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

Abstract

Background

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

Methods

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.

Results

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).

Conclusions

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.

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Funding

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).

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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.

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Correspondence to Waldiceu A. Verri Jr..

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Bussmann, A.J.C., Borghi, S.M., Zaninelli, T.H. et al. The citrus flavanone naringenin attenuates zymosan-induced mouse joint inflammation: induction of Nrf2 expression in recruited CD45+ hematopoietic cells. Inflammopharmacol 27, 1229–1242 (2019). https://doi.org/10.1007/s10787-018-00561-6

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Keywords

  • Naringenin
  • Arthritis
  • Zymosan
  • Pain
  • Inflammation
  • NFκB
  • Nrf2