The citrus flavanone naringenin attenuates zymosan-induced mouse joint inflammation: induction of Nrf2 expression in recruited CD45+ hematopoietic cells

  • Allan J. C. Bussmann
  • Sergio M. Borghi
  • Tiago H. Zaninelli
  • Telma S. dos Santos
  • Carla F. S. Guazelli
  • Victor Fattori
  • Talita P. Domiciano
  • Felipe A. Pinho-Ribeiro
  • Kenji W. Ruiz-Miyazawa
  • Antonio M. B. Casella
  • Josiane A. Vignoli
  • Doumit Camilios-Neto
  • Rubia Casagrande
  • Waldiceu A. VerriJr.Email author
Original Article



Naringenin is a biologically active analgesic, anti-inflammatory, and antioxidant flavonoid. Naringenin targets in inflammation-induced articular pain remain poorly explored.


The present study investigated the cellular and molecular mechanisms involved in the analgesic/anti-inflammatory effects of naringenin in zymosan-induced arthritis. Mice were pre-treated orally with naringenin (16.7–150 mg/kg), followed by intra-articular injection of zymosan. Articular mechanical hyperalgesia and oedema, leucocyte recruitment to synovial cavity, histopathology, expression/production of pro- and anti-inflammatory mediators and NFκB activation, inflammasome component expression, and oxidative stress were evaluated.


Naringenin inhibited articular pain and oedema in a dose-dependent manner. The dose of 50 mg/kg inhibited leucocyte recruitment, histopathological alterations, NFκB activation, and NFκB-dependent pro-inflammatory cytokines (TNF-α, IL-1β, and IL-33), and preproET-1 mRNA expression, but increased anti-inflammatory IL-10. Naringenin also inhibited inflammasome upregulation (reduced Nlrp3, ASC, caspase-1, and pro-IL-1β mRNA expression) and oxidative stress (reduced gp91phox mRNA expression and superoxide anion production, increased GSH levels, induced Nrf2 protein in CD45+ hematopoietic recruited cells, and induced Nrf2 and HO-1 mRNA expression).


Naringenin presents analgesic and anti-inflammatory effects in zymosan-induced arthritis by targeting its main physiopathological mechanisms. These data highlight this flavonoid as an interesting therapeutic compound to treat joint inflammation, deserving additional pre-clinical and clinical studies.


Naringenin Arthritis Zymosan Pain Inflammation NFκB Nrf2 


Authors contributions

RC and WAV Jr designed the study. AJCB, SMB, THZ, TSS, CFSG, VF, TPD, FAP-R, and KWR-M conducted the experiments. AMBC, JAV, DC-N, RC, and WAV Jr contributed with reagents, analytical tools, interpretation of data, and intellectual support for the study. AJCB, SMB, THZ, TSS, CFSG, VF, TPD, FAP-R, and KWR-M performed data analysis. SMB, RC, and WAV Jr wrote the paper. All authors read and approved the final version of the manuscript.


This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenacão de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Ministério da Ciência Tecnologia e Inovação (MCTI), Secretaria da Ciência, Tecnologia e Ensino Superior (SETI), Fundação Araucária, and Paraná State Government, Brazil. Sergio M. Borghi received a postdoctoral fellowship from CAPES and CNPq (152792/2016-3). The authors also thank the support of Central Multiusuário de Laboratórios de Pesquisa da Universidade Estadual de Londrina (CMLP-UEL).

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Allan J. C. Bussmann
    • 1
  • Sergio M. Borghi
    • 1
  • Tiago H. Zaninelli
    • 1
  • Telma S. dos Santos
    • 1
  • Carla F. S. Guazelli
    • 1
  • Victor Fattori
    • 1
  • Talita P. Domiciano
    • 1
  • Felipe A. Pinho-Ribeiro
    • 1
  • Kenji W. Ruiz-Miyazawa
    • 1
  • Antonio M. B. Casella
    • 2
  • Josiane A. Vignoli
    • 3
  • Doumit Camilios-Neto
    • 3
  • Rubia Casagrande
    • 4
  • Waldiceu A. VerriJr.
    • 1
    Email author
  1. 1.Department of PathologyBiological Science Center, Londrina State UniversityLondrinaBrazil
  2. 2.Department of Clinical Medicine, Health Science CenterLondrina State University, University HospitalLondrinaBrazil
  3. 3.Department of Biochemistry and Biotechnology, Exact Sciences CenterLondrina State UniversityLondrinaBrazil
  4. 4.Department of Pharmaceutical Sciences, Health Science CenterLondrina State University, University HospitalLondrinaBrazil

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