox-2 mRNA expression. In vitro, budlein reduced TNF- and IL-1β-induced NF-κB activity in RAW 264.7 macrophages. Altogether, we demonstrate that budlein A ameliorates AIA-induced inflammation and pain by targeting NF-κB. Importantly, budlein A does not induce in vivo side effects, suggesting that it possesses a favorable pre-clinical profile as analgesic and it is a prosperous molecule to be further investigated for the treatment of RA.
KEY WORDSantigen-induced arthritis articular pain experimental arthritis inflammation rheumatoid arthritis
Acknowledgment and Funding
This work was supported by grants from Departamentode Ciência e Tecnologia da Secretaria de Ciência, Tecnologia e Insumos Estratégicos, Ministério da Saúde (Decit/SCTIE/MS, Brazil) intermediated by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil) with support of Fundação Araucária and Secretaria Estadual de Saúde, Paraná (SESA-PR, Brazil); São Paulo Research Foundation under grant agreements 2011/19670-0 (Thematic Project) and 2013/08216-2 (Center for Research in Inflammatory Disease); Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil); and Financiadora de Estudos e Projetos and Secretaria de Estado da Ciência, Tecnologia e Ensino Superior do Paraná under grant agreements 01.12.0294.00 (0476/11) (FINEP/SETI-PR, Brazil). ACZ received CAPES/Fundação Araucária Post-Doc fellowship. TMC, FBC, FQC, RC, and WAVJ receive senior research fellowship from CNPq.
Compliance with Ethical Standards
All experiments were conducted in accordance with animal care and handling procedures of the International Association for Study of Pain (IASP) and with the approval Londrina State University Ethics Committee on Animal Research and Welfare (protocol number 14544.2013.46).
The authors declare that they have no competing interests.
- 5.M.S.N. Hohmann, D.T. Longhi-Balbinot, C.F.S. Guazelli, S.A. Navarro, A.C. Zarpelon, R. Casagrande, N.S. Arakawa, W.A. Verri Jr. 2016. Chapter 7 - Sesquiterpene Lactones: Structural Diversity and Perspectives as Anti-Inflammatory Molecules, in: R. Atta ur (Ed.) Studies in Natural Products Chemistry, Elsevier, pp. 243–264.Google Scholar
- 7.Valerio, D.A., T.M. Cunha, N.S. Arakawa, H.P. Lemos, F.B. Da Costa, C.A. Parada, S.H. Ferreira, F.Q. Cunha, and W.A. Verri Jr. 2007. Anti-inflammatory and analgesic effects of the sesquiterpene lactone budlein a in mice: Inhibition of cytokine production-dependent mechanism. European Journal of Pharmacology 562: 155–163.CrossRefPubMedGoogle Scholar
- 8.Nicolete, R., N.S. Arakawa, C. Rius, A. Nomizo, P.J. Jose, F.B. Da Costa, M.J. Sanz, and L.H. Faccioli. 2009. Budlein a from Viguiera Robusta inhibits leukocyte-endothelial cell interactions, adhesion molecule expression and inflammatory mediators release. Phytomedicine 16: 904–915.CrossRefPubMedGoogle Scholar
- 10.Arakawa, N.S., K. Schorr, S.R. Ambrosio, I. Merfort, and F.B. Da Costa. 2008. Further sesquiterpene lactones from Viguiera Robusta and the potential anti-inflammatory activity of a heliangolide: Inhibition of human neutrophil elastase release. Zeitschrift für Naturforschung. Section C 63: 533–538.Google Scholar
- 13.Zhao, Y., S.J. Chen, J.C. Wang, H.X. Niu, Q.Q. Jia, X.W. Chen, X.Y. Du, L. Lu, B. Huang, Q. Zhang, Y. Chen, and H.B. Long. 2015. Sesquiterpene lactones inhibit advanced oxidation protein product-induced MCP-1 expression in podocytes via an IKK/NF-kappaB-dependent mechanism. Oxidative Medicine and Cellular Longevity 2015: 934058.PubMedPubMedCentralGoogle Scholar
- 15.Da Costa F.B., Schorr K., Arakawa N.S., Schilling E.E., Spring O. 2001. Infraspecific Variation in the Chemistry of Glandular Trichomes of two Brazilian Viguiera Species (Heliantheae; Asteraceae). Journal of the Brazilian Chemical Society 12: 403–407Google Scholar
- 16.Verri, W.A., Jr., A.T. Guerrero, S.Y. Fukada, D.A. Valerio, T.M. Cunha, D. Xu, S.H. Ferreira, F.Y. Liew, and F.Q. Cunha. 2008. IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice. Proceedings of the National Academy of Sciences of the United States of America 105: 2723–2728.CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Guerrero, A.T., W.A. Verri Jr., T.M. Cunha, T.A. Silva, F.A. Rocha, S.H. Ferreira, F.Q. Cunha, and C.A. Parada. 2006. Hypernociception elicited by tibio-tarsal joint flexion in mice: A novel experimental arthritis model for pharmacological screening. Pharmacology, Biochemistry, and Behavior 84: 244–251.CrossRefPubMedGoogle Scholar
- 18.Ruiz-Miyazawa K.W., Staurengo-Ferrari L., Mizokami S.S., Domiciano T.P., Vicentini F., Camilios-Neto D., Pavanelli W.R., Pinge-Filho P., Amaral F.A., Teixeira M.M., Casagrande R., Verri W.A., Jr. 2017. Quercetin inhibits gout arthritis in mice: induction of an opioid-dependent regulation of inflammasome. Inflammopharmacology 1–16. doi: 10.1007/s10787-017-0356-x.
