Ligustrazine attenuates inflammation and oxidative stress in a rat model of arthritis via the Sirt1/NF-κB and Nrf-2/HO-1 pathways

  • Yongji Li
  • Zaihua Zhu
  • Ting Zhang
  • Yan ZhouEmail author
Research Article


Inflammation responses and oxidative stress are closely involved in the pathogenesis of arthritis. Ligustrazine (Lig), a natural four methyl which is isolated from Chinese herb ligusticum chuanxiong hort, has been proved significantly anti-inflammation and anti-oxidative stress effects. The present study aimed to evaluate the effect of Lig on inflammation and oxidative stress in Freund’s complete adjuvant (FCA)-induced arthritis in rats. The treatment of Lig significantly decreased the hind-paw volume change and alleviated the histopathological changes in sections of rat paws induced by arthritis. Lig also reduced the serum levels of pro-inflammatory cytokines (interleukin [IL]-6, IL-1 beta, and tumor necrosis factor-alpha), increased the activity of superoxide dismutase (SOD) and reduced the concentration of malondialdehyde (MDA). Besides that, the protein expressions of the sirtuin 1 (Sirt1)/nuclear factor kappa B (NF-κB) and nuclear factor (erythroid-derived 2)-like-2 factor (Nrf-2)/heme oxygenase (HO)-1 pathways determined by western bolt further confirmed that Lig effectively inhibited the Sirt1/NF-κB pathway and activated the Nrf-2/HO-1 pathway. Taken together, our results suggest Lig has therapeutic potential for arthritis, which might be via the regulation of Sirt1/NF-κB and Nrf-2/HO-1 pathways.


Ligustrazine Arthritis Inflammation Sirt1/NF-κB Nrf-2/HO-1 



This work was supported by the Grants from the Wenzhou public welfare science and technology plan (No.Y20150193).

Compliance with ethical standards

Conflict of interest

The authors have declared that there is no conflict of interest.


