Chunghyuldan Downregulates the Activation of Transcription Factors NF - kB and AP-1 of BV-2 Cells Induced by Lipopolysaccharide

  • WEE Sung-SooK (College of Pharmacy, Kyung Hee University) ;
  • BAE Eun-Ah (College of Pharmacy, Kyung Hee University) ;
  • PARK Jin-Sun (Department of Neuroscience, Ewha Womans University Medical School) ;
  • KIM Hee-Sun (Department of Neuroscience, Ewha Womans University Medical School) ;
  • CHo Hee Jae (Kwangdong Central Research Institute, Kwangdong Pharm. Co., Ltd,) ;
  • Ryu Jong-Hoon (College of Pharmacy, Kyung Hee University) ;
  • KIM Dong-Hyun (College of Pharmacy, Kyung Hee University)
  • Published : 2005.12.01

Abstract

Chunghyuldan (Qingxuedan in Chinese) (CHD) has been used for patients with atherosclerosis and brain ischemia in Korea. To evaluate antiischemic activity of CHD, its antiinflammatory effect in lipopolysaccharide-induced BV-2 cells was investigated. CHD potently inhibited nitric oxide (NO) production in LPS-induced BV-2 cells with an $IC_{50}$ value of 4.8${\mu}g/ml$. CHD did not only inhibit mRNA and protein expression levels of inducible NO synthase and cyclooxygenase-2 in LPS-induced BV-2 cells, but also repressed mRNA expression levels of proinflammatory cytokines IL-l$\beta$ and TNF-$\alpha$. CHD also downregulated the activation of NF-kB and AP-l transcription factors induced by LPS. These results suggest that CHD may improve inflammatory brain ischemia by the downregulation the activation of NF-kB and AP-l transcription factors.

