Advertisement

Inflammation Research

, Volume 66, Issue 7, pp 591–602 | Cite as

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

  • Amanda Z. Zucoloto
  • Marília F. Manchope
  • Larrisa Staurengo-Ferrari
  • José C. Alves-Filho
  • Thiago M. Cunha
  • Maísa M. Antunes
  • Gustavo B. Menezes
  • Fernando Q. Cunha
  • Rubia Casagrande
  • Waldiceu A. VerriJr.Email author
Original Research Paper

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.

Keywords

Probucol Carrageenan Pain Acute inflammation 

Notes

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.

References

  1. 1.
    Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454:428–35.CrossRefPubMedGoogle Scholar
  2. 2.
    Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, et al. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature. 2001;410:471–5.CrossRefPubMedGoogle Scholar
  3. 3.
    Jin X, Gereau RW IV. Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-a. J Neurosci. 2006;26:246–55.CrossRefPubMedGoogle Scholar
  4. 4.
    Binshtok A, Wang H, Zimmermann K. Nociceptors are interleukin-1ßsensors. J Neurosci. 2008;28:14062–73.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Talbot S, Foster SL, Woolf CJ. Neuroimmune physiology and pathology. Annu Rev Immunol. 2016;34.Google Scholar
  6. 6.
    Hudmon A, Choi JS, Tyrrell L, Black JA, Rush AM, Waxman SG, et al. Phosphorylation of sodium channel Na(v)1.8 by p38 mitogen-activated protein kinase increases current density in dorsal root ganglion neurons. J Neurosci. 2008;28:3190–201.CrossRefPubMedGoogle Scholar
  7. 7.
    Verri WA Jr, Cunha TM, Parada CA, Poole S, Cunha FQ, Ferreira SH. Hypernociceptive role of cytokines and chemokines: targets for analgesic drug development? Pharmacol Ther. 2006;112:116–38.CrossRefPubMedGoogle Scholar
  8. 8.
    Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440:228–32.CrossRefPubMedGoogle Scholar
  9. 9.
    Zarpelon AC, Rodrigues FC, Lopes AH, Souza GR, Carvalho TT, Pinto LG, et al. Spinal cord oligodendrocyte-derived alarmin IL-33 mediates neuropathic pain. FASEB J. 2016;30:54–65.CrossRefPubMedGoogle Scholar
  10. 10.
    Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001;1:135–45.CrossRefPubMedGoogle Scholar
  11. 11.
    Anrather J, Racchumi G, Iadecola C. NF-κB regulates phagocytic NADPH oxidase by inducing the expression of gp91phox. J Biol Chem. 2006;281:5657–67.CrossRefPubMedGoogle Scholar
  12. 12.
    Ghosh S, Hayden MS. New regulators of NF-kB in inflammation. Nat Rev Immunol. 2008;8:837–48.CrossRefPubMedGoogle Scholar
  13. 13.
    Hattori H, Subramanian KK, Sakai J, Jia Y, Li Y, Porter TF, et al. Small-molecule screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis. PNAS. 2010;107:3546–51.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Maioli NA, Zarpelon AC, Mizokami SS, Calixto-Campos C, Guazelli CFS, Hohmann MSN, et al. The superoxide anion donor, potassium superoxide, induces pain and inflammation in mice through production of reactive oxygen species and cyclooxygenase-2. Braz J Med Biol Res. 2015;48:321–31.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Süleyman H, Demircan B, Karagöz Y. Anti-inflammatory and side effects of cyclooxygenase inhibitors. Pharmacol Rep. 2007;59:247–58.PubMedGoogle Scholar
  16. 16.
