Skip to main content

Advertisement

SpringerLink
Log in

Artesunate Ameliorates Functional Limitations in Freund’s Complete Adjuvant-Induced Monoarthritis in Rat by Maintaining Oxidative Homeostasis and Inhibiting COX-2 Expression

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Drugs exhibiting anti-inflammatory and analgesic properties have been clinically used in the management of pain and impairment of joint functions in arthritis. In view of available studies on the beneficial effect of artesunate in various inflammatory conditions, the present study was carried out to evaluate its efficacy in ameliorating functional limitations of arthritis and to understand the underlying mechanisms. The study was carried out in rat model of Freund’s complete adjuvant-induced monoarthritis where artesunate was found to produce a dose-dependent reduction in joint inflammation, improvement in functional parameters like stair climbing ability, motility, and suppression of mechanical allodynia at the doses of 50 and 150 mg/kg. Our study shows that protection afforded by artesunate was brought about by decreasing the levels of nitric oxide, influx of neutrophils, maintenance of oxidative homeostasis, inhibition of COX-2 expression, and apoptosis. Further, histological analysis of the arthritic joints also substantiated the anti-inflammatory property of artesunate. Thus, our study shows that artesunate has a potential for use in the treatment of arthritis.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Gabriel, S.E. 2010. Heart disease and rheumatoid arthritis: understanding the risks. Ann Rheum Dis 69: i61–i64.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Wong, J.B., D.R. Ramey, and G. Singh. 2001. Long-term morbidity, mortality, and economics of rheumatoid arthritis. Arthritis Rheum 44: 2746–2749.

    Article  CAS  PubMed  Google Scholar 

  3. Kunkel, S.L., N. Lukacs, T. Kasama, and R.M. Strieter. 1996. The role of chemokines in inflammatory joint disease. J Leukoc Biol 59: 6–12.

    CAS  PubMed  Google Scholar 

  4. Hootman, J.M., and C.G. Helmick. 2006. Projections of US prevalence of arthritis and associated activity limitations. Arthritis Rheum 54: 226–229.

    Article  PubMed  Google Scholar 

  5. Crofford, L.J. 2013. Use of NSAIDs in treating patients with arthritis. Arthritis Res Ther 15: S2.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Vane, J.R., and R.M. Botting. 1997. Mechanism of action of aspirin-like drugs. Semin Arthritis Rheum 26: 2–10.

    Article  CAS  PubMed  Google Scholar 

  7. Salliot, C., A. Finckh, W. Katchamart, Y. Lu, Y. Sun, C. Bombardier, and E. Keystone. 2011. Indirect comparisons of the efficacy of biological antirheumatic agents in rheumatoid arthritis in patients with an inadequate response to conventional disease-modifying antirheumatic drugs or to an anti-tumour necrosis factor agent: a meta-analysis. Ann Rheum Dis 70: 266–271.

    Article  CAS  PubMed  Google Scholar 

  8. Watson, D.J., J.A. Bolognese, C. Yu, D. Krupa, and S. Curtis. 2004. Use of gastroprotective agents and discontinuations due to dyspepsia with the selective cyclooxygenase-2 inhibitor etoricoxib compared with non-selective NSAIDs. Curr Med Res Opin 20: 1899–1908.

    Article  CAS  PubMed  Google Scholar 

  9. Graziose, R., M.A. Lila, and I. Raskin. 2010. Merging traditional Chinese medicine with modern drug discovery technologies to find novel drugs and functional food. Curr Drug Discov Technol 7: 2–12.

  10. Jin, O., H. Zhang, Z. Gu, S. Zhao, T. Xu, K. Zhou, B. Jiang, J. Wang, X. Zeng, and L. Sun. 2009. A pilot study of the therapeutic efficacy and mechanism of artesunate in the MRL/lpr murine model of systemic lupus erythematosus. Cell Mol Immunol 6: 461–467.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Li, B., R. Zhang, J. Li, L. Zhang, G. Ding, P. Luo, S. He, Y. Dong, W. Jiang, Y. Lu, H. Cao, J. Zhang, and H. Zhou. 2008. Antimalarial artesunate protects sepsis model mice against heat-killed Escherichia coli challenge by decreasing TLR4, TLR9 mRNA expressions and transcription factor NF-kappa B activation. Int Immunopharmacol 8: 379–389.

  12. Li, B., J. Li, X. Pan, G. Ding, H. Cao, W. Jiang, J. Zheng, and H. Zhou. 2010. Artesunate protects sepsis model mice challenged with Staphylococcus aureus by decreasing TNF- alpha release via inhibition of TLR2 and Nod2 mRNA expressions and transcription factor NF-kappaB activation. Int Immunopharmacol 10: 344–350.