Keywords

References

  1. Appleton I., Tomlinsom A, Willoughby D.A, (1996). Induction of cyclo-oxygenase and nitric oxide synthase in inflammation. Adv. Pharmacol. 35, 27-78 https://doi.org/10.1016/S1054-3589(08)60274-4
  2. Barber, P.A, Demchuk, A.M., and Hirt, L. Buchan A.M., (2003). Biochemistry of ischemic stroke. Adv. Neurol. 92, 151-164
  3. Bartosik-Psujek, H., Belniak, E. and Stelmasiak, Z. (2003) Markers of inflammation in cerebral ischemia. Neurol. Sci. 24, 279280 https://doi.org/10.1007/s10072-003-0156-5
  4. Bocchini, V., Mazzolla, R, Barluzzi ,R, Blasi, E., Sick, P. and Kettenmann, H. (1992). An immortalized cell line expresses properties of activated microglial cells. J. Neurosci Res. 31, 616-621 https://doi.org/10.1002/jnr.490310405
  5. Chi, Y.S., Lim, H., Park, H. and Kim, H.P. (2003). Effects of wogonin, a plant flavone from Scutellaria radix, on skin inflammation: in vivo regulation of inflammation-associated gene expression. Biochem. Pharmacol. 66, 1271-1278 https://doi.org/10.1016/S0006-2952(03)00463-5
  6. Cho, K.H., Kim, Y.S., Bae, H.S., Moon, S.K., Jung, W.S., Park, E.K. and Kim D.H. (2004). Inhibitory effect of Chunghyuldan in prostaglandin E2 and nitric oxide biosynthesis of lipopolysaccharide-induced RAW 264.7 cells. Biol. Pharm. Bull. 27,1810-1813 https://doi.org/10.1248/bpb.27.1810
  7. Cho, K.H., Kang, H.S., Jung, W.S., Park, S.U. and Moon, S.K (2005). Efficacy and safety of Chunghyul-dan (qingwie-dan) in patients with hypercholesterolemia. Am. J. Chin. Med. 33, 241248
  8. Dolan, S., Field, L.C. and Nolan, A.M. (2000). The role of nitric oxide and prostaglandin signaling pathways in spinal nociceptive processing in chronic inflammation. Pain 86, 311-320 https://doi.org/10.1016/S0304-3959(00)00262-1
  9. Dubois, R.N., Abramson, S.B., Crofford, L., Gupta, R.A, Simon, L.S., Van De Putte, L.B.A. and Lipsky, P.E. (1998). Cyclooxygenase in biology and disease. FASEB J. 12, 1063-1073 https://doi.org/10.1096/fasebj.12.12.1063
  10. Flora, G., Lee, Y.W., Nath, A, Maragos, W., Hennig, B. and Toborek, M. (2002). Methamphetamine-induced TNF-alpha gene expression and activation of AP-1 in discrete regions of mouse brain: potential role of reactive oxygen intermediates and lipid peroxidation. Neuromolecular Med. 2, 71-85 https://doi.org/10.1385/NMM:2:1:71
  11. Ishihara, T., Kohno, K, Ushio, S., Iwaki, K, Ikeda, M. and Kurimoto, M. (2000). Tryptanthrin inhibits nitric oxide and prostaglandin E(2) synthesis by murine macrophages. Eur. J. Pharmacol. 407, 197-204 https://doi.org/10.1016/S0014-2999(00)00674-9
  12. Jongeneel, C.V. (1995). Transcriptional regulation of the tumor necrosis factor alpha gene. lrnmunobiol. 193, 210-216
  13. Jung, W.S., Choi, D.J., Cho, K.H., Lee, K.S., Moon, S.K., Kim, Y.S. and Bae H.S. (2003). Safety and efficacy assessment of chungpyesagan-tang for acute ischemic stroke. Am. J. Chin. Med. 31,181-190 https://doi.org/10.1142/S0192415X03000898
  14. Khan, M., Sekhon, B., Jatana, M., Giri, S., Gilg, AG., Sekhon, C; Singh, I. and Singh, A.K (2004). Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. J. Neurosci. Res. 76, 519-27 https://doi.org/10.1002/jnr.20087
  15. Kim, Y.S., Jung, E.A, Shin, J.E., Chang, J.C, Yang, H.K., Kim, N.J., Cho, KH. and Kim, D.-H. (2002). Daio-Orengedokuto inhibits HMG-CoA reductase and pancreatic lipase. Biol. Pharm. Bull. 25, 1442-1445 https://doi.org/10.1248/bpb.25.1442
  16. Kim, W.K, Jang, P.G., Woo, M.S., Han, I.O., Pia, H.Z., Lee, K., Lee, H., Joh, T. and Kim H.S. (2004). A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia. Neuropharmacology 47, 243-252 https://doi.org/10.1016/j.neuropharm.2004.03.019
  17. Lennard, C.M., Mann, E.A, Sun, L.L., Chang, A.S. and Bolger W.E. (2000). Interleukin-1b, interleukin-5, interleukin-6, interleukin-8, and tumor necrosis factor-alpha in chronic sinusitis: response to systemic corticosteroids. Am. J. Rhinol. 14,367-73 https://doi.org/10.2500/105065800779954329
  18. Lindsberg, P.J. and Grau A.J. (2003). Inflammation and infections as risk factors for ischemic stroke. Stroke 34, 2518-2532 https://doi.org/10.1161/01.STR.0000089015.51603.CC
  19. Lowenstein, C.J., Alley, E.W, Rava, L.P., Snowman, A.M., Snyder, S.H., Russell, S.W and Murphy W.J. (1993). Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc. Natl. Acad. Sci. USA 90, 9730-9734
  20. MacMicking, J., Xie, Q.W and Nathan, C. (1997). Nitric oxide and macrophage function. Ann. Rev. Immunol. 15, 323-350 https://doi.org/10.1146/annurev.immunol.15.1.323
  21. Perkins, D.J. and Kniss, D.A (1999) Blockade of nitric oxide formation down-regulates cyclooxygenase-2 and decreases PGE2. biosynthesis in macrophages. J. Leukoc. Biol. 65, 792-799 https://doi.org/10.1002/jlb.65.6.792
  22. Reynolds, M.A, Kirchick, H.J., Dahlen, J.R., Anderberg, J.M., McPherson, P.H., Nakamura, K.K, Laskowitz, D.T., VaIkirs, G.E. and Buechler K.F. (2003). Early biomarkers of stroke. Clin. Chem. 49, 1733-1739 https://doi.org/10.1373/49.10.1733
  23. Ryu, S.Y., Ock, M.H. and Kim K.M. (2000). Yomogin inhibits the degranulation of mast cells and the production of the nitric oxide in activated RAW 264.7 cells. Planta Med. 66, 171-173 https://doi.org/10.1055/s-0029-1243124
  24. Saleh A, Schroeter, M., Jonkrnanns, C., Hartung, H.P., Modder U. and Jander S. (2004). In vivo MRI of brain inflammation in human ischaemic stroke. Brain 127, 1670-1677 https://doi.org/10.1093/brain/awh191
  25. Smith, W.L., Garavito, R.M. and DeWitt, D.L. (1996). Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. J. Biol. Chem. 271, 33157-33160 https://doi.org/10.1074/jbc.271.52.33157
  26. Stefanovic-Racic, S., Stadler, J. and Evans, C.H. (1993). Nitric oxide and arthritis. Arthritis Rheum. 36, 1036-1044 https://doi.org/10.1002/art.1780360803
  27. Valles, S.L., Blanco, A.M., Pascual, M. and Guerri C. (2004). Chronic ethanol treatment enhances inflammatory mediators and cell death in the brain and in astrocytes. Brain Pathol. 14, 365-371 https://doi.org/10.1111/j.1750-3639.2004.tb00079.x