Abstract
The effect of the lipid-lowering agent probucol in inflammatory hyperalgesia and leukocyte recruitment was evaluated in a model of subacute inflammation by Complete Freund’s adjuvant (CFA). As CFA induces long-lasting nociception characterized by peripheral and spinal cord inflammation, the anti-inflammatory activity of probucol was assessed at both foci. Probucol at 0.3–3 mg/kg was administrated per oral daily starting 24 h after CFA intraplantar injection. Mechanical and thermal hyperalgesia induced by CFA were determined using an electronic anesthesiometer and hot plate apparatus, respectively. Post-treatment with probucol at 3 mg/kg inhibited CFA-induced hyperalgesia over the course of 7 days as well as paw edema. Overt pain-like behaviors, which were determined by the number of flinches and time spent licking paw immediately following CFA injection, were also reduced by probucol at 3 mg/kg administered as a pre-treatment. To investigate the mechanisms underlying the analgesic effect of probucol, neutrophil recruitment to paw was assessed by myeloperoxidase activity, cytokine production, Cox-2 expression, and NF-κB activation in both paw and spinal cord by ELISA. Iba-1, GFAP, and substance P protein expression and nuclear localization of phosphorylated NF-κB were evaluated in the spinal cord by immunofluorescence. Probucol at 3 mg/kg attenuated neutrophil recruitment, cytokine levels, and NF-κB activation as well microglia and astrocyte activation, and substance P staining in the spinal cord. Taken together, the results suggest that probucol exerts its analgesic and anti-inflammatory activity in an experimental model of persistent inflammation by targeting the NF-κB pathway in peripheral and spinal cord foci.
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The authors would like to thank the technical support of Maria Rosana F. de Paula.
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Conselho Nacional do Desenvolvimento Científico e Tecnológico (CNPq), Coordenação do Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Programa de Apoio a Grupos de Excelência (PRONEX) grant supported by SETI/Araucária Foundation, MCTI/CNPq, and Parana State Government (agreement 014/2017, protocol 46.843).
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Zucoloto, A.Z., Manchope, M.F., Borghi, S.M. et al. Probucol Ameliorates Complete Freund’s Adjuvant-Induced Hyperalgesia by Targeting Peripheral and Spinal Cord Inflammation. Inflammation 42, 1474–1490 (2019). https://doi.org/10.1007/s10753-019-01011-3
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DOI: https://doi.org/10.1007/s10753-019-01011-3