- 19.Verri, W.A., Jr., F.O. Souto, S.M. Vieira, S.C. Almeida, S.Y. Fukada, D. Xu, J.C. Alves-Filho, T.M. Cunha, A.T. Guerrero, R.B. Mattos-Guimaraes, F.R. Oliveira, M.M. Teixeira, J.S. Silva, I.B. McInnes, S.H. Ferreira, P. Louzada-Junior, F.Y. Liew, and F.Q. Cunha. 2010. IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy. Annals of the Rheumatic Diseases 69: 1697–1703.CrossRefPubMedGoogle Scholar
- 22.Verri, W.A., Jr., T.M. Cunha, C.A. Parada, X.Q. Wei, S.H. Ferreira, F.Y. Liew, and F.Q. Cunha. 2006. IL-15 mediates immune inflammatory hypernociception by triggering a sequential release of IFN-gamma, endothelin, and prostaglandin. Proceedings of the National Academy of Sciences of the United States of America 103: 9721–9725.CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Talbot, J., F.J. Bianchini, D.C. Nascimento, R.D. Oliveira, F.O. Souto, L.G. Pinto, R.S. Peres, J.R. Silva, S.C. Almeida, P. Louzada-Junior, T.M. Cunha, F.Q. Cunha, and J.C. Alves-Filho. 2015. CCR2 expression in neutrophils plays a critical role in their migration into the joints in rheumatoid arthritis. Arthritis & Rhematology 67: 1751–1759.CrossRefGoogle Scholar
- 25.Guerrero, A.T., W.A. Verri Jr., T.M. Cunha, T.A. Silva, I.R. Schivo, D. Dal-Secco, C. Canetti, F.A. Rocha, C.A. Parada, F.Q. Cunha, and S.H. Ferreira. 2008. Involvement of LTB4 in zymosan-induced joint nociception in mice: Participation of neutrophils and PGE2. Journal of Leukocyte Biology 83: 122–130.CrossRefPubMedGoogle Scholar
- 26.Sachs, D., F.Q. Cunha, and S.H. Ferreira. 2004. Peripheral analgesic blockade of hypernociception: Activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K+ channel pathway. Proceedings of the National Academy of Sciences of the United States of America 101: 3680–3685.CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Cunha, T.M., D. Roman-Campos, C.M. Lotufo, H.L. Duarte, G.R. Souza, W.A. Verri Jr., M.I. Funez, Q.M. Dias, I.R. Schivo, A.C. Domingues, D. Sachs, S. Chiavegatto, M.M. Teixeira, J.S. Hothersall, J.S. Cruz, F.Q. Cunha, and S.H. Ferreira. 2010. Morphine peripheral analgesia depends on activation of the PI3Kgamma/AKT/nNOS/NO/KATP signaling pathway. Proceedings of the National Academy of Sciences of the United States of America 107: 4442–4447.CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Zarpelon, A.C., F.C. Rodrigues, A.H. Lopes, G.R. Souza, T.T. Carvalho, L.G. Pinto, D. Xu, S.H. Ferreira, J.C. Alves-Filho, I.B. McInnes, B. Ryffel, V.F. Quesniaux, F. Reverchon, S. Mortaud, A. Menuet, F.Y. Liew, F.Q. Cunha, T.M. Cunha, and W.A. Verri Jr. 2016. Spinal cord oligodendrocyte-derived alarmin IL-33 mediates neuropathic pain. The FASEB Journal 30: 54–65.CrossRefPubMedGoogle Scholar
- 33.Zarpelon, A.C., T.M. Cunha, J.C. Alves-Filho, L.G. Pinto, S.H. Ferreira, I.B. McInnes, D. Xu, F.Y. Liew, F.Q. Cunha, and W.A. Verri Jr. 2013. IL-33/ST2 signalling contributes to carrageenin-induced innate inflammation and inflammatory pain: Role of cytokines, endothelin-1 and prostaglandin E2. British Journal of Pharmacology 169: 90–101.CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Siedle, B., A.J. Garcia-Pineres, R. Murillo, J. Schulte-Monting, V. Castro, P. Rungeler, C.A. Klaas, F.B. Da Costa, W. Kisiel, and I. Merfort. 2004. Quantitative structure-activity relationship of sesquiterpene lactones as inhibitors of the transcription factor NF-kappaB. Journal of Medicinal Chemistry 47: 6042–6054.CrossRefPubMedGoogle Scholar