DOI QR코드

DOI QR Code

Kalopanaxsaponin A Exerts Anti-Inflammatory Effects in Lipopolysaccharide-Stimulated Microglia via Inhibition of JNK and NF-κB/AP-1 Pathways

  • Received : 2013.09.04
  • Accepted : 2013.09.23
  • Published : 2013.09.30

Abstract

Microglial activation plays an important role in the development and progression of various neurological disorders such as cerebral ischemia, multiple sclerosis, and Alzheimer's disease. Thus, controlling microglial activation can serve as a promising therapeutic strategy for such brain diseases. In the present study, we showed that kalopanaxsaponin A, a triterpenoid saponin isolated from Kalopanax pictus, inhibited inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and tumor necrosis factor (TNF)-${\alpha}$ expression in lipopolysaccharide (LPS)-stimulated microglia, while kalopanaxsaponin A increased anti-inflammatory cytokine interleukin (IL)-10 expression. Subsequent mechanistic studies revealed that kalopanaxsaponin A inhibited LPS-induced DNA binding activities of NF-${\kappa}B$ and AP-1, and the phosphorylation of JNK without affecting other MAP kinases. Furthermore, kalopanaxsaponin A inhibited the intracellular ROS production with upregulation of anti-inflammatory hemeoxygenase-1 (HO-1) expression. Based on the previous reports that JNK pathway is largely involved in iNOS and proinflammatory cytokine gene expression via modulating NF-${\kappa}B$/AP-1 and ROS, our data collectively suggest that inhibition of JNK pathway plays a key role in anti-inflammatory effects of kalopanaxsaponin A in LPS-stimulated microglia.

