Abstract
Pemetrexed (PMTX) is an anti-folate drug as methotrexate. The purpose of this study was to assess the efficacy of PMTX on collagen-induced arthritis (CIA). Forty Wistar albino rats were randomized into four groups. Arthritis was induced by intradermal injection of chicken type II collagen combined with incomplete Freund’s adjuvant. Animals were sacrificed at the 15th day after the onset of arthritis. Tumor necrosis factor alpha (TNF-α), interleukin (IL)-17, and malondialdehyde (MDA) levels were increased, and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities and the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were decreased in the arthritis group. In the PMTX-treated (0.2 and 1 mg/kg/week i.p.) groups, the levels of TNF-α, IL-17, and MDA were decreased; the activities of SOD, CAT, and GPx and the expressions of Nrf2 and HO-1 were restored, and perisynovial inflammation and cartilage–bone destruction were decreased. PMTX has anti-arthritic potential in the CIA model and may be a therapeutic agent for rheumatoid arthritis.
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References
Hobbs, K.F., and M.D. Cohen. 2012. Rheumatoid arthritis disease measurement: A new old idea. Rheumatology (Oxford) 51: vi21–27.
Schett, G., and E. Gravallese. 2012. Bone erosion in rheumatoid arthritis: Mechanisms, diagnosis and treatment. Nature Reviews. Rheumatology 8(11): 656–664.
Breedveld, F.C., M.H. Weisman, A.F. Kavanaugh, S.B. Cohen, K. Pavelka, R. van Vollenhoven, et al. 2006. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis and Rheumatism 54(1): 26–37.
Shih, C., V.J. Chen, L.S. Gossett, S.B. Gates, W.C. MacKellar, L.L. Habeck, et al. 1997. LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Research 57(6): 1116–1123.
Vogelzang, N.J., J.J. Rusthoven, J. Symanowski, C. Denham, E. Kaukel, P. Ruffie, et al. 2003. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. Journal of Clinical Oncology 21(14): 2636–2644.
Cohen, M.H., R. Justice, and R. Pazdur. 2009. Approval summary: Pemetrexed in the initial treatment of advanced/metastatic non-small cell lung cancer. The Oncologist 14(9): 930–935.
Williams, R.O. 2004. Collagen-induced arthritis as a model for rheumatoid arthritis. Methods in Molecular Medicine 98: 207–216.
Lawson, B.R., S.M. Belkowski, J.F. Whitesides, P. Davis, and J.W. Lawson. 2007. Immunomodulation of murine collagen-induced arthritis by N, N-dimethylglycine and a preparation of Perna canaliculus. BMC Complementary and Alternative Medicine 7: 20.
Trentham, D.E., A.S. Townes, and A.H. Kang. 1977. Autoimmunity to type II collagen an experimental model of arthritis. Journal of Experimental Medicine 146(3): 857–868.
Larsson, P., S. Kleinau, R. Holmdahl, and L. Klareskog. 1990. Homologous type II collagen-induced arthritis in rats. Characterization of the disease and demonstration of clinically distinct forms of arthritis in two strains of rats after immunization with the same collagen preparation. Arthritis and Rheumatism 33(5): 693–701.
Barsante, M.M., E. Roffe, C.M. Yokoro, W.L. Tafuri, S.G. Souza, V. Pinho, et al. 2005. Anti-inflammatory and analgesic effects of atorvastatin in a rat model of adjuvant-induced arthritis. European Journal of Pharmacology 516(3): 282–289.
Choi, J., B.J. Yoon, Y.N. Han, K.T. Lee, J. Ha, H.J. Jung, et al. 2003. Antirheumatoid arthritis effect of Rhus verniciflua and of the active component, sulfuretin. Planta Medica 69(10): 899–904.
Lowry, O.H., N.J. Rosebrough, A.L. Farr, and R.J. Randall. 1951. Protein measurement with the folin phenol reagent. Journal of Biological Chemistry 193: 165–175.
Sokka, T. 2003. Work disability in early rheumatoid arthritis. Clinical and Experimental Rheumatology 21(5 Suppl 31): S71–74.
Young, A., G. Koduri, M. Batley, E. Kulinskaya, A. Gough, S. Norton, et al. 2007. Mortality in rheumatoid arthritis. Increased in the early course of disease, in ischaemic heart disease and in pulmonary fibrosis. Rheumatology (Oxford) 46(2): 350–357.
Finckh, A., N. Bansback, C.A. Marra, A.H. Anis, K. Michaud, S. Lubin, et al. 2009. Treatment of very early rheumatoid arthritis with symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: A cost-effectiveness analysis. Annals of Internal Medicine 151(9): 612–621.
Nam, J.L., K.L. Winthrop, R.F. van Vollenhoven, K. Pavelka, G. Valesini, E.M. Hensor, et al. 2010. Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: A systematic literature review informing the EULAR recommendations for the management of RA. Annals of the Rheumatic Diseases 69(6): 976–986.
Lu, L.J., C.D. Bao, M. Dai, J.L. Teng, W. Fan, F. Du, et al. 2009. Multicenter, randomized, double-blind, controlled trial of treatment of active rheumatoid arthritis with T-614 compared with methotrexate. Arthritis and Rheumatism 61(7): 979–987.
Fan, P.T., and K.H. Leong. 2007. The use of biological agents in the treatment of rheumatoid arthritis. Annals of the Academy of Medicine, Singapore 36(2): 128–134.
Xinqiang, S., L. Fei, L. Nan, L. Yuan, Y. Fang, X. Hong, et al. 2010. Therapeutic efficacy of experimental rheumatoid arthritis with low-dose methotrexate by increasing partially CD4+CD25+ Treg cells and inducing Th1 to Th2 shift in both cells and cytokines. Biomedicine and Pharmacotherapy 64(7): 463–471.