  1. Bao L, Zhu Y, Elhassan AM, Wu Q, Xiao B, Zhu J, Lindgren JU (2001) Adjuvant-induced arthritis: IL-1 beta, IL-6 and TNF-alpha are up-regulated in the spinal cord. NeuroReport 12:3905–3908CrossRefGoogle Scholar
  2. Comar JF, Babeto De Sa-Nakanishi A, De Oliveira AL, Marques Nogueira Wendt M, Bersani Amado CA, Ishii Iwamoto EL, Peralta RM, Bracht A (2013) Oxidative state of the liver of rats with adjuvant-induced arthritis. Free Radic Biol Med 58:144–153CrossRefGoogle Scholar
  3. Garcia-Gonzalez A, Gaxiola-Robles R, Zenteno-Savin T (2015) Oxidative stress in patients with rheumatoid arthritis. Rev Invest Clin 67:46–53PubMedGoogle Scholar
  4. Gupta M, Sasmal S, Mukherjee A (2014) Therapeutic effects of acetone extract of saraca asoca seeds on rats with adjuvant-induced arthritis via attenuating inflammatory responses. ISRN Rheumatol 2014:959687CrossRefGoogle Scholar
  5. Jiang F, Qian J, Chen S, Zhang W, Liu C (2011) Ligustrazine improves atherosclerosis in rat via attenuation of oxidative stress. Pharm Biol 49:856CrossRefGoogle Scholar
  6. Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A (2013) Antagonistic crosstalk between NF-kappa B and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 25:1939–1948CrossRefGoogle Scholar
  7. Lemarechal H, Allanore Y, Chenevier-Gobeaux C, Kahan A, Ekindjian OG, Borderie D (2006) Serum protein oxidation in patients with rheumatoid arthritis and effects of infliximab therapy. Clin Chim Acta 372:147–153CrossRefGoogle Scholar
  8. Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW (2010) Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell 38:864–878CrossRefGoogle Scholar
  9. Liu XH, Li J, Li QX, Ai YX, Zhang L (2008) Protective effects of ligustrazine on cisplatin-induced oxidative stress, apoptosis and nephrotoxicity in rats. Environ Toxicol Pharmacol 26:49–55CrossRefGoogle Scholar
  10. Liu MD, Wu H, Wang S, Pang P, Jin S, Sun CF, Liu FY (2017a) MiR-1275 promotes cell migration, invasion and proliferation in squamous cell carcinoma of head and neck via up-regulating IGF-1R and CCR7. Gene 646:1–7CrossRefGoogle Scholar
  11. Liu ZK, Ng CF, Shiu HT, Wong HL, Wong CW, Li KK, Zhang JF, Lam PK, Poon WS, Lau CBS, Leung PC, Ko CH (2017b) A traditional Chinese formula composed of Chuanxiong Rhizoma and Gastrodiae Rhizoma (Da Chuanxiong Formula) suppresses inflammatory response in LPS -induced RAW 264.7 cells through inhibition of NF-kappa B pathway. J Ethnopharmacol 196:20–28CrossRefGoogle Scholar
  12. Lu J, Zhang L, Chen X, Lu Q, Yang Y, Liu J, Ma X (2014) SIRT1 counteracted the activation of STAT3 and NF-kappaB to repress the gastric cancer growth. Int J Clin Exp Med 7:5050–5058PubMedPubMedCentralGoogle Scholar
  13. Mcinnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219CrossRefGoogle Scholar
  14. Mori T, Miyamoto T, Yoshida H, Asakawa M, Kawasumi M, Kobayashi T, Morioka H, Chiba K, Toyama Y, Yoshimura A (2011) IL-1 beta and TNF alpha-initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis. Int Immunol 23:701–712CrossRefGoogle Scholar
  15. Pearson CM (1964) Experimental models in rheumatoid disease. Arthritis Rheum 7:80–86CrossRefGoogle Scholar
  16. Quinonez-Flores CM, Gonzalez-Chavez SA, Del Rio Najera D, Pacheco-Tena C (2016) Oxidative stress relevance in the pathogenesis of the rheumatoid arthritis: a systematic review. Biomed Res Int 2016:6097417CrossRefGoogle Scholar
  17. Roman-Blas JA, Jimenez SA (2006) NF-kappaB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthr Cartil 14:839–848CrossRefGoogle Scholar
  18. Shinozaki S, Chang K, Sakai M, Shimizu N, Yamada M, Tanaka T, Nakazawa H, Ichinose F, Yamada Y, Ishigami A, Ito H, Ouchi Y, Starr ME, Saito H, Shimokado K, Stamler JS, Kaneki M (2014) Inflammatory stimuli induce inhibitory S-nitrosylation of the deacetylase SIRT1 to increase acetylation and activation of p53 and p65. Sci Signal 7(351):ra106CrossRefGoogle Scholar
  19. Smolen JS, Steiner G (2003) Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov 2:473–488CrossRefGoogle Scholar
  20. Sukkar SG, Rossi E (2004) Oxidative stress and nutritional prevention in autoimmune rheumatic diseases. Autoimmun Rev 3:199–206CrossRefGoogle Scholar
  21. Wang S, Wang Y, Liu X, Guan L, Yu L, Zhang X (2016) Anti-inflammatory and anti-arthritic effects of taraxasterol on adjuvant-induced arthritis in rats. J Ethnopharmacol 187:42–48CrossRefGoogle Scholar
  22. Yang G, Li S, Yuan L, Yang Y, Pan MH (2017) Effect of nobiletin on the MAPK/NF-kappaB signaling pathway in the synovial membrane of rats with arthritis induced by collagen. Food Funct 8:4668–4674CrossRefGoogle Scholar
  23. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW (2004) Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23:2369–2380CrossRefGoogle Scholar
  24. Yu T, Qu J, Wang Y, Jin H (2018) Ligustrazine protects chondrocyte against IL-1beta induced injury by regulation of SOX9/NF-kappaB signaling pathway. J Cell Biochem. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Zhang L, Wang XF, Tian XH, Zhao W, Liu TS, Feng GY, Cai H, Liu J (2016) Hydrogen has a neuroprotective effect via activation of Nrf-2/HO-1 pathway in ischemia reperfusion rat. Int J Clin Exp Med 9:10521–10528Google Scholar
  26. Zhang M, Wu YQ, Xie L, Wu J, Xu K, Xiao J, Chen DQ (2018) Isoliquiritigenin protects against pancreatic injury and intestinal dysfunction after severe acute pancreatitis via Nrf2 signaling. Front Pharmacol 9:936CrossRefGoogle Scholar
  27. Zhu L, Wang J, Wei T, Gao J, He H, Chang X, Yan T (2015) Effects of naringenin on inflammation in complete freund’s adjuvant-induced arthritis by regulating Bax/Bcl-2 balance. Inflammation 38:245–251CrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2018

Authors and Affiliations

  1. 1.Department of Rheumatology and ImmunologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina

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