Abstract
Osteoarthritis is a type of joint disease that results from the breakdown of joint cartilage and underlying bone and is believed to be caused by mechanical stress on the joint and low-grade inflammatory processes. Acamprosate significantly ameliorates the pathological features of experimental autoimmune encephalomyelitis due to its anti-inflammatory effect. The aims of the present study were to investigate the anti-arthritis activities of acamprosate and elucidate the underlying mechanisms. Adjuvant-induced arthritis (AIA) was induced by intradermal injection of complete Freund’s adjuvant. Male Wistar rats were randomly divided into five groups: (1) sham control group, (2) AIA group, (3) acamprosate 10 mg/kg (AIA + ACA10), (4) acamprosate 30 mg/kg (AIA + ACA30), and (5) acamprosate 100 mg/kg (AIA + ACA100). Paw swelling and the arthritis index were measured, and the production of IL-1β, IL-6, and TNF-α was detected by ELISA in serum. The expression of inflammation-related molecules, including c-Raf, ERK1/2, and NF-κB, was determined by Western blotting. We found that acamprosate significantly suppressed paw swelling and the arthritis index in AIA rats. Moreover, acamprosate also significantly suppressed the production of TNF-α, IL-1β, and IL-6 in serum, which is elevated by AIA induction. Finally, acamprosate inhibited p-c-Raf and p-ERK1/2 and NF-κB activation after AIA treatment. These results indicate that acamprosate has an anti-inflammatory effect on adjuvant-induced arthritic rats via inhibiting the ERK/MAPK and NF-κB signaling pathways, and acamprosate may serve as a promising novel therapeutic agent for osteoarthritis.
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References
Rahmati, M., A. Mobasheri, and M. Mozafari. 2016. Inflammatory mediators in osteoarthritis: a critical review of the state-of-the-art, current prospects, and future challenges. Bone 85: 81–90. https://doi.org/10.1016/j.bone.2016.01.019.
Poulet, B., and K.A. Staines. 2016. New developments in osteoarthritis and cartilage biology. Current Opinion in Pharmacology 28: 8–13. https://doi.org/10.1016/j.coph.2016.02.009.
Xue, H., Y. Tu, T. Ma, X. Liu, T. Wen, M. Cai, Z. Xia, and J. Mei. 2015. Lactoferrin inhibits IL-1beta-induced chondrocyte apoptosis through AKT1-induced CREB1 activation. Cellular Physiology and Biochemistry 36 (6): 2456–2465. https://doi.org/10.1159/000430206.
Chen, Y.J., K.S. Tsai, D.C. Chan, K.C. Lan, C.F. Chen, R.S. Yang, and S.H. Liu. 2014. Honokiol, a low molecular weight natural product, prevents inflammatory response and cartilage matrix degradation in human osteoarthritis chondrocytes. Journal of Orthopaedic Research 32 (4): 573–580. https://doi.org/10.1002/jor.22577.
Lepetsos, P., and A.G. Papavassiliou. 2016. ROS/oxidative stress signaling in osteoarthritis. Biochimica et Biophysica Acta 1862 (4): 576–591. https://doi.org/10.1016/j.bbadis.2016.01.003.
Zhang, L., M. Zhu, M. Li, Y. Du, S. Duan, Y. Huang, et al. 2017. Ginsenoside Rg1 attenuates adjuvant-induced arthritis in rats via modulation of PPAR-gamma/NF-kappaB signal pathway. Oncotarget 8 (33): 55384–55393. https://doi.org/10.18632/oncotarget.19526.
Sternberg, Z., A. Cesario, K. Rittenhouse-Olson, R.A. Sobel, Y.K. Leung, O. Pankewycz, B. Zhu, T. Whitcomb, D.S. Sternberg, and F.E. Munschauer. 2012. Acamprosate modulates experimental autoimmune encephalomyelitis. Inflammopharmacology 20 (1): 39–48. https://doi.org/10.1007/s10787-011-0097-1.
Mann, K., F. Kiefer, R. Spanagel, and J. Littleton. 2008. Acamprosate: recent findings and future research directions. Alcoholism, Clinical and Experimental Research 32 (7): 1105–1110. https://doi.org/10.1111/j.1530-0277.2008.00690.x.
Li, W., Z. Chen, M. Yan, P. He, Z. Chen, and H. Dai. 2016. The protective role of isorhamnetin on human brain microvascular endothelial cells from cytotoxicity induced by methylglyoxal and oxygen-glucose deprivation. Journal of Neurochemistry 136 (3): 651–659. https://doi.org/10.1111/jnc.13436.
Aborehab, N.M., M.H. El Bishbishy, A. Refaiy, and N.E. Waly. 2017. A putative chondroprotective role for IL-1beta and MPO in herbal treatment of experimental osteoarthritis. BMC Complementary and Alternative Medicine 17 (1): 495. https://doi.org/10.1186/s12906-017-2002-y.
Wang, S.X., S.B. Abramson, M. Attur, M.A. Karsdal, R.A. Preston, C.J. Lozada, M.P. Kosloski, F. Hong, P. Jiang, M.J. Saltarelli, B.A. Hendrickson, and J.K. Medema. 2017. Safety, tolerability, and pharmacodynamics of an anti-interleukin-1alpha/beta dual variable domain immunoglobulin in patients with osteoarthritis of the knee: a randomized phase 1 study. Osteoarthritis and Cartilage 25 (12): 1952–1961. https://doi.org/10.1016/j.joca.2017.09.007.
Hou, S.M., C.H. Hou, and J.F. Liu. 2017. CX3CL1 promotes MMP-3 production via the CX3CR1, c-Raf, MEK, ERK, and NF-kappaB signaling pathway in osteoarthritis synovial fibroblasts. Arthritis Research & Therapy 19 (1): 282. https://doi.org/10.1186/s13075-017-1487-6.
Lee, A.S., M.B. Ellman, D. Yan, J.S. Kroin, B.J. Cole, A.J. van Wijnen, and H.J. Im. 2013. A current review of molecular mechanisms regarding osteoarthritis and pain. Gene 527 (2): 440–447. https://doi.org/10.1016/j.gene.2013.05.069.
Viegas, C.S.B., R.M. Costa, L. Santos, P.A. Videira, Z. Silva, N. Araujo, et al. 2017. Gla-rich protein function as an anti-inflammatory agent in monocytes/macrophages: implications for calcification-related chronic inflammatory diseases. PLoS One 12 (5): e0177829. https://doi.org/10.1371/journal.pone.0177829.
Nennig, S.E., and J.R. Schank. 2017. The role of NFkB in drug addiction: beyond inflammation. Alcohol and Alcoholism 52 (2): 172–179. https://doi.org/10.1093/alcalc/agw098.
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This study was supported by National Natural Science Foundation of China (No. 81772311).
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Conceived and designed the experiments: XS. Performed the experiments: PJ JR. Analyzed the data: SM WR. Wrote the paper: XS PJ.
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The experiment was approved by the ethical guidelines of the Zhejiang University Animal Experimentation Committee.
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The authors declare that they have no competing interests.
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Pan, J., Jin, R., Shen, M. et al. Acamprosate Protects Against Adjuvant-Induced Arthritis in Rats via Blocking the ERK/MAPK and NF-κB Signaling Pathway. Inflammation 41, 1194–1199 (2018). https://doi.org/10.1007/s10753-018-0766-y
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DOI: https://doi.org/10.1007/s10753-018-0766-y