, Volume 38, Issue 3, pp 1028–1035 | Cite as

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

  • B. Guruprasad
  • Priyanka Chaudhary
  • Tenzin Choedon
  • Vijay L. KumarEmail author


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.


artesunate arthritis COX-2 expression inflammatory hyperalgesia oxidative homeostasis 



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.


  1. 1.
    Gabriel, S.E. 2010. Heart disease and rheumatoid arthritis: understanding the risks. Ann Rheum Dis 69: i61–i64.CrossRefPubMedCentralPubMedGoogle Scholar
  2. 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.CrossRefPubMedGoogle Scholar
  3. 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.PubMedGoogle Scholar
  4. 4.
    Hootman, J.M., and C.G. Helmick. 2006. Projections of US prevalence of arthritis and associated activity limitations. Arthritis Rheum 54: 226–229.CrossRefPubMedGoogle Scholar
  5. 5.
    Crofford, L.J. 2013. Use of NSAIDs in treating patients with arthritis. Arthritis Res Ther 15: S2.CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Vane, J.R., and R.M. Botting. 1997. Mechanism of action of aspirin-like drugs. Semin Arthritis Rheum 26: 2–10.CrossRefPubMedGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefPubMedGoogle Scholar
  9. 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.Google Scholar
  10. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  11. 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.Google Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 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).Google Scholar
  16. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 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.CrossRefGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 20.
    Wahane, V.D., and V.L. Kumar. 2010. Atorvastatin ameliorates inflammatory hyperalgesia in rat model of monoarticular arthritis. Pharmacol Res 61: 329–333.CrossRefPubMedGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 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.Google Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 24.
    Ellman, G.L. 1959. Tissue sulfhydryl groups. Arch Biochem Biophys 82: 70–77.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  28. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Leung, L., and C.M. Cahill. 2010. TNF-alpha and neuropathic pain-a review. J Neuroinflammation 7: 27.CrossRefPubMedCentralPubMedGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 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.PubMedGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 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.CrossRefPubMedGoogle Scholar
  34. 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.Google Scholar
  35. 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.CrossRefPubMedGoogle Scholar
  36. 36.
    Hitchon, C.A., and H.S. El-Gabalawy. 2004. Oxidation in rheumatoid arthritis. Arthritis Res Ther 6: 265–278.CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Kannan, K., and S.K. Jain. 2000. Oxidative stress and apoptosis. Pathophysiology 7: 153–163.CrossRefPubMedGoogle Scholar
  38. 38.
    Moncada, S., and A. Higgs. 1993. The L-arginine-nitric oxide pathway. N Engl J Med 329: 2002–2012.CrossRefPubMedGoogle Scholar
  39. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  40. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  41. 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.CrossRefPubMedCentralPubMedGoogle Scholar
  42. 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.CrossRefPubMedGoogle Scholar
  43. 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.Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • B. Guruprasad
    • 1
  • Priyanka Chaudhary
    • 1
  • Tenzin Choedon
    • 2
  • Vijay L. Kumar
    • 1
    Email author
  1. 1.Department of PharmacologyAll India Institute of Medical SciencesNew DelhiIndia
  2. 2.Virology Group, International Centre for Genetic Engineering and BiotechnologyNew DelhiIndia

Personalised recommendations