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Pyrrolidine dithiocarbamate inhibits superoxide anion-induced pain and inflammation in the paw skin and spinal cord by targeting NF-κB and oxidative stress

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Abstract

We evaluated the effect of pyrrolidine dithiocarbamate (PDTC) in superoxide anion-induced inflammatory pain. Male Swiss mice were treated with PDTC and stimulated with an intraplantar or intraperitoneal injection of potassium superoxide, a superoxide anion donor. Subcutaneous PDTC treatment attenuated mechanical hyperalgesia, thermal hyperalgesia, paw oedema and leukocyte recruitment (neutrophils and macrophages). Intraplantar injection of superoxide anion activated NF-κB and increased cytokine production (IL-1β, TNF-α and IL-10) and oxidative stress (nitrite and lipid peroxidation levels) at the primary inflammatory foci and in the spinal cord (L4–L6). PDTC treatment inhibited superoxide anion-induced NF-κB activation, cytokine production and oxidative stress in the paw and spinal cord. Furthermore, intrathecal administration of PDTC successfully inhibited superoxide anion-induced mechanical hyperalgesia, thermal hyperalgesia and inflammatory response in peripheral foci (paw). These results suggest that peripheral stimulus with superoxide anion activates the local and spinal cord oxidative- and NF-κB-dependent inflammatory nociceptive mechanisms. PDTC targets these events, therefore, inhibiting superoxide anion-induced inflammatory pain in mice.

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Acknowledgments

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), São Paulo Research Foundation (FAPESP) under grant agreements number 2011/19670-0 (Thematic project) and 2013/08216-2 (Center for Research in Inflammatory Disease-CRID), Coordenação 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 Parana State Government grants supported this study (Brazil). A.C.Z. received a post-doc fellowship from CAPES/Fundação Araucária, S.M.B. received a post-doc fellowship from CAPES, and L.S.F. received a post-doc fellowship from CNPq. It is noteworthy to mention that this manuscript has been read and approved by all the authors, which contributed substantially to the work.

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  1. Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR445 KM380, 86057-970, Londrina, Paraná, Brazil

    Felipe A. Pinho-Ribeiro, Victor Fattori, Ana C. Zarpelon, Sergio M. Borghi, Larissa Staurengo-Ferrari, Thacyana T. Carvalho, Jose C. Alves-Filho, Fernando Q. Cunha & Waldiceu A. Verri Jr.

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

    Thiago M. Cunha

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

    Rubia Casagrande

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  1. Felipe A. Pinho-Ribeiro
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  2. Victor Fattori
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  11. Waldiceu A. Verri Jr.
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Pinho-Ribeiro, F.A., Fattori, V., Zarpelon, A.C. et al. Pyrrolidine dithiocarbamate inhibits superoxide anion-induced pain and inflammation in the paw skin and spinal cord by targeting NF-κB and oxidative stress. Inflammopharmacol 24, 97–107 (2016). https://doi.org/10.1007/s10787-016-0266-3

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