    Manson SC, Brown RE, Cerulli A, Vidaurre CF. The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use. Respir Med Elsevier Ltd. 2009;103:975–94.CrossRefGoogle Scholar
  17. 17.
    Mizokami SS, Arakawa NS, Ambrosio SR, Zarpelon AC, Casagrande R, Cunha TM, et al. Kaurenoic acid from Sphagneticola trilobata inhibits inflammatory pain: effect on cytokine production and activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway. J Nat Prod. 2012;75:896–904.CrossRefPubMedGoogle Scholar
  18. 18.
    Fattori V, Pinho-Ribeiro FA, Borghi SM, Alves-Filho JC, Cunha TM, Cunha FQ, et al. Curcumin inhibits superoxide anion-induced pain-like behavior and leukocyte recruitment by increasing Nrf2 expression and reducing NF-kB activation. Inflamm Res. 2015;64:993–1003.CrossRefPubMedGoogle Scholar
  19. 19.
    Manchope MF, Calixto-Campos C, Coelho-Silva L, Zarpelon AC, Pinho-Ribeiro FA, Georgetti SR, et al. Naringenin inhibits superoxide anion-induced inflammatory pain: role of oxidative stress, cytokines, Nrf-2 and the NO–cGMP–PKG–KATPChannel signaling pathway. PLoS One. 2016;11:1–20.CrossRefGoogle Scholar
  20. 20.
    Ruiz-Miyazawa KW, Zarpelon AC, Pinho-Ribeiro FA, Pavão-De-Souza GF, Casagrande R, Verri WA Jr. Vinpocetine reduces carrageenan-induced inflammatory hyperalgesia in mice by inhibiting oxidative stress, cytokine production and NF-κB activation in the paw and spinal cord. PLoS One. 2015;10:1–18.CrossRefGoogle Scholar
  21. 21.
    Ruiz-Miyazawa KW, Pinho-Ribeiro FA, Zarpelon AC, Staurengo-Ferrari L, Silva RL, Alves-Filho JC, et al. Vinpocetine reduces lipopolysaccharide-induced inflammatory pain and neutrophil recruitment in mice by targeting oxidative stress, cytokines and NF-κB. Chem Biol Interact Elsevier Irel Ltd. 2015;237:9–17.CrossRefGoogle Scholar
  22. 22.
    Navarro SA, Serafim KGG, Mizokami SS, Hohmann MSN, Casagrande R, Verri WA Jr. Analgesic activity of piracetam: effect on cytokine production and oxidative stress. Pharmacol Biochem Behav. 2013;105:183–92.CrossRefPubMedGoogle Scholar
  23. 23.
    Bridges AB, Scott NA, Belch JJF. Probucol, a superoxide free radical scavenger in vitro. Atherosclerosis. 1991;89:263–5.CrossRefPubMedGoogle Scholar
  24. 24.
    Siveski-Iliskovic N, Kaul N, Singal PK. Probucol promotes endogenous antioxidants and provides protection against adriamycin-induced cardiomyopathy in rats. Circulation. 1994;89:2829–35.CrossRefPubMedGoogle Scholar
  25. 25.
    Al-Majed AA. Probucol attenuates oxidative stress, energy starvation, and nitric acid production following transient forebrain ischemia in the rat hippocampus. Oxid Med Cell Longev. 2011;2011:1–8.CrossRefGoogle Scholar
  26. 26.
    Colle D, Santos DB, Moreira ELG, Hartwig JM, dos Santos AA, Zimmermann LT, et al. Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats. PLoS One. 2013;8:1–15.CrossRefGoogle Scholar
  27. 27.
    Zhang X, Li Z, Liu D, Xu X, Shen W, Mei Z. Effects of probucol on hepatic tumor necrosis factor-alpha, interleukin-6 and adiponectin receptor-2 expression in diabetic rats. J Gastroenterol Hepatol. 2009;24:1058–63.CrossRefPubMedGoogle Scholar
  28. 28.
    Ku G, Doherty NS, Schmidt LF, Jackson R, Dinerstein RJ. Ex vivo lipopolysaccharide-induced interleukin-1 secretion inhibited agent from murine peritoneal macrophages by probucol, a hypocholesterolemic agent with antioxidant properties. FASEB J. 1990;4:1645–53.PubMedGoogle Scholar
  29. 29.
