Skip to main content
Log in

Curcumin Attenuates CFA Induced Thermal Hyperalgesia by Modulation of Antioxidant Enzymes and Down Regulation of TNF-α, IL-1β and IL-6

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Reactive oxygen species are signaling mediators of nociceptive pathways. Exogenous administrations of antioxidants show anti-hyperalgesic effect. However, very little is known about the role of endogenous antioxidant defense system in pain pathology. Curcumin is a dietary antioxidant which shows ameliorative effect on thermal hypersensitivity, however detailed study is lacking. Present study was aimed to analyze the changes in oxidative stress, modulation of antioxidant enzymes and pro-inflammatory cytokines in complete Freund’s adjuvant induced inflammatory hyperalgesia and the effect of curcumin on antioxidant defense system and pro-inflammatory cytokines. Anti-hyperalgesic activity of curcumin was evidenced after 6 h of treatment. Oxidative stress was evidenced in paw skin and spinal cord of hyperalgesic rats by high level of lipid peroxidation. A decrease in activity of antioxidant enzymes like catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and an increase in level of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in paw skin was observed as compared to normal rats. However, activity of antioxidant enzymes was enhanced in spinal cord. The changes were brought towards normal level after curcumin treatment. The results suggest that modulation of antioxidant defense system is early event in initiation of inflammatory hyperalgesia which might lead to initiation of other signaling pathways mediated by lipid peroxide, TNF-α, IL-1β and IL-6. Decrease in oxidative stress and down regulation of these cytokines by curcumin is suggested to be involved in its anti-hyperalgesic effect.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Kim HK, Park SK, Zhou JL, Taglialatela G, Chung K, Coggeshall RE et al (2004) Reactive oxygen species (ROS) play an important role in a rat model of neuropathic pain. Pain 111:116–124

    Article  CAS  PubMed  Google Scholar 

  2. Lee KimHK, Kim JH, Chung K, Chung JM (2007) The role of reactive oxygen species in capsaicin-induced mechanical hyperalgesia and in the activities of dorsal horn neurons. Pain 133:9–17

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Schwartz ES, Lee I, Chung K, Chung JM (2008) Oxidative stress in the spinal cord is an important contributor in capsaicin-induced mechanical secondary hyperalgesia in mice. Pain 138:514–524

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Jenner P (1994) Oxidative damage in neurodegenerative disease. Lancet 344:796–798

    Article  CAS  PubMed  Google Scholar 

  5. Tal M (1996) A novel antioxidant alleviates heat hyperalgesia in rats with an experimental painful peripheral neuropathy. NeuroReport 7:1382–1384

    Article  CAS  PubMed  Google Scholar 

  6. Wang ZQ, Porreca F, Cuzzocrea S, Galen K, Lightfoot R, Masini E et al (2004) A newly identified role for superoxide in inflammatory pain. J Pharmacol Exp Ther 309:869–878

    Article  CAS  PubMed  Google Scholar 

  7. Kohli K, Ali J, Ansari MJ, Raheman Z (2005) Curcumin: a natural anti-inflammatory agent. Indian J Pharmacol 37:141–147

    Article  CAS  Google Scholar 

  8. Yeon KY, Kim SA, Kim YH, Lee MK, Ahn DK, Kim HJ et al (2010) Curcumin produces an antihyperalgesic effect via antagonism of TRPV1. J Dent Res 89(2):170–174

    Article  CAS  PubMed  Google Scholar 

  9. Kunchandy E, Rao MNA (1990) Oxygen radical scavenging activity of curcumin. Int Pharm 58:237–240

    Article  CAS  Google Scholar 

  10. Sharma S, Kulkarni SK, Agrewala JN, Chopra K (2006) Curcumin attenuates thermal hyperalgesia in a diabetic mouse model of neuropathic pain. Eur J Pharmacol 536:256–261

    Article  CAS  PubMed  Google Scholar 

  11. Khattab MM (2006) TEMPOL, a membrane permeable radical scavenger, attenuates peroxynitrite and superoxide anion enhanced carrageenan induced paw edema and hyperalgesia: a key role for superoxide anion. Eur J Pharmacol 548:167–173

