Skip to main content

Nardosinone-Type Sesquiterpenes from the Hexane Fraction of Nardostachys jatamansi Attenuate NF-κB and MAPK Signaling Pathways in Lipopolysaccharide-Stimulated BV2 Microglial Cells

Inflammation volume 41, pages 1215–1228 (2018)Cite this article

Abstract

Four nardosinone-type sesquiterpenes, nardosinone, isonardosinone, kanshone E, and kanshone B, were isolated from the hexane fraction of Nardostachys jatamansi (Valerianaceae) methanol extract. The structures of these compounds were mainly established by analyzing the data obtained from nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). In this study, we investigated their anti-neuroinflammatory effects in lipopolysaccharide (LPS)-induced BV2 microglial cells. The results showed that nardosinone-type sesquiterpenes inhibited the production of pro-inflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS-induced BV2 microglial cells. These inhibitory effects were correlated with the downregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, these sesquiterpenes also attenuated the mRNA expression of pro-inflammatory cytokines including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) in LPS-induced BV2 microglial cells. During the evaluation of the signaling pathways involved in these anti-neuroinflammatory effects, western blot analysis and DNA-binding activity assay revealed that the suppression of inflammatory reaction by these sesquiterpenes was mediated by the inactivation of nuclear factor-kappa B (NF-κB) pathway. These sesquiterpenes also suppressed the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) signaling pathways in LPS-stimulated BV2 microglial cells. Taken together, these four nardosinone-type sesquiterpenes inhibited NF-κB- and MAPK-mediated inflammatory pathways, demonstrating their potential role in the treatment of neuroinflammation conditions.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

References

  1. Streit, W.J., S.A. Walter, and N.A. Pennell. 1999. Reactive microgliosis. Progress in Neurobiology 57 (6): 563–581.

    Article  PubMed  CAS  Google Scholar 

  2. Hanisch, U.K., and H. Kettenmann. 2007. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nature Neuroscience 10 (11): 1387–1394.

    Article  PubMed  CAS  Google Scholar 

  3. Horvath, R.J., N. Nutile-McMenemy, M.S. Alkaitis, and J.A. Deleo. 2008. Differential migration, LPS-induced cytokine, chemokine, and NO expression in immortalized BV-2 and HAPI cell lines and primary microglial cultures. Journal of Neurochemistry 107 (2): 557–569.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Sarkar, F.H., Y. Li, Z. Wang, and D. Kong. 2008. NF-kappaB signaling pathway and its therapeutic implications in human diseases. International Reviews of Immunology 27 (5): 293–319.

    Article  PubMed  CAS  Google Scholar 

  5. Mankan, A.K., M.W. Lawless, S.G. Gray, D. Kelleher, and R. McManus. 2009. NF-kappaB regulation: the nuclear response. Journal of Cellular and Molecular Medicine 13 (4): 631–643.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Ajizian, S.J., B.K. English, and E.A. Meals. 1999. Specific inhibitors of p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways block inducible nitric oxide synthase and tumor necrosis factor accumulation in murine macrophages stimulated with lipopolysaccharide and interferon-gamma. The Journal of Infectious Diseases 179 (4): 939–944.

    Article  PubMed  CAS  Google Scholar 

  7. Carter, A.B., K.L. Knudtson, M.M. Monick, and G.W. Hunninghake. 1999. The p38 mitogen-activated protein kinase is required for NF-kappaB-dependent gene expression. The role of TATA-binding protein (TBP). The Journal of Biological Chemistry 274 (43): 30858–30863.

    Article  PubMed  CAS  Google Scholar 

  8. Chatterjee, A., B. Basak, M. Saha, U. Dutta, C. Mukhopadhyay, J. Banerji, Y. Konda, and Y. Harigaya. 2000. Structure and stereochemistry of nardostachysin, a new terpenoid ester constituent of the rhizomes of Nardostachys jatamansi. Journal of Natural Products 63 (11): 1531–1533.

    Article  PubMed  CAS  Google Scholar 

  9. Bagchi, A., Y. Oshima, and H. Hikino. 1991. Neolignans and lignans of Nardostachys jatamansi roots1. Planta Medica 57 (1): 96–97.