Chattopadhyay, S., R.G. Moran, and I.D. Goldman. 2007. Pemetrexed: Biochemical and cellular pharmacology, mechanisms, and clinical applications. Molecular Cancer Therapeutics 6(2): 404–417.
Niimoto, T., T. Nakasa, M. Ishikawa, A. Okuhara, B. Izumi, M. Deie, et al. 2010. MicroRNA-146a expresses in interleukin-17 producing T cells in rheumatoid arthritis patients. BMC Musculoskeletal Disorders 11: 209.
Miranda-Carus, M.E., A. Balsa, M. Benito-Miguel, C. Perez de Ayala, and E. Martin-Mola. 2004. IL-15 and the initiation of cell contact-dependent synovial fibroblast-T lymphocyte cross-talk in rheumatoid arthritis: Effect of methotrexate. Journal of Immunology 173(2): 1463–1476.
Manicourt, D.H., R. Triki, K. Fukuda, J.P. Devogelaer, C. Nagant de Deuxchaisnes, and E.J. Thonar. 1993. Levels of circulating tumor necrosis factor alpha and interleukin-6 in patients with rheumatoid arthritis. Relationship to serum levels of hyaluronan and antigenic keratan sulfate. Arthritis and Rheumatism 36(4): 490–499.
Seitz, M., M. Zwicker, and P.M. Villiger. 2003. Pretreatment cytokine profiles of peripheral blood mononuclear cells and serum from patients with rheumatoid arthritis in different American college of rheumatology response groups to methotrexate. Journal of Rheumatology 30(1): 28–35.
Hitchon, C.A., and H.S. El-Gabalawy. 2004. Oxidation in rheumatoid arthritis. Arthritis Research and Therapy 6(6): 265–278.
Halliwell, B., J.R. Hoult, and D.R. Blake. 1988. Oxidants, inflammation, and anti-inflammatory drugs. FASEB Journal 2(13): 2867–2873.
Imadaya, A., K. Terasawa, H. Tosa, M. Okamoto, and K. Toriizuka. 1988. Erythrocyte antioxidant enzymes are reduced in patients with rheumatoid arthritis. Journal of Rheumatology 15(11): 1628–1631.
Nivsarkar, M. 2000. Improvement in circulating superoxide dismutase levels: Role of nonsteroidal anti-inflammatory drugs in rheumatoid arthritis. Biochemical and Biophysical Research Communications 270(3): 714–716.
Rasool, M., and P. Varalakshmi. 2007. Protective effect of Withania somnifera root powder in relation to lipid peroxidation, antioxidant status, glycoproteins and bone collagen on adjuvant-induced arthritis in rats. Fundamental and Clinical Pharmacology 21(2): 157–164.
Kerimova, A.A., M. Atalay, E.Y. Yusifov, S.P. Kuprin, and T.M. Kerimov. 2000. Antioxidant enzymes; possible mechanism of gold compound treatment in rheumatoid arthritis. Pathophysiology 7(3): 209–213.
Salvemini, D., E. Mazzon, L. Dugo, I. Serraino, A. De Sarro, A.P. Caputi, et al. 2001. Amelioration of joint disease in a rat model of collagen-induced arthritis by M40403, a superoxide dismutase mimetic. Arthritis and Rheumatism 44(12): 2909–2921.
Dalle-Donne, I., R. Rossi, D. Giustarini, A. Milzani, and R. Colombo. 2003. Protein carbonyl groups as biomarkers of oxidative stress. Clinica Chimica Acta 329(1–2): 23–38.
Girotti, A.W. 1998. Lipid hydroperoxide generation, turnover, and effector action in biological systems. Journal of Lipid Research 39(8): 1529–1542.
Garg, N., R. Singh, J. Dixit, A. Jain, and V. Tewari. 2006. Levels of lipid peroxides and antioxidants in smokers and nonsmokers. Journal of Periodontal Research 41(5): 405–410.
Kamanli, A., M. Naziroglu, N. Aydilek, and C. Hacievliyagil. 2004. Plasma lipid peroxidation and antioxidant levels in patients with rheumatoid arthritis. Cell Biochemistry and Function 22(1): 53–57.
Bauerova, K., E. Paulovicova, D. Mihalova, F. Drafi, M. Strosova, C. Mascia, et al. 2010. Combined methotrexate and coenzyme Q(1)(0) therapy in adjuvant-induced arthritis evaluated using parameters of inflammation and oxidative stress. Acta Biochimica Polonica 57(3): 347–354.
Hayes, J.D., and A.T. Dinkova-Kostova. 2014. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends in Biochemical Sciences 39(4): 199–218.
Wruck, C.J., A. Fragoulis, A. Gurzynski, L.O. Brandenburg, Y.W. Kan, K. Chan, et al. 2011. Role of oxidative stress in rheumatoid arthritis: Insights from the Nrf2-knockout mice. Annals of the Rheumatic Diseases 70: 844–850.
Maicas, N., M.L. Ferrándiz, R. Brines, L. Ibáñez, A. Cuadrado, M.I. Koenders, W.B. van den Berg, and M.J. Alcaraz. 2011. Deficiency of Nrf2 accelerates the effector phase of arthritis and aggravates joint disease. Antioxidants and Redox Signaling 15(4): 889–901.
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Karatas, A., Koca, S.S., Ozgen, M. et al. Pemetrexed Ameliorates Experimental Arthritis in Rats. Inflammation 38, 9–15 (2015). https://doi.org/10.1007/s10753-014-0002-3
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DOI: https://doi.org/10.1007/s10753-014-0002-3