Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Quercetin Derivatives from Siegesbeckia glabrescens Inhibit the Expression of COX-2 Through the Suppression of NF-κB Activation in Microglia

  • Lim, Hyo-Jin (College of Pharmacy, Sookmyung Women's University) ;
  • Li, Hua (College of Pharmacy, Sookmyung Women's University) ;
  • Kim, Jae-Yeon (College of Pharmacy, Sookmyung Women's University) ;
  • Ryu, Jae-Ha (College of Pharmacy, Sookmyung Women's University)
  • Received : 2010.10.11
  • Accepted : 2010.11.09
  • Published : 2011.01.31
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Abstract

The activation of microglia induces the overproduction of inflammatory mediators that are responsible for the neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. The large amounts of prostaglandin $E_2$ ($PGE_2$) produced by inducible cyclooxygenase (COX-2) is one of the main inflammatory mediators that can contribute to neurodegeneration. The inhibition of COX-2 thus may provide therapeutic strategy for the treatment of neurodegenerative diseases. From the activity-guided purification of EtOAc soluble fraction of Siegesbeckia glabrescens, four compounds were isolated as inhibitors of $PGE_2$ production in LPS-activated microglia. Their structures were determined as 3, 4'-dimethylquercetin (1), 3, 7-dimethylquercetin (2), 3-methylquercetin (3) and 3, 7, 4'-trimethylquercetin (4) by the mass and NMR spectral data analysis. The compounds 1-4 showed dose-dependent inhibition of $PGE_2$ production in LPS-activated microglia with their $IC_{50}$ values of 7.1, 4.9, 4.4, $12.4\;{\mu}M$ respectively. They reduced the expression of protein and mRNA of COX-2 through the inhibition of I-${\kappa}B{\alpha}$ degradation and NF-$\kappa}B$ activity that were correlated with the inactivation of p38 and ERK. Therefore the active compounds from Siegesbeckia glabrescens may have therapeutic effects on neuro-inflammatory diseases through the inhibition of overproduction of $PGE_2$ and suppression of COX-2 overexpression.