    Article  PubMed  CAS  Google Scholar 

  10. Bagchi, A., Y. Oshima, and H. Hikino. 1991. Jatamols A and B: sesquiterpenoids of Nardostachys jatamansi roots1. Planta Medica 57 (3): 282–283.

    Article  PubMed  CAS  Google Scholar 

  11. Bae, G.S., H.J. Park, D.Y. Kim, J.M. Song, T.H. Kim, H.J. Oh, K.J. Yun, R.K. Park, J.H. Lee, B.C. Shin, H.J. Sim, S.P. Hong, H.J. Song, and S.J. Park. 2010. Nardostachys jatamansi protects against cerulein-induced acute pancreatitis. Pancreas 39 (4): 520–529.

    Article  PubMed  Google Scholar 

  12. Rasheed, A.S., S. Venkataraman, K.N. Jayaveera, A.M. Fazil, K.J. Yasodha, M.A. Aleem, M. Mohammed, Z. Khaja, B. Ushasri, H.A. Pradeep, and M. Ibrahim. 2010. Evaluation of toxicological and antioxidant potential of Nardostachys jatamansi in reversing haloperidol-induced catalepsy in rats. International Journal of General Medicine 3: 127–136.

    PubMed  PubMed Central  CAS  Google Scholar 

  13. Bae, G.S., S.W. Seo, M.S. Kim, K.C. Park, B.S. Koo, W.S. Jung, G.H. Cho, H.C. Oh, S.W. Yun, J.J. Kim, S.G. Kim, S.Y. Hwang, H.J. Song, and S.J. Park. 2011. The roots of Nardostachys jatamansi inhibits lipopolysaccharide-induced endotoxin shock. Journal of Natural Medicines 65 (1): 63–72.

    Article  PubMed  Google Scholar 

  14. Bae, G.S., M.S. Kim, K.C. Park, B.S. Koo, I.J. Jo, S.B. Choi, D.S. Lee, Y.C. Kim, T.H. Kim, S.W. Seo, Y.K. Shin, H.J. Song, and S.J. Park. 2012. Effect of biologically active fraction of Nardostachys jatamansi on cerulein-induced acute pancreatitis. World Journal of Gastroenterology 18 (25): 3223–3234.

    PubMed  PubMed Central  Google Scholar 

  15. Madhu, L.N., N.S. Kumari, P. Naveen, and G. Sanjeev. 2012. Protective effect of Nardostachys jatamansi against radiation-induced damage at biochemical and chromosomal levels in Swiss albino mice. Indian Journal of Pharmaceutical Sciences 74 (5): 460–465.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Sharma, S.K., and A.P. Singh. 2012. In vitro antioxidant and free radical scavenging activity of Nardostachys jatamansi DC. Journal of Acupuncture and Meridian Studies 5 (3): 112–118.

    Article  PubMed  Google Scholar 

  17. Bae, G.S., K.C. Park, B.S. Koo, I.J. Jo, S.B. Choi, D.S. Lee, Y.C. Kim, J.J. Kim, Y.K. Shin, S.H. Hong, T.H. Kim, H.J. Song, and S.J. Park. 2013. The beneficial effects of Nardostachys jatamansi extract on diet-induced severe acute pancreatitis. Pancreas 42 (2): 362–363.

    Article  PubMed  Google Scholar 

  18. Dhuna, K., V. Dhuna, G. Bhatia, J. Singh, and S.S. Kamboj. 2013. Cytoprotective effect of methanolic extract of Nardostachys jatamansi against hydrogen peroxide induced oxidative damage in C6 glioma cells. Acta Biochimica Polonica 60 (1): 21–31.

    PubMed  CAS  Google Scholar 

  19. Bae, G.S., K.H. Heo, S.B. Choi, I.J. Jo, D.G. Kim, J.Y. Shin, S.H. Seo, K.C. Park, D.S. Lee, H. Oh, Y.C. Kim, H.J. Song, B.C. Shin, and S.J. Park. 2014. Beneficial effects of fractions of Nardostachys jatamansi on lipopolysaccharide-induced inflammatory response. Evidence-based Complementary and Alternative Medicine 2014: 837835.

