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Probucol attenuates overt pain-like behavior and carrageenan-induced inflammatory hyperalgesia and leukocyte recruitment by inhibiting NF-кB activation and cytokine production without antioxidant effects

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Abstract

Objective and design

This study aimed to evaluate the effect of probucol in inflammatory hyperalgesia and leukocyte recruitment in mice.

Treatment

Probucol at 0.3–3 mg/kg was administrated per oral 1 h before inflammatory stimulus.Author: Kindly check and confirm the affiliation 1 have been correctly processed or not and amend if necessary.Thank you. We have corrected affiliation 1. We added the information to the appropriate boxes. However the state and the postal code are in a different order when compared to the other affiliations.

Methods

Overt pain-like behaviors were determined by the number of abdominal writhings induced by phenyl-p-benzoquinone and acetic acid. Mechanical and thermal hyperalgesia induced by carrageenan were determined using an electronic anesthesiometer and hot plate apparatus, respectively. Leukocyte recruitment was evaluated by direct count or by determination of myeloperoxidase and N-acetylglucosaminidase activities. Antioxidant ability was determined by measurement of GSH levels, ABTS and FRAP assays. Cytokine production and NF-кB activation were evaluated by ELISA. Data were analyzed by ANOVA followed by Tukey’s post-hoc. p < 0.05 was considered significant.

Results

Probucol reduced overt pain-like behavior, and carrageenan-induced mechanical and thermal hyperalgesia. These effects were accompanied by reduced leukocyte influx in both paw skin and peritoneum exudate. Probucol did not alter carrageenan-induced tissue antioxidant capacity at anti-inflammatory/analgesic dose. On the other hand, probucol inhibited carrageenan-induced IL-1β, TNF-α and CXCL1 production as well as NF-кB activation.

Conclusion

Probucol presents analgesic and anti-inflammatory activities by employing mechanisms other than its antioxidant properties. These mechanisms involve targeting of pro-inflammatory cytokines and NF-кB activation.

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Acknowledgements

The authors would like to thank the methodological support of Sandra S. Mizokami, the technical support of Giuliana Bertozi Francisco and the financial support of Conselho Nacional do Desenvolvimento Científico e Tecnológico (CNPq), Coordenação do Aperfeiçoamento de Pessoal de Nível Superior (CAPES), São Paulo Research Foundation under Grant agreements No. 2011/19670-0 (Thematic project) and 2013/08216-2 (Center for Research in Inflammatory Disease), Ministério da Ciência, Tecnologia e Inovação (MCTI), Secretaria da Ciência, Tecnologia e Inovação (SETI), Fundação Araucária and Parana State Government.

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Authors and Affiliations

  1. Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Caixa Postal 10.011, Rod. Celso Garcia Cid PR445 km 480, Londrina, Paraná, CEP 86057-970, Brazil

    Amanda Z. Zucoloto, Marília F. Manchope, Larrisa Staurengo-Ferrari & Waldiceu A. Verri Jr.

  2. Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, CEP 14049-900, Brazil

    José C. Alves-Filho, Thiago M. Cunha & Fernando Q. Cunha

  3. Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Presidente Antonio Carlos 6627, Belo Horizonte, Minas Gerais, CEP 31270-901, Brazil

    Maísa M. Antunes & Gustavo B. Menezes

  4. Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Estadual de Londrina, Av. Robert Koch, 60, Londrina, Paraná, CEP 86038-350, Brazil

    Rubia Casagrande

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  1. Amanda Z. Zucoloto
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  2. Marília F. Manchope
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Zucoloto, A.Z., Manchope, M.F., Staurengo-Ferrari, L. et al. Probucol attenuates overt pain-like behavior and carrageenan-induced inflammatory hyperalgesia and leukocyte recruitment by inhibiting NF-кB activation and cytokine production without antioxidant effects. Inflamm. Res. 66, 591–602 (2017). https://doi.org/10.1007/s00011-017-1040-8

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