    Ferns GAA, Forster L, Stewart-Lee A, Nourooz-Zadeh J, Anggard EE. Probucol inhibits mononuclear cell adhesion to vascular endothelium in the cholesterol-fed rabbit. Atherosclerosis. 1993;100:171–81.CrossRefPubMedGoogle Scholar
  30. 30.
    Meng CQ, Somers PK, Hoong LK, Zheng XS, Ye Z, Worsencroft KJ, et al. Discovery of novel phenolic antioxidants as inhibitors of vascular cell adhesion molecule-1 expression for use in chronic inflammatory diseases. J Med Chem. 2004;47:6420–32.CrossRefPubMedGoogle Scholar
  31. 31.
    Kaneko M, Hayashi J, Saito I, Miyasaka N. Probucol downregulates E-selectin expression on cultured human vascular endothelial cells. Arterioscler Thromb Vasc Biol. 1996;16:1047–51.CrossRefPubMedGoogle Scholar
  32. 32.
    Zapolska-Downar D, Zapolski-Downar A, Markiewski M, Ciechanowicz A, Kaczmarczyk M, Naruszewicz M. Selective inhibition by alpha-tocopherol of vascular cell adhesion molecule-1 expression in human vascular endothelial cells. Biochem Biophys Res Commun. 2000;155:609–15.CrossRefGoogle Scholar
  33. 33.
    Zanardo RC, Cruz JWM., Martinez LL, de Oliveira MA, Fortes ZB. Probucol restores the defective leukocyte–endothelial interaction in experimental diabetes. Eur J Pharmacol. 2003;478:211–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Fu H, Li G, Liu C, Li J, Wang X, Cheng L, et al. Probucol prevents atrial remodeling by inhibiting oxidative stress and TNFa/NF-kB/TGF-b signal transduction pathway in alloxan-induced diabetic rabbits. J Cardiovasc Electrophysiol. 2015;26:211–22.CrossRefPubMedGoogle Scholar
  35. 35.
    Park SY, Lee JH, Kim CD, Rhim BY, Hong KW, Lee WS. Beneficial synergistic effects of concurrent treatment with cilostazol and probucol against focal cerebral ischemic injury in rats. Brain Res. 2007;1157:112–20.CrossRefPubMedGoogle Scholar
  36. 36.
    Niimi M, Keyamura Y, Nozako M, Koyama T, Kohashi M, Yasufuku R, et al. Probucol inhibits the initiation of atherosclerosis in cholesterol-fed rabbits. Lipids Health Dis. 2013;12:1–8.CrossRefGoogle Scholar
  37. 37.
    Li S, Liang J, Niimi M, Bilal Waqar A, Kang D, Koike T, et al. Probucol suppresses macrophage infiltration and MMP expression in atherosclerotic plaques of WHHL rabbits. J Atheroscler Thromb. 2014;21:648–58.CrossRefPubMedGoogle Scholar
  38. 38.
    Li T, Chen W, An F, Tian H, Zhang J, Peng J, et al. Probucol attenuates inflammation and increases stability of vulnerable atherosclerotic plaques in rabbits. Tohoku J Exp Med. 2011;225:23–34.CrossRefPubMedGoogle Scholar
  39. 39.
    Pinho-Ribeiro FA, Zarpelon AC, Fattori V, Manchope MF, Mizokami SS, Casagrande R, et al. Naringenin reduces inflammatory pain in mice. Neuropharmacology Elsevier Ltd. 2016;105:508–19.CrossRefGoogle Scholar
  40. 40.
    Mizokami SS, Hohmann MSN, Staurengo-Ferrari L, Carvalho TT, Zarpelon AC, Possebon MI, et al. Pimaradienoic acid inhibits carrageenan-induced inflammatory leukocyte recruitment and edema in mice: inhibition of oxidative stress, nitric oxide and cytokine production. PLoS One. 2016;11:1–17.Google Scholar
  41. 41.
    Verri WA Jr, Cunha TM, Magro DA, Domingues AC, Vieira SM, Souza GR, et al. Role of IL-18 in overt pain-like behaviour in mice. Eur J Pharmacol. 2008;588:207–12.CrossRefPubMedGoogle Scholar
  42. 42.