    Article  CAS  PubMed  Google Scholar 

  13. He, Y., J. Fan, H. Lin, X. Yang, Y. Ye, L. Liang, Z. Zhan, X. Dong, L. Sun, and H. Xu. 2011. The anti-malaria agent artesunate inhibits expression of vascular endothelial growth factor and hypoxia-inducible factor-1α in human rheumatoid arthritis fibroblast-like synoviocyte. Rheumatol Int 31: 53–60.

    Article  CAS  PubMed  Google Scholar 

  14. Li, Y., S. Wang, Y. Wang, C. Zhou, G. Chen, W. Shen, C. Li, W. Lin, S. Lin, H. Huang, P. Liu, and X. Shen. 2013. Inhibitory effect of the antimalarial agent artesunate on collagen-induced arthritis in rats through nuclear factor kappa B and mitogen-activated protein kinase signaling pathway. Transl Res 161: 89–98.

    Article  CAS  PubMed  Google Scholar 

  15. Kumar, V.L., B. Guruprasad, and P. Chaudhary. 2014. Antimalarial drug artesunate affords protection against carrageenan induced acute inflammation in rat. Biocell (in press).

  16. Lam, F.F., and E.S. Ng. 2010. Substance P and glutamate receptor antagonists improve the anti-arthritic actions of dexamethasone in rats. Br J Pharmacol 159: 958–969.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Kumar, V.L., P. Chaudhary, R.M. Oliveira, and M.V. Ramos. 2014. Calotropis procera latex proteins ameliorate functional limitations associated with adjuvant induced inflammation in rat. Musculoskelet Biol 1: 1.

    Article  Google Scholar 

  18. De Castro Costa, M., P. De Sutter, J. Gybels, and J. Van Hees. 1981. Adjuvant-induced arthritis in rats: a possible animal model of chronic pain. Pain 10: 173–185.

    Article  PubMed  Google Scholar 

  19. Butler, S.H., F. Godefroy, J.M. Besson, and J. Weil-Fugazza. 1992. A limited arthritic model for chronic pain studies in the rat. Pain 48: 73–81.

    Article  CAS  PubMed  Google Scholar 

  20. Wahane, V.D., and V.L. Kumar. 2010. Atorvastatin ameliorates inflammatory hyperalgesia in rat model of monoarticular arthritis. Pharmacol Res 61: 329–333.

    Article  CAS  PubMed  Google Scholar 

  21. Wang, Y., C. Huang, Y. Cao, and J.S. Han. 2000. Repeated administration of low dose ketamine for the treatment of monoarthritic pain in the rat. Life Sci 67: 261–267.

    Article  CAS  PubMed  Google Scholar 

  22. Bradley, P.P., D.A. Preibat, R.D. Christensen, and G. Rothstein. 1982. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 78: 206–209.

  23. Feng, Q., X. Lu, D.L. Jones, J. Shen, and J.M. Arnold. 2001. Increased inducible nitric oxide synthase expression contributes to myocardial dysfunction and higher mortality after myocardial infarction in mice. Circulation 104: 700–704.

    Article  CAS  PubMed  Google Scholar 

  24. Ellman, G.L. 1959. Tissue sulfhydryl groups. Arch Biochem Biophys 82: 70–77.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. Lin, N., C. Liu, C. Xiao, H. Jia, K. Imada, H. Wu, and A. Ito. 2007. Triptolide, diterpenoid triepoxide, suppresses inflammation and cartilage destruction in collagen-induced arthritis mice. Biochem Pharmacol 73: 136–146.

    Article  CAS  PubMed  Google Scholar 

  27. de Grauw, J.C., C.H.A. van de Lest, and P.R. van Weeren. 2009. Inflammatory mediators and cartilage biomarkers in synovial fluid after a single inflammatory insult: a longitudinal experimental study. Arthritis Res Ther 11: R35.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Kroon, J., S. Tol, S. van Amstel, J.A. Elias, and M. Fernandez- Borja. 2013. The small GTPase RhoB regulates TNFα signaling in endothelial cells. PLoS One 8: e75031.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Leung, L., and C.M. Cahill. 2010. TNF-alpha and neuropathic pain-a review. J Neuroinflammation 7: 27.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Nakao, S., Y. Ogtata, E. Shimizu, M. Yamazaki, S. Furuyama, and H. Sugiya. 2002. Tumor necrosis factor alpha (TNF-alpha)-induced prostaglandin E2 release is mediated by the activation of cyclooxygenase-2 (COX-2) transcription via NFkappaB in human gingival fibroblasts. Mol Cell Biochem 238: 11–18.

