All authors of this paper are employees of Japan Tobacco Inc. The authors declare that they have no competing interests.
NK, YK, YS, and AT performed most experiments. AT, YS, TY, and MM designed the study, interpreted the findings, and wrote the manuscript. WA and AM assisted with interpretation of the findings. All authors have read and approved the manuscript.
Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to joint destruction, disability, and decreased quality of life (QOL). Inhibition of Janus kinase (JAK) signaling ameliorates articular inflammation and joint destruction in animal models of RA, but its effects on behaviors indicating well-being are poorly understood. In this study, we evaluated the effect of JAK inhibition on spontaneous locomotor activity in rats with adjuvant-induced arthritis, a rodent model of RA.
Arthritis was induced in male Lewis rats by a single subcutaneous injection of Freund’s complete adjuvant. The novel JAK inhibitor JTE-052 was orally administered for 7 days after the onset of arthritis.
Induction of arthritis suppressed the spontaneous locomotor activity of the rats. Administration of JTE-052 completely improved the spontaneous locomotor activity, with partial reductions in articular inflammation and joint destruction. Hyperalgesia and motor functions were also improved, but the efficacy was not complete. However, serum interleukin (IL)-6 levels were completely decreased at 4 h after administration of the first dose of JTE-052.
This study demonstrated that JAK inhibition improved the spontaneous locomotor activity of rats with adjuvant-induced arthritis, in association with amelioration of pain and physical dysfunction as a consequence of suppression of joint inflammation. Moreover, although further studies are needed, there was possible participation of IL-6 downregulation in the improvement of locomotor activity by JAK inhibition.
van der Heijde D, Tanaka Y, Fleischmann R, Keystone E, Kremer J, Zerbini C, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013;65:559–70. CrossRefPubMed
Coombs JH, Bloom BJ, Breedveld FC, Fletcher MP, Gruben D, Kremer JM, et al. Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2010;69:413–6. CrossRefPubMed
Philippe L, Gegout-Pottie P, Guingamp C, Bordji K, Terlain B, Netter P, et al. Relations between functional, inflammatory, and degenerative parameters during adjuvant arthritis in rats. Am J Physiol. 1997;273:R1550–6. PubMed
Randall LO, Selitto JJ. A method for measurement of analgesic activity on inflamed tissue. Arch Int Pharmacodyn Ther. 1957;111:409–19. PubMed
Stolina M, Schett G, Dwyer D, Vonderfecht S, Middleton S, Duryea D, et al. RANKL inhibition by osteoprotegerin prevents bone loss without affecting local or systemic inflammation parameters in two rat arthritis models: comparison with anti-TNFalpha or anti-IL-1 therapies. Arthritis Res Ther. 2009;11:R187. CrossRefPubMedPubMedCentral
Meyer DM, Jesson MI, Li X, Elrick MM, Funckes-Shippy CL, Warner JD, et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond). 2010;7:41. CrossRef
Courvoisier DS, Agoritsas T, Glauser J, Michaud K, Wolfe F, Cantoni E, et al. Pain as an important predictor of psychosocial health in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64:190–6. CrossRef
Wolfe F, Hawley DJ, Wilson K. The prevalence and meaning of fatigue in rheumatic disease. J Rheumatol. 1996;23:1407–17. PubMed
Druce KL, Jones GT, Macfarlane GJ, Basu N. Patients receiving anti-TNF therapies experience clinically important improvements in RA-related fatigue: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Rheumatology (Oxford). 2015;54:964–71. CrossRef
Dayer JM, Choy E. Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor. Rheumatology (Oxford). 2010;49:15–24. CrossRef
- Improvement of spontaneous locomotor activity with JAK inhibition by JTE-052 in rat adjuvant-induced arthritis
- BioMed Central
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