    Cunha TM, Verri WA Jr, Vivancos GG, Moreira IF, Reis S, Parada CA, et al. An electronic pressure-meter nociception paw test for rats. Braz J Med Biol Res. 2004;37:401–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Bradley P, Christensen D. Cellular and extracellular myeloperoxidade in pyogenic inflammation. Blood. 2016;60:618–23.Google Scholar
  44. 44.
    Barcelos LS, Talvani A, Teixira AS, Vieira LQ, Cassali GD, Andrade SP, et al. Impaired inflammatory angiogenesis, but not leukocyte influx, in mice lacking TNFR1. J Leukoc Biol. 2005;78:352–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Cunha TM, Verri WA Jr, Silva JS, Poole S, Cunha FQ, Ferreira SH. A cascade of cytokines mediates mechanical inflammatory hypernociception in mice. Proc Natl Acad Sci USA. 2005;102:1755–60.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Cunha TM, Verri WA Jr, Schivo IR, Napimoga MH, Parada C a, Poole S, et al. Crucial role of neutrophils in the development of mechanical inflammatory hypernociception. J Leukoc Biol. 2008;83:824–32.CrossRefPubMedGoogle Scholar
  47. 47.
    Kim MJ, Lee SY, Yang KY, Nam SH, Kim HJ, Kim YJ, et al. Differential regulation of peripheral IL-1β-induced mechanical allodynia and thermal hyperalgesia in rats. Pain Int Assoc Study Pain. 2014;155:723–32.Google Scholar
  48. 48.
    Calabrese E. The emergence of the dose–response concept in biology and medicine. Int J Mol Sci. 2016;17:2034.CrossRefPubMedCentralGoogle Scholar
  49. 49.
    Lutfy K, Cowan A. Buprenorphine: a unique drug with complex pharmacology. Curr Neuropharmacol. 2004;2:395–402.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Santos ARS, Vedana EMA, De Freitas GAG. Antinociceptive effect of meloxicam, in neurogenic and inflammatory nociceptive models in mice. Inflamm Res. 1998;47:302–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Pinho-Ribeiro FA, Zarpelon AC, Mizokami SS, Borghi SM, Bordignon J, Silva RL, et al. The citrus flavonone naringenin reduces lipopolysaccharide-induced inflammatory pain and leukocyte recruitment by inhibiting NF-κB activation. J Nutr Biochem. 2016;33:8–14. doi: 10.1016/j.jnutbio.2016.03.013. ([Internet] Elsevier B.V.).CrossRefPubMedGoogle Scholar
  52. 52.
    Zarpelon AC, Cunha TM, Alves-Filho JC, Pinto LG, Ferreira SH, McInnes IB, et al. IL-33/ST2 signalling contributes to carrageenin-induced innate inflammation and inflammatory pain: role of cytokines, endothelin-1 and prostaglandin E 2. Br J Pharmacol. 2013;169:90–101.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Akeson AL, Woods CW, Mosher LB, Thomas CE, Jackson RL. Inhibition of IL-1b expression in THP-1 cells by probucol and tocopherol. Atherosclerosis. 1991;86:261–70.CrossRefPubMedGoogle Scholar
  54. 54.
    Ku G, Doherty NS, Wolos JA, Schmidt LF, Hendricks D, Jackson RL. Inhibition by probucol of interleukin 1 secretion and its implication in atherosclerosis. Am J Cardiol. 1988;62:77B–81B.CrossRefPubMedGoogle Scholar
  55. 55.
    Liu G-X, Ou D-M, Liu J-H, Huang H-L, Liao D-F. Probucol inhibits lipid peroxidation of macrophage and affects its secretory properties. Act Pharmacol Sin. 2000;21:637–40.Google Scholar
  56. 56.
    Oliveira SHP, Canetti C, Ribeiro RA, Cunha FQ. Neutrophil migration induced by IL-1b depends upon LTB4 released by macrophages and upon TNF-a and IL-1b released by mast cells. Inflammation. 2008;31:36–46.CrossRefPubMedGoogle Scholar
  57. 57.
