Inflammation Research

, Volume 68, Issue 2, pp 147–155 | Cite as

Intravenous anesthetic ketamine attenuates complete Freund’s adjuvant-induced arthritis in rats via modulation of MAPKs/NF-κB

  • Hui Lin
  • Zhe Wang
  • Jinmei Shen
  • Junmei Xu
  • Hui LiEmail author
Original Research Paper



The current study was intended to investigate the effect of ketamine (KET) on complete Freund’s adjuvant (CFA)-induced arthritis in rats.


The CFA was administered in the hind paw of the rats for the induction of adjuvant-induced arthritis. The paw swelling of experimental animals was measured as hind paw volume. Hematoxylin and eosin staining was estimated and pathological changes in the joint tissues were observed under a light microscope. Furthermore, the bicinchoninic acid assay was used for protein quantification. The antibody-reactive bands were visualized using enhanced chemiluminescence.


The present study showed that KET significantly reduces the severity of arthritis in CFA mice. The therapeutic effects were linked with reduced joint swelling and destruction, as evidenced by analyzing rat paws. The KET also revealed to attenuate the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). In western blot analysis, KET inhibit phosphorylation of MAPKs, IκBα and nuclear translocation NF-κB in the inflammatory joints of AIA rats. Moreover, KET showed to induce apoptosis via mitochondrial signalling pathways (Bcl2, Bax, cytochrome C, cleaved caspase-3 and cleaved caapse-9).


Taken together, KET show significant anti-rheumatoid arthritis activity via multiple mechanisms and may thus have therapeutic benefits for RA.


Arthritis Inflammation Pro-inflammatory cytokines IκBα NF-κB 



Authors wished to thanks authorities of Hunan Provincial Natural Science Foundation (2017JJ3445); Hunan science and technology project (2015SK2085); Natural Science Foundation of China (81500658), Hunan Provincial Natural Science Foundation (2014JJ3040).

Author contributions

HL conceived and designed the study, ZW performed the animal experiment, JS collected, and analyzed the data. JX performed the literature research and statistical analysis. HL prepared the paper and revised the manuscript accordingly. All authors have read and agreed with the final version of this manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no competing interests associated with the manuscript.