Keywords

Microglia;Kalopanaxsaponin A;Anti-inflammation;JNK;NF-${\kappa}B$;AP-1

References

  1. Bedard, K. and Krause, K. H. (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol. Rev. 87, 245-313. https://doi.org/10.1152/physrev.00044.2005
  2. Block, M. L., Zecca, L. and Hong, J. S. (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 8, 57-69. https://doi.org/10.1038/nrn2038
  3. Bocchini, V., Mazzolla, R., Barluzzi, R., Blasi, E. and Sick, P. (1992) An immortalized cell line expresses properties of activated microglial cells. J. Neurosci. Res. 31, 616-621. https://doi.org/10.1002/jnr.490310405
  4. Gao, H. M., Zhou, H. and Hong J. S. (2012) NADPH oxidases: novel therapeutic targets for neurodegenerative diseases. Trends. Pharmacol. Sci. 33, 295-303. https://doi.org/10.1016/j.tips.2012.03.008
  5. Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C. and Gage, F. H. (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918-934. https://doi.org/10.1016/j.cell.2010.02.016
  6. Graeber, M. B. and Streit, W. J. (2010) Microglia: biology and pathology. Acta Neuropathol. 119, 89-105. https://doi.org/10.1007/s00401-009-0622-0
  7. Hwang, Y. S., Park, K. K. and Chung, W. Y. (2012) Kalopanaxsaponin A inhibits the invasion of human oral squamous cell carcinoma by reducing metalloproteinase-9 mRNA stability and protein trafficking. Biol. Pharm. Bull. 35, 289-300. https://doi.org/10.1248/bpb.35.289
  8. Jeong, Y. H., Jung, J. S., Le, T. K., Kim, D. H. and Kim, H. S. (2013) Lancemaside A inhibits microglial activation via modulation of JNK signaling pathway. Biochem. Biophys. Res. Commun. 431, 369-375. https://doi.org/10.1016/j.bbrc.2013.01.049
  9. Joh, E. H. and Kim, D.H. (2011) Kalopanaxsaponin A ameliorates experimental colitis in mice by inhibiting IRAK-1 activation in the NFkB and MAPK pathways. Br. J. Pharmacol. 162, 1731-1742. https://doi.org/10.1111/j.1476-5381.2010.01195.x
  10. Joh, E. H., Lee I. A. and Kim, D. H. (2012) Kalopanaxsaponins A and B isolated from Kalopanax pictus ameliorate memory deficits in mice. Phytother. Res. 26, 546-551. https://doi.org/10.1002/ptr.3596
  11. Jung, J. S., Shin, J. A., Park, E. M., Lee, J. E., Kang, Y. S., Min, S. W., Kim, D. H., Hyun, J. W., Shin, C. Y. and Kim, H. S. (2010) Anti-inflammatory mechanism of ginsenoside Rh1 in lipopolysaccharide-stimulated microglia: critical role of the protein kinase A pathway and hemeoxygenase-1 expression. J. Neurochem. 115, 1668-1680. https://doi.org/10.1111/j.1471-4159.2010.07075.x
  12. Kaminska, B. (2005) MAPK signaling pathways as molecular targets for anti-inflammatory therapy-from molecular mechanisms to therapeutic benefits. Biochem. Biophys. Acta 1754, 253-262. https://doi.org/10.1016/j.bbapap.2005.08.017
  13. Keum, Y. S. (2012) Regulation of Nrf2-mediated phase II detoxification and anti-oxidant genes. Biomol. Ther. 20, 144-151. https://doi.org/10.4062/biomolther.2012.20.2.144
  14. Kim, D. H., Bae, E. A., Han, M. J., Park, H. J. and Choi, J. W. (2002a) Metabolism of kalopanaxsaponin A by human intestinal bacteria and antirhematoid arthritis activity of their metabolites. Biol. Pharm. Bull. 25, 68-71. https://doi.org/10.1248/bpb.25.68
  15. Kim, Y. K., Kim, R. G., Park, S. J., Ha J. H., Choi, J. W., Park, H. J. and Lee K. T. (2002b) In vitro antiinflammatory activity of kalopanaxsaponin A isolated from Kalopanax pictus in murine macrophage RAW 264.7 cells. Biol. Pharm. Bull. 25, 472-476. https://doi.org/10.1248/bpb.25.472
  16. Lee, E. B., Li, D. W., Hyun, J. E., Kim, I. H. and Whang, W. K. (2001) Anti-inflammatory activity of methanol extract of Kalopanax pictus bark and its fractions. J. Ethnopharmacol. 77, 197-201. https://doi.org/10.1016/S0378-8741(01)00301-4
  17. Lee, K. M., Kang, H. S., Yun, C. H. and Kwak H. S. (2012) Potential in vitro protective effect of quercetin, catechin, caffeic acid and phytic acid against ethanol-induced oxidative stress in SK-Hep-1 cells. Biomol. Ther. 20, 492-498. https://doi.org/10.4062/biomolther.2012.20.5.492
  18. Park, H. J., Kim, D. H., Choi, J. W., Park, J. H. and Han, Y. N. (1998) A potent anti-diabetic agent from Kalopanax pictus. Arch. Pharm. Res. 21, 24-29. https://doi.org/10.1007/BF03216748
  19. Park, H. J., Kwon, S. H., Lee, J. H., Lee, K. H., Miyamoto K. and Lee K. T. (2001) Kalopanaxsaponin A is a basic saponin structure for the anti-tumor activity of hederagenin monodesmosides. Planta Med. 67, 118-121. https://doi.org/10.1055/s-2001-11516
  20. Park J. S., Park E. M., Kim D. H., Jung K., Jung J. S., Lee E. J., Hyun J. W., Kang J. L. and Kim H. S. (2009a) Anti-inflammatory mechanism of ginseng saponins in activated microglia. J. Neuroimmunol. 209, 40-49. https://doi.org/10.1016/j.jneuroim.2009.01.020
  21. Park, S. K., Hwang, Y. S., Park, K. K., Park, H. J., Seo J. Y. and Chung, W. Y. (2009b) Kalopanaxsaponin A inhibits PMA-induced invasion by reducing matrix metalloproteinase-9 via PI3K/Akt- and $PKC{\delta}$-mediated signaling in MCF-7 human breast cancer cells. Carcinogenesis 30, 1225-1233. https://doi.org/10.1093/carcin/bgp111
  22. Quang, T. H., Ngan N. T., Van Minh C., Van Kiem P., Nhiem N. X., Tai B. H., Thao N. P., Chae D., Mathema V.B, Koh Y. S., Lee J. H., Yang S. Y. and Kim Y. H. (2013) Inhibitory effects of oleanane-type triterpenes and saponins from the stem bark of Kalopanax pictus on LPS-stimulated pro-inflammatory cytokine production in bone marrow-derived dendritic cells. Arch. Pharm. Res. 36, 327-334. https://doi.org/10.1007/s12272-013-0031-8
  23. Tremblay, M. E., Stevens, B., Sierra, A., Wake, H., Bessis, A. and Nimmerjahn, A. (2011) The role of microglia in the healthy brain. J. Neurosci. 31, 16064-16069. https://doi.org/10.1523/JNEUROSCI.4158-11.2011
  24. Watkins, L. R. and Maier, S. F. (2003) Glia: a novel drug discovery target for clinical pain. Nat. Rev. Drug Discov. 2, 973-985. https://doi.org/10.1038/nrd1251
  25. Woo, M. S., Jang, P. G., Park, J. S., Kim, W. K. Joh, T. H. and Kim, H. S. (2003) Selective modulation of lipopolysaccharide-stimulated cytokine expression and mitogen-activated protein kinase pathways by dibutyryl-cAMP in BV2 microglial cells. Brain Res. Mol. Brain Res. 113, 86-96. https://doi.org/10.1016/S0169-328X(03)00095-0