    Article  CAS  PubMed  Google Scholar 

  12. Salvemini D, Wang ZQ, Zweier JL, Samouilov A, Macarthur H, Misko TP et al (1999) A nonpeptidyl mimic of superoxide dismutase with therapeutic activity in rats. Science 286:304–306

    Article  CAS  PubMed  Google Scholar 

  13. Keeble JE, Bodkin JV, Liang L (2009) Hydrogen peroxide is a novel mediator of inflammatory hyperalgesia, acting via transient receptor potential vanilloid 1-dependent and independent mechanisms. Pain 141:135–142

    Article  CAS  PubMed  Google Scholar 

  14. Mittal N, Joshi R, Hota D, Chakrabarti A (2009) Evaluation of antihyperalgesic effect of curcumin on formalin-induced orofacial pain in rat. Phytother Res 23:507–512

    Article  CAS  PubMed  Google Scholar 

  15. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  CAS  PubMed  Google Scholar 

  16. Sharma R, Vinayak M (2011) α-Tocopherol attenuates NF-κB activation and pro-inflammatory cytokine secretion in cancer-bearing mice. Biosci Rep 31:421–428

    Article  PubMed  Google Scholar 

  17. Aebi H (1974) catalase. In: Bergmeyer HU (ed) Methods in enzymatic analysis, 2nd edn. Academic Press, New York, pp 673–678

    Chapter  Google Scholar 

  18. Winterbourne CC, Hawkins RE, Brian M, Carrell RW (1975) The estimation of red cell superoxide dismutase activity. J Lab Clin Med 85:337–341

    Google Scholar 

  19. Pagalia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70:158–169

    Google Scholar 

  20. Ho YS, Magnenat JL, Bronson RT, Cao J, Gargano M, Sugawara M et al (1997) Mice deficient in cellular glutathione peroxidase develop normally and show no increased sensitivity to hyperoxia. J Biol Chem 272(26):16644–16651

    Article  CAS  PubMed  Google Scholar 

  21. Horn HD (1965) Glutathione reductase. In: Bergmeyer H (ed) Methods of enzyme analysis. Academic Press, New York, pp 875–879

    Chapter  Google Scholar 

  22. Ren K, Dubner R (1999) Inflammatory models of pain and hyperalgesia. ILAR J 40(3):111–118

    Article  PubMed  Google Scholar 

  23. Billiau A, Matthys P (2001) Modes of action of Freund’s adjuvants in experimental models of autoimmune diseases. J Leukoc Biol 70:849–860

    CAS  PubMed  Google Scholar 

  24. Salvemini D, Little JW, Doyle T, Neumann WL (2011) Roles of reactive oxygen and nitrogen species in pain. Free Radic Biol Med 51(951–966):4

    Google Scholar 

  25. Bowie A, O’Neill LA (2000) Oxidative stress and nuclear factor-kappaB activation: a reassessment of the evidence in the light of recent discoveries. Biochem Pharmacol 59(1):13–23

    Article  CAS  PubMed  Google Scholar 

  26. Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413:203–210

    Article  CAS  PubMed  Google Scholar 

  27. Varija D, Kumar KP, Reddy KP, Reddy VK (2008) Prolonged constriction of sciatic nerve affecting oxidative stressors and antioxidant enzymes in rat. Indian J Med Res 129(587–592):7

    Google Scholar 

  28. Guedes RP, Bosco LD, Teixeira CM, Araújo ASR, Llesuy S, Belló-Klein A et al (2006) Neuropathic pain modifies antioxidant activity in rat spinal cord. Neurochem Res 31:603–609

    Article  CAS  PubMed  Google Scholar 

  29. Stefanson AL, Bakovic M (2014) Dietary regulation of Keap1/Nrf2/ARE pathway: focus on plant-derived compounds and trace minerals. Nutrients 6:3777–3801

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R et al (2003) Curcumin activates the haemoxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J 371:887–895