  1. 1.
    Ogrendik M. Rheumatoid arthritis is an autoimmune disease caused by periodontal pathogens. Int J Gen Med. 2013;6:383–6. Scholar
  2. 2.
    Valesini G, Gerardi MC, Iannuccelli C, Pacucci VA, Pendolino M, Shoenfeld Y. Citrullination and autoimmunity. Autoimmun Rev. 2015;14(6):490–7. Scholar
  3. 3.
    Torpy JM, Perazza GD. Golub RM JAMA patient page. Rheumatoid arthritis. JAMA. 2011;305:1824. Scholar
  4. 4.
    Kim J-M, Kim H-Y. Pathogenesis of rheumatoid arthritis. J Korean Med Assoc. 2010;53(10):853–61. Scholar
  5. 5.
    Langley PC, Mu R, Wu M, Dong P, Tang B. The impact of rheumatoid arthritis on the burden of disease in urban China. J Med Econ. 2011;14:709–19. Scholar
  6. 6.
    Xu C, Wang X, Mu R, Yang L, Zhang Y, Han S, Li X, Wang Y, Wang G, Zhu P, Jin H, Sun L, Chen H, Cui L, Zhang Z, Li Z, Li J, Zhang F, Lin J, Liu X, Hu S, Yang X, Lai B, Li X, Wang X, Su Y, Li Z. Societal costs of rheumatoid arthritis in China: a hospital-based cross-sectional study. Arthritis Care Res. 2014;66:523–31. Scholar
  7. 7.
    Martin L. Clinical. Rheumatoid arthritis: symptoms, diagnosis, and management. Nurs Times. 2004;100:40–4. Scholar
  8. 8.
    Charles P, Elliott MJ, Davis D, Potter A, Kalden JR, Antoni C, Breedveld FC, Smolen JS, Eberl G, deWoody K, Feldmann M, Maini R. Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-a therapy in rheumatoid arthritis 1. J Immunol. 1999;163:1521–8.
  9. 9.
    Furst DE, Emery P. Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets. Rheumatol (United Kingdom). 2014;53(9):1560–9. Scholar
  10. 10.
    Kumar P, Banik S. Pharmacotherapy options in rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord. 2013;6:35–43. Scholar
  11. 11.
    Quan L, Thiele GM, Tian J, Wang D. The development of novel therapies for rheumatoid arthritis. Expert Opin Ther Pat. 2008;18:723–38. Scholar
  12. 12.
    Hanna AF, Abraham B, Hanna A, McKenna M, Smith AJ. Intravenous ketamine alleviates pain in a rheumatoid arthritis patient with comorbid fibromyalgia. J Med Cases. 2018;9(5):142–4. Scholar
  13. 13.
    Lu W, Wang L, Wo C, Yao J. Ketamine attenuates osteoarthritis of the knee via modulation of inflammatory responses in a rabbit model. Mol Med Rep. 2016;13:5013–20. Scholar
  14. 14.
    Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2014;77:357–67. Scholar
  15. 15.
    Chang X, He H, Zhu L, Gao J, Wei T, Ma Z, Yan T. Protective effect of apigenin on Freund’s complete adjuvant-induced arthritis in rats via inhibiting P2 × 7/NF-κB pathway. Chem Biol Interact. 2015;236:41–6. Scholar
  16. 16.
    Coelho M, Reis P, Gava V, Marques P, Gayer C, Laranja G, et al. Anti-arthritic effect and subacute toxicological evaluation of Baccharis genistelloides aqueous extract. Toxicol Lett. 2004;154:69–80. Scholar
  17. 17.
    Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018;6:15. Scholar
  18. 18.
    Fischer BD, Adeyemo A, O’Leary ME, Bottaro A. Animal models of rheumatoid pain: experimental systems and insights. Arthritis Res Ther. 2017;19(1):146. Scholar
  19. 19.
    Zhang L, Zhu M, Li M, Du Y, Duan S, Huang Y, Lu Y, Zhang J, Wang T, Fu F. Ginsenoside Rg1 attenuates adjuvant-induced arthritis in rats via modulation of PPAR-gamma/NF-kappaB signal pathway. Oncotarget. 2017;8:55384–93. Scholar
  20. 20.
    Mellado M, Martínez-Muñoz L, Cascio G, Lucas P, Pablos JL, Rodríguez-Frade JM. T cell migration in rheumatoid arthritis. Front Immunol. 2015;6:384. Scholar
  21. 21.
    Turner MD, Nedjai B, Hurst T, Pennington DJ. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta Mol Cell Res. 2014;1843(11):2563–82. Scholar
  22. 22.
    Choi HM, Oh DH, Bang JS, Yang HI, Yoo MC, Kim KS. Differential effect of IL-1β and TNF-α on the production of IL-6, IL-8 and PGE2 in fibroblast-like synoviocytes and THP-1 macrophages. Rheumatol Int. 2010;30(8):1025–33. Scholar
  23. 23.
    Song X-M, Li J-G, Wang Y-L, Zhou Q, Du Z-H, Jia B-H, Ke J-J. Effects of ketamine on proinflammatory cytokines and nuclear factor kappaB in polymicrobial sepsis rats. World J Gastroenterol. 2006;12(45):7350–4. Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Hui Lin
    • 1
    • 2
  • Zhe Wang
    • 1
  • Jinmei Shen
    • 1
  • Junmei Xu
    • 1
  • Hui Li
    • 1
    Email author
  1. 1.Department of Anesthesiology, The Second Xiangya HospitalCentral South UniversityChangshaChina
  2. 2.Department of AnesthesiologyHainan General HospitalHaikouChina

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