    Wyble CW, Hynes KL, Kuchibhotla J, Marcus BC, Hallahan D, Gewertz BL. TNF-alpha and IL-1 upregulate membrane-bound and soluble E-selectin through a common pathway. J Surg Res. 1997;73:107–12.CrossRefPubMedGoogle Scholar
  58. 58.
    Kawabata A. Prostaglandin E2 and pain—an update. Biol Pharm Bull. 2011;34:1170–3.CrossRefPubMedGoogle Scholar
  59. 59.
    Ozaki M, Yamada Y, Matoba K, Otani H, Mune M, Yukawa S, et al. Phospholipase A 2 activity in ox-LDL-stimulated mesangial cells and modulation by a -tocopherol. Kidney Int. 1999;56:171–3.CrossRefGoogle Scholar
  60. 60.
    Tanaka K, Hayashi K, Shingu T, Kuga Y, Nomura K, Kajiyama G. Probucol inhibits neointimal formation in carotid arteries of normocholesterolemic rabbits and the proliferation of cultured rabbit vascular smooth muscle cells. Cardiovasc Drugs Ther. 1998;12:19–28.CrossRefPubMedGoogle Scholar
  61. 61.
    Ranganathan PV, Jayakumar C, Mohamed R, Dong Z, Ramesh G. Netrin-1 regulates the inflammatory response of neutrophils and macrophages, and suppresses ischemic acute kidney injury by inhibiting COX-2 mediated PGE2 productioness. Kidney Int. 2013;83:1087–98.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Dieterich LC, Huang H, Massena S, Golenhofen N, Phillipson M, Dimberg A. ab-crystallin/HspB5 regulates endothelial-leukocyte interactions by enhancing NF-bB-induced up-regulation of adhesion molecules ICAM-1, VCAM-1 and E-selectin. Angiogenesis. 2013;16:975–83.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Chang WC, Chen CH, Lee MF, Chang T, Yu YM. Chlorogenic acid attenuates adhesion molecules upregulation in IL-1b-treated endothelial cells. Eur J Nutr. 2010;49:267–75.CrossRefPubMedGoogle Scholar
  64. 64.
    Chen J-W, Chen Y-H, Lin F-Y, Chen Y-L, Lin S-J. Ginkgo biloba extract inhibits tumor necrosis factor-α-induced reactive oxygen species generation, transcription factor activation, and cell adhesion molecule expression in human aortic endothelial cells. Arter Thromb Vasc Biol. 2003;23:1559–66.CrossRefGoogle Scholar
  65. 65.
    Zhang M, Wang J, Liu JH, Chen SJ, Zhen B, Wang CH, et al. Effects of probucol on angiotensin II-induced BMP-2 expression in human umbilical vein endothelial cells. Mol Med Rep. 2013;7:177–82.PubMedGoogle Scholar
  66. 66.
    Aoki M, Nata T, Morishita R, Matsushita H, Nakagami H, Yamamoto K, et al. Endothelial apoptosis induced by oxidative stress through activation of NF-κB: antiapoptotic effect of antioxidant agents on endothelial cells. Hypertension. 2001;38:48–55.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  • Amanda Z. Zucoloto
    • 1
  • Marília F. Manchope
    • 1
  • Larrisa Staurengo-Ferrari
    • 1
  • José C. Alves-Filho
    • 2
  • Thiago M. Cunha
    • 2
  • Maísa M. Antunes
    • 3
  • Gustavo B. Menezes
    • 3
  • Fernando Q. Cunha
    • 2
  • Rubia Casagrande
    • 4
  • Waldiceu A. VerriJr.
    • 1
    Email author
  1. 1.Departamento de Ciências Patológicas, Centro de Ciências BiológicasUniversidade Estadual de LondrinaLondrinaBrazil
  2. 2.Department of Pharmacology, Ribeirão Preto Medical SchoolUniversity of São PauloRibeirão PretoBrazil
  3. 3.Departamento de Morfologia, Instituto de Ciências BiológicasUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  4. 4.Departamento de Ciências Farmacêuticas, Centro de Ciências da SaúdeUniversidade Estadual de LondrinaLondrinaBrazil

Personalised recommendations