    PubMed  PubMed Central  Google Scholar 

  20. Itokawa, H., K. Masuyama, H. Morita, and K. Takeya. 1993. Cytotoxic sesquiterpenes from Nardostachys chinensis. Chemical & Pharmaceutical Bulletin 41 (6): 1183–1184.

    Article  CAS  Google Scholar 

  21. Bagchi, A., Y. Oshima, and H. Hikino. 1988. Kanshones D and E, sesquiterpenoids of Nardostachys chinensis roots. Phytochemistry 27 (11): 3667–3669.

    Article  CAS  Google Scholar 

  22. Bagchi, A., Y. Oshima, and H. Hikino. 1988. Kanshones A and B, sesquiterpenoids of Nardostachys chinensis. Phytochemistry 27 (4): 1199–1201.

    Article  CAS  Google Scholar 

  23. Ko, W., J.H. Sohn, J.H. Jang, J.S. Ahn, D.G. Kang, H.S. Lee, J.S. Kim, Y.C. Kim, and H. Oh. 2016. Inhibitory effects of alternaramide on inflammatory mediator expression through TLR4-MyD88-mediated inhibition of NF-κB and MAPK pathway signaling in lipopolysaccharide-stimulated RAW264.7 and BV2 cells. Chemico-Biological Interactions 244: 16–26.

    Article  PubMed  CAS  Google Scholar 

  24. Titheradge, M.A. 1998. The enzymatic measurement of nitrate and nitrite. Methods in Molecular Biology 100: 83–91.

    PubMed  CAS  Google Scholar 

  25. Yuan, G., M.L. Wahlqvist, G. He, M. Yang, and D. Li. 2006. Natural products and anti-inflammatory activity. Asia Pacific Journal of Clinical Nutrition 15 (2): 143–152.

    PubMed  CAS  Google Scholar 

  26. Gosslau, A., S. Li, C.T. Ho, K.Y. Chen, and N.E. Rawson. 2011. The importance of natural product characterization in studies of their anti-inflammatory activity. Molecular Nutrition & Food Research 55 (1): 74–82.

    Article  CAS  Google Scholar 

  27. Shin, J.Y., G.S. Bae, S.B. Choi, I.J. Jo, D.G. Kim, D.S. Lee, R.B. An, H. Oh, Y.C. Kim, Y.K. Shin, H.W. Jeong, H.J. Song, and S.J. Park. 2015. Anti-inflammatory effect of desoxo-narchinol-A isolated from Nardostachys jatamansi against lipopolysaccharide. International Immunopharmacology 29 (2): 730–738.

    Article  PubMed  CAS  Google Scholar 

  28. MacMicking, J., Q.W. Xie, and C. Nathan. 1997. Nitric oxide and macrophage function. Annual Review of Immunology 15: 323–350.

    Article  PubMed  CAS  Google Scholar 

  29. Aoki, T., and S. Narumiya. 2012. Prostaglandins and chronic inflammation. Trends in Pharmacological Sciences 33 (6): 304–311.

    Article  PubMed  CAS  Google Scholar 

  30. Hwang, J.S., S.A. Lee, S.S. Hong, X.H. Han, C. Lee, D. Lee, C.K. Lee, J.T. Hong, Y. Kim, M.K. Lee, and B.Y. Hwang. 2012. Inhibitory constituents of Nardostachys chinensis on nitric oxide production in RAW 264.7 macrophages. Bioorganic & Medicinal Chemistry Letters 22 (1): 706–708.

    Article  CAS  Google Scholar 

  31. Libby, P. 2006. Inflammation and cardiovascular disease mechanisms. The American Journal of Clinical Nutrition 83 (2): 456S–460S.

    Article  PubMed  CAS  Google Scholar 

  32. de Jong, H.K., T. van der Poll, and W.J. Wiersinga. 2010. The systemic pro-inflammatory response in sepsis. Journal of Innate Immunity 2 (5): 422–430.

    Article  PubMed  CAS  Google Scholar 

  33. Solinas, G., F. Marchesi, C. Garlanda, A. Mantovani, and P. Allavena. 2010. Inflammation-mediated promotion of invasion and metastasis. Cancer Metastasis Reviews 29 (2): 243–248.

    Article  PubMed  CAS  Google Scholar 

  34. Bonizzi, G., and M. Karin. 2004. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends in Immunology 25 (6): 280–288.