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Singh S, Aggarwal BB (1995) Activation of transcription factor NF-kB is suppressed by curcumin (diferulolylmethane). J Biol Chem 270(20):24995–25000

    Article  CAS  PubMed  Google Scholar 

  32. Viggiano A, Monda M, Viggiano A, Viggiano D, Viggiano E, Chiefari M et al (2005) Trigeminal pain transmission requires reactive oxygen species production. Brain Res 1050:72–78

    Article  CAS  PubMed  Google Scholar 

  33. Chen Y, Boettger MK, Reif A, Schmitt A, Üçeyler N, Sommer C (2010) Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice. Mol Pain 6:13

    Article  PubMed Central  PubMed  Google Scholar 

  34. Matata BM, Galinanes M (2002) Peroxynitrite is an essential component of cytokine production mechanism in human monocytes through modulation of nuclear factor-kappa B DNA binding activity. J Biol Chem 277:2330–2335

    Article  CAS  PubMed  Google Scholar 

  35. Das L, Vinayak M (2014) Curcumin attenuates carcinogenesis by down regulating proinflammatory cytokine interleukin-1 (IL-1α and IL-1β) via modulation of AP-1 and NF-IL6 in lymphoma bearing mice. Int Immunopharmacol 20:141–147

    Article  CAS  PubMed  Google Scholar 

  36. Sancho P, Martín-Sanz P, Fabregat I (2011) Reciprocal regulation of NADPH oxidases and the cyclooxygenase-2 pathway. Free Radic Biol Med 51:1789–1798

    Article  CAS  PubMed  Google Scholar 

  37. Watkins LR, Milligan ED, Maier SF (2001) Glial activation: a driving force for pathological pain. Trends Neurosci 24:450–455

    Article  CAS  PubMed  Google Scholar 

  38. Rittner HL, Machelska H, Stein C (2005) Leuckocyte in the regulation of pain and analgesia. J Leukoc Biol 78:1215–1222

    Article  CAS  PubMed  Google Scholar 

  39. Hensellek S, Brell P, Schaible HG, Bräuer R, von Bancheta GS (2007) The cytokine TNFα increases the proportion of DRG neurons expressing the TRPV1 receptor via the TNFR1 receptor and ERK activation. Mol Cell Neurosci 36:381–391

    Article  CAS  PubMed  Google Scholar 

  40. Ji RR, Befort K, Brenner GJ, Woolf CJ (2002) ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity. J Neurosci 22(2):478–485

    CAS  PubMed  Google Scholar 

  41. Puntambekar P, Mukharjea D, Jajoo S, Ramkumar V (2005) Essential role of Rac1/NADPH oxidase in nerve growth factor induction of TRPV1 expression. J Neurochem 95(6):1689–1703

    Article  CAS  PubMed  Google Scholar 

  42. Cunha FQ, Ferrreria SH (2003) Peripheral hyperalgesic cytokines. Adv Exp Med Biol 521:22–39

    CAS  PubMed  Google Scholar 

  43. Colston JT, Chandrasekar B, Freeman GL (2002) A novel peroxide-induced calcium transient regulates interleukin-6 expression in cardiac-derived fibroblasts. J Biol Chem 277:23477–23483

    Article  CAS  PubMed  Google Scholar 

  44. Sredni-Kenigsbuch D, Kambayashi T, Strassmann G (2000) Neutrophils augment the release of TNF alpha from LPS-stimulated macrophages via hydrogen peroxide. Immunol Lett 71:97–102

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Authors are thankful to DRDO, India for financial support (Grant No. ERIP/ER/1003851/M/01/1336). A.K.S. thanks UGC, India for JRF & SRF.

Conflict of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Manjula Vinayak.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Singh, A.K., Vinayak, M. Curcumin Attenuates CFA Induced Thermal Hyperalgesia by Modulation of Antioxidant Enzymes and Down Regulation of TNF-α, IL-1β and IL-6. Neurochem Res 40, 463–472 (2015). https://doi.org/10.1007/s11064-014-1489-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-014-1489-6

Keywords

Navigation