Acamprosate Protects Against Adjuvant-Induced Arthritis in Rats via Blocking the ERK/MAPK and NF-κB Signaling Pathway
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.
KEY WORDSacamprosate adjuvant-induced arthritis osteoarthritis inflammation ERK/MAPK NF-κB
This study was supported by National Natural Science Foundation of China (No. 81772311).
Conceived and designed the experiments: XS. Performed the experiments: PJ JR. Analyzed the data: SM WR. Wrote the paper: XS PJ.
Compliance with Ethical Standards
The experiment was approved by the ethical guidelines of the Zhejiang University Animal Experimentation Committee.
Conflicts of Interest
The authors declare that they have no competing interests.
- 4.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.CrossRefPubMedGoogle Scholar
- 7.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.CrossRefPubMedGoogle Scholar
- 9.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.CrossRefPubMedGoogle Scholar
- 10.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. CrossRefPubMedPubMedCentralGoogle Scholar
- 11.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.CrossRefPubMedGoogle Scholar
- 14.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.CrossRefPubMedPubMedCentralGoogle Scholar