    Article  PubMed  CAS  Google Scholar 

  35. Hayden, M.S., and S. Ghosh. 2004. Signaling to NF-kappaB. Genes & Development 18 (18): 2195–2224.

    Article  CAS  Google Scholar 

  36. Choi, Y.E., H. Ahn, and J.H. Ryu. 2000. Polyacetylenes from Angelica gigas and their inhibitory activity on nitric oxide synthesis in activated macrophages. Biological & Pharmaceutical Bulletin 23 (7): 884–886.

    Article  CAS  Google Scholar 

  37. Kim, J.H., J.H. Jeong, S.T. Jeon, H. Kim, J. Ock, K. Suk, S.I. Kim, K.S. Song, and W.H. Lee. 2006. Decursin inhibits induction of inflammatory mediators by blocking nuclear factor-kappaB activation in macrophages. Molecular Pharmacology 69 (6): 1783–1790.

    Article  PubMed  CAS  Google Scholar 

  38. Yang, Y., S.C. Kim, T. Yu, Y.S. Yi, M.H. Rhee, G.H. Sung, B.C. Yoo, and J.Y. Cho. 2014. Functional roles of p38 mitogen-activated protein kinase in macrophage-mediated inflammatory responses. Mediators of Inflammation 2014: 352371.

    PubMed  PubMed Central  Google Scholar 

  39. Zeng, K.W., S. Wang, X. Dong, Y. Jiang, and P.F. Tu. 2014. Sesquiterpene dimer (DSF-52) from Artemisia argyi inhibits microglia-mediated neuroinflammation via suppression of NF-κB, JNK/p38 MAPKs and Jak2/Stat3 signaling pathways. Phytomedicine 21 (3): 298–306.

    Article  PubMed  CAS  Google Scholar 

  40. Liu, S.H., T.H. Lu, C.C. Su, I.S. Lay, H.Y. Lin, K.M. Fang, T.J. Ho, K.L. Chen, Y.C. Su, W.C. Chiang, and Y.W. Chen. 2014. Lotus leaf (Nelumbo nucifera) and its active constituents prevent inflammatory responses in macrophages via JNK/NF-κB signaling pathway. The American Journal of Chinese Medicine 42 (4): 869–889.

    Article  PubMed  Google Scholar 

  41. Choi, K.C., J.M. Hwang, S.J. Bang, B.T. Kim, D.H. Kim, M. Chae, S.A. Lee, G.J. Choi, D.H. Kim, and J.C. Lee. 2013. Chloroform extract of alfalfa (Medicago sativa) inhibits lipopolysaccharide-induced inflammation by downregulating ERK/NF-κB signaling and cytokine production. Journal of Medicinal Food 16 (5): 410–420.

    Article  PubMed  Google Scholar 

  42. Bae, G.S., K.C. Park, B.S. Koo, I.J. Jo, S.B. Choi, H.J. Song, and S.J. Park. 2012. Nardostachys jatamansi inhibits severe acute pancreatitis via mitogen-activated protein kinases. Experimental and Therapeutic Medicine 4 (3): 533–537.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2016R1A2B4007472).

Author information

Author notes

  1. Wonmin Ko and Jin-Soo Park contributed equally to this work.

Affiliations

  1. College of Pharmacy, Wonkwang University, Iksan, 54538, Republic of Korea

    Wonmin Ko, Jin-Soo Park, Kwan-Woo Kim, Jongwon Kim, Youn-Chul Kim & Hyuncheol Oh

Authors
  1. Wonmin Ko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin-Soo Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kwan-Woo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jongwon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Youn-Chul Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hyuncheol Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hyuncheol Oh.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ko, W., Park, JS., Kim, KW. et al. Nardosinone-Type Sesquiterpenes from the Hexane Fraction of Nardostachys jatamansi Attenuate NF-κB and MAPK Signaling Pathways in Lipopolysaccharide-Stimulated BV2 Microglial Cells. Inflammation 41, 1215–1228 (2018). https://doi.org/10.1007/s10753-018-0768-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-018-0768-9

KEY WORDS

  • Nardostachys jatamansi
  • sesquiterpene
  • nuclear factor-kappa B (NF-κB)
  • mitogen-activated protein kinase (MAPK)
  • anti-neuroinflammation