    Article  CAS  PubMed  Google Scholar 

  31. Dubois, R.N., S.B. Abramson, L. Crofford, R.A. Gupta, L.S. Simon, L.B. Van De Putte, and P.E. Lipsky. 1998. Cyclooxygenase in biology and disease. FASEB J 12: 1063–1073.

    CAS  PubMed  Google Scholar 

  32. Telleria-Diaz, A., M. Schmidt, S. Kreusch, A.K. Neubert, F. Schache, E. Vazquez, H. Vanegas, H.G. Schaible, and A. Ebersberger. 2010. Spinal antinociceptive effects of cyclooxygenase inhibition during inflammation: Involvement of prostaglandins and endocannabinoids. Pain 148: 26–35.

    Article  CAS  PubMed  Google Scholar 

  33. Ben-Baruch, A., D.F. Michiel, and J.J. Oppenheim. 1995. Signals and receptors involved in recruitment of inflammatory cells. J Biol Chem 270: 11703–11706.

    Article  CAS  PubMed  Google Scholar 

  34. Lemos, H.P., R. Grespan, S.M. Vieira, T.M. Cunha, W.A. Verri Jr., K.S. Fernandes, F.O. Souto, I.B. McInnes, S.H. Ferreira, F.Y. Liew, and F.Q. Cunha. 2009. Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNgamma production. Proc Natl Acad Sci U S A 106: 5954–5959.

  35. Ziskoven, C., M. Jäger, J. Kircher, T. Patzer, W. Bloch, K. Brixius, and R. Krauspe. 2011. Physiology and pathophysiology of nitrosative and oxidative stress in osteoarthritic joint destruction. Can J Physiol Pharmacol 89: 455–466.

    Article  CAS  PubMed  Google Scholar 

  36. Hitchon, C.A., and H.S. El-Gabalawy. 2004. Oxidation in rheumatoid arthritis. Arthritis Res Ther 6: 265–278.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Kannan, K., and S.K. Jain. 2000. Oxidative stress and apoptosis. Pathophysiology 7: 153–163.

    Article  CAS  PubMed  Google Scholar 

  38. Moncada, S., and A. Higgs. 1993. The L-arginine-nitric oxide pathway. N Engl J Med 329: 2002–2012.

    Article  CAS  PubMed  Google Scholar 

  39. Salvemini, D., S.L. Settle, J.L. Masferrer, K. Seibert, M.G. Currie, and P. Needleman. 1995. Regulation of prostaglandin production by nitric oxide; an in vivo analysis. Br J Pharmacol 114: 1171–1178.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Ersoy, Y., E. Ozerol, O. Baysal, I. Temel, R.S. MacWalter, U. Meral, and Z.E. Altay. 2002. Serum nitrate and nitrite levels in patients with rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. Ann Rheum Dis 61: 76–78.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Yang, Y.H., P. Hutchinson, L.L. Santos, and E.F. Morand. 1998. Glucocorticoid inhibition of adjuvant arthritis synovial macrophage nitric oxide production: role of lipocortin 1. Clin Exp Immunol 111: 117–122.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Wright, H.L., R.J. Moots, R.C. Bucknall, and S.W. Edwards. 2010. Neutrophil function in inflammation and inflammatory diseases. Rheumatology 49: 1618–1631.

    Article  CAS  PubMed  Google Scholar 

  43. Adán, N., J. Guzmán-Morales, M.G. Ledesma-Colunga, S.I. Perales-Canales, A. Quintanar-Stéphano, F. López-Barrera, I. Mendez, B. Moreno-Carranza, J. Triebel, N. Binart, G. Martinez de la Escalera, S. Thebault, and C. Clapp. 2013. Prolactin promotes cartilage survival and attenuates inflammation in inflammatory arthritis. J Clin Invest 123: 3902–3913.

Download references

Acknowledgements

This work was funded by a research grant from All India Institute of Medical Sciences, New Delhi, India (A-059).

Conflict of Interest

The authors declare that there is no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pharmacology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India

    B. Guruprasad, Priyanka Chaudhary & Vijay L. Kumar

  2. Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, 110067, India

    Tenzin Choedon

Authors
  1. B. Guruprasad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Priyanka Chaudhary
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tenzin Choedon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vijay L. Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vijay L. Kumar.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guruprasad, B., Chaudhary, P., Choedon, T. et al. Artesunate Ameliorates Functional Limitations in Freund’s Complete Adjuvant-Induced Monoarthritis in Rat by Maintaining Oxidative Homeostasis and Inhibiting COX-2 Expression. Inflammation 38, 1028–1035 (2015). https://doi.org/10.1007/s10753-014-0067-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-014-0067-z

KEY WORDS

Search

Navigation