Nardosinone-Type Sesquiterpenes from the Hexane Fraction of Nardostachys jatamansi Attenuate NF-κB and MAPK Signaling Pathways in Lipopolysaccharide-Stimulated BV2 Microglial Cells
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.
KEY WORDSNardostachys jatamansi sesquiterpene nuclear factor-kappa B (NF-κB) mitogen-activated protein kinase (MAPK) anti-neuroinflammation
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2016R1A2B4007472).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- 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.CrossRefPubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.PubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.PubMedPubMedCentralGoogle 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.PubMedPubMedCentralGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle Scholar