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Inflammation

, Volume 40, Issue 6, pp 2020–2032 | Cite as

The Sesquiterpene Lactone, Budlein A, Inhibits Antigen-Induced Arthritis in Mice: Role of NF-κB and Cytokines

  • Ana C. Zarpelon
  • Victor Fattori
  • Fabricio O. Souto
  • Larissa G. Pinto
  • Felipe A. Pinho-Ribeiro
  • Kenji W. Ruiz-Miyazawa
  • Walter M. Turato
  • Thiago M. Cunha
  • Fernando B. da Costa
  • Fernando Q. Cunha
  • Rubia Casagrande
  • Nilton S. Arakawa
  • Waldiceu A. VerriJrEmail author
ORIGINAL ARTICLE

Abstract

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 WORDS

antigen-induced arthritis articular pain experimental arthritis inflammation rheumatoid arthritis 

Notes

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).

Competing Interests

The authors declare that they have no competing interests.

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Ana C. Zarpelon
    • 1
  • Victor Fattori
    • 1
  • Fabricio O. Souto
    • 2
  • Larissa G. Pinto
    • 2
  • Felipe A. Pinho-Ribeiro
    • 1
  • Kenji W. Ruiz-Miyazawa
    • 1
  • Walter M. Turato
    • 2
  • Thiago M. Cunha
    • 2
  • Fernando B. da Costa
    • 3
  • Fernando Q. Cunha
    • 2
  • Rubia Casagrande
    • 4
  • Nilton S. Arakawa
    • 4
  • Waldiceu A. VerriJr
    • 1
    • 5
    Email author
  1. 1.Departamento de Ciências Patológicas, Centro de Ciências BiológicasUniversidade Estadual de LondrinaLondrinaBrazil
  2. 2.Department of Pharmacology, Ribeirão Preto Medical School, PretoUniversity of São PauloRibeirão PretoBrazil
  3. 3.Department of Pharmaceutical SciencesUniversity of São PauloRibeirão PretoBrazil
  4. 4.Departamento de Ciências Farmacêuticas, Centro de Ciências da SaúdeUniversidade Estadual de LondrinaLondrinaBrazil
  5. 5.Departamento de Patologia, Centro de Ciências BiologicasUniversidade Estadual de LondrinaLondrinaBrazil

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