Cited by

  1. Simultaneous quantitative analysis of nine triterpenoid saponins for the quality control ofStauntonia obovatifoliolaHayata subsp.intermediastems vol.37, pp.24, 2014, https://doi.org/10.1002/jssc.201400771
  2. AP-1-Targeted Inhibition of Macrophage Function and Lipopolysaccharide/D-Galactosamine-Induced Hepatitis by Phyllanthus acidus Methanolic Extract vol.43, pp.06, 2015, https://doi.org/10.1142/S0192415X15500652
  3. In vivo and in vitro anti-inflammatory activities of Persicaria chinensis methanolic extract targeting Src/Syk/NF-κB vol.159, 2015, https://doi.org/10.1016/j.jep.2014.10.064
  4. Etanercept Alleviates Early Brain Injury Following Experimental Subarachnoid Hemorrhage and the Possible Role of Tumor Necrosis Factor-α and c-Jun N-Terminal Kinase Pathway vol.40, pp.3, 2015, https://doi.org/10.1007/s11064-014-1506-9
  5. HPLC-ESI-MS/MS validation and pharmacokinetics of kalopanaxsaponin A in rats vol.5, pp.10, 2015, https://doi.org/10.1039/C4RA14264K
  6. In vitro antioxidative and anti-inflammatory effects of the compound K-rich fraction BIOGF1K, prepared from Panax ginseng vol.41, pp.1, 2017, https://doi.org/10.1016/j.jgr.2015.12.009
  7. Butein provides neuroprotective and anti-neuroinflammatory effects through Nrf2/ARE-dependent haem oxygenase 1 expression by activating the PI3K/Akt pathway vol.173, pp.19, 2016, https://doi.org/10.1111/bph.13569
  8. Therapeutically Targeting Neuroinflammation and Microglia after Acute Ischemic Stroke vol.2014, 2014, https://doi.org/10.1155/2014/297241
  9. Pycnogenol Attenuates the Release of Proinflammatory Cytokines and Expression of Perilipin 2 in Lipopolysaccharide-Stimulated Microglia in Part via Inhibition of NF-κB and AP-1 Activation vol.10, pp.9, 2015, https://doi.org/10.1371/journal.pone.0137837
  10. AP-1-Targeting Anti-Inflammatory Activity of the Methanolic Extract ofPersicaria chinensis vol.2015, 2015, https://doi.org/10.1155/2015/608126
  11. Methyl syringate, a TRPA1 agonist represses hypoxia-induced cyclooxygenase-2 in lung cancer cells vol.23, pp.3, 2016, https://doi.org/10.1016/j.phymed.2016.01.009
  12. Chondroprotective Effects of a Standardized Extract (KBH-JP-040) from Kalopanax pictus, Hericium erinaceus, and Astragalus membranaceus in Experimentally Induced In Vitro and In Vivo Osteoarthritis Models vol.10, pp.3, 2018, https://doi.org/10.3390/nu10030356
  13. Gleditsia Saponin C Induces A549 Cell Apoptosis via Caspase-Dependent Cascade and Suppresses Tumor Growth on Xenografts Tumor Animal Model vol.8, pp.1663-9812, 2018, https://doi.org/10.3389/fphar.2017.00988