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References

  1. Allen, R. G. and Tresini, M. (2000) Oxidative stress and gene regulation. Free Radic. Biol. Med. 28, 463-499. https://doi.org/10.1016/S0891-5849(99)00242-7
  2. Barbera, J., Marco, J. A., Sanz, J. F. and Sanchez-Parareda, J. (1986) 3-Methoxyfl avones and coumarins from Artemisia incanescens. Phytochem. 25, 2357-2360. https://doi.org/10.1016/S0031-9422(00)81695-7
  3. Bauer, M. K., Lieb, K., Schulze-Osthoff, K., Berger, M., Gebicke-Haerter, P. J., Bauer, J. and Fiebich, B. L. (1997) Expression and regulation of cyclooxygenase-2 in rat microglia. Eur. J. Biochem. 243, 726-731. https://doi.org/10.1111/j.1432-1033.1997.00726.x
  4. 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
  5. Brock, T. G., McNish, R. W. and Peters-Golden, M. (1999) Arachidonic acid is preferentially metabolized by cyclooxygenase-2 to prostacyclin and prostaglandin E2. J. Biol. Chem. 274, 11660-11666. https://doi.org/10.1074/jbc.274.17.11660
  6. Chen, Y. C., Shen, S. C., Lee, W. R., Hou, W. C., Yang, L. L. and Lee, T. J. (2001) Inhibition of nitric oxide synthase inhibitors and lipopolysaccharide induced inducible NOS and cyclooxygenase-2 gene expressions by rutin, quercetin, and quercetin pentaacetate in RAW 264.7 macrophages. J. Cell. Biochem. 82, 537-548. https://doi.org/10.1002/jcb.1184
  7. Gonzalez-Scarano, F. and Baltuch, G. (1999) Microglia as mediators of infl ammatory and degenerative diseases. Annu. Rev. Neurosci. 22, 219-240. https://doi.org/10.1146/annurev.neuro.22.1.219
  8. Harris, S. G., Padilla, J., Koumas, L., Ray, D. and Phipps, R. P. (2002) Prostaglandins as modulators of immunity. Trends Immunol. 23, 144-150. https://doi.org/10.1016/S1471-4906(01)02154-8
  9. Jun, S. Y., Choi, Y. H. and Shin, H. M. (2006) Siegesbeckia glabrescens induces apoptosis with different pathways in human MCF-7 and MDA-MB-231 breast carcinoma cells. Oncol. Rep. 15,1461-1467.
  10. Jung, W. K., Ahn, Y. W., Lee, S. H., Choi, Y. H., Kim, S. K., Yea, S. S., Choi, I., Park, S. G., Seo, S. K., Lee, S. W. and Choi, I. W. (2009) Ecklonia cava ethanolic extracts inhibit lipopolysaccharide-induced cyclooxygenase-2 and inducible nitric oxide synthase expression in BV2 microglia via the MAP kinase and NF-kappaB pathways. Food Chem. Toxicol. 47, 410-417. https://doi.org/10.1016/j.fct.2008.11.041
  11. Kim, H. M., Lee, J. H., Won, J. H., Park, E. J., Chae, H. J., Kim, H. R., Kim, C. H. and Baek, S. H. (2001) Inhibitory effect on immunoglobulin E production in vivo and in vitro by Siegesbeckia glabrescens. Phytother. Res. 15, 572-576. https://doi.org/10.1002/ptr.749
  12. Kim, J. Y., Lim, H. J. and Ryu, J. H. (2008) In vitro anti-infl ammatory activity of 3-O-methyl-fl avones isolated from Siegesbeckia glabrescens. Bioorg. Med. Chem. Lett. 18, 1511-1514. https://doi.org/10.1016/j.bmcl.2007.12.052
  13. Kim, Y. M., Lee, B. S., Yi, K. Y. and Paik, S. G. (1997) Upstream NF-kappaB site is required for the maximal expression of mouse inducible nitric oxide synthase gene in interferon-gamma plus lipopolysaccharide-induced RAW 264.7 macrophages. Biochem. Biophys. Res. Commun. 236, 655-660. https://doi.org/10.1006/bbrc.1997.7031
  14. Klein, J. A. and Ackerman, S. L. (2003) Oxidative stress, cell cycle, and neurodegeneration. J. Clin. Invest. 111, 785-793. https://doi.org/10.1172/JCI200318182
  15. Kyrkanides, S., Moore, A. H., Olschowka, J. A., Daeschner, J. C., Williams, J. P., Hansen, J. T. and Kerry O'Banion, M. (2002) Cyclooxygenase-2 modulates brain infl ammation-related gene expression in central nervous system radiation injury. Brain Res. Mol. Brain Res. 104, 159-169. https://doi.org/10.1016/S0169-328X(02)00353-4
  16. Lee, J., Hur, J., Lee, P., Kim, J. Y., Cho, N., Kim, S. Y., Kim, H., Lee, M. S. and Suk, K. (2001) Dual role of infl ammatory stimuli in activation-induced cell death of mouse microglial cells. Initiation of two separate apoptotic pathways via induction of interferon regulatory factor-1 and caspase-11. J. Biol. Chem. 276, 32956-32965. https://doi.org/10.1074/jbc.M104700200
  17. Lee, M. H., Kim, J. Y. and Ryu, J. H. (2005) Prenylfl avones from Psoralea corylifolia inhibit nitric oxide synthase expression through the inhibition of I-kappaB-alpha degradation in activated microglial cells. Biol. Pharm. Bull. 28, 2253-2257. https://doi.org/10.1248/bpb.28.2253
  18. Lehnardt, S., Massillon, L., Follett, P., Jensen, F. E., Ratan, R., Rosenberg, P. A., Volpe, J. J. and Vartanian, T. (2003) Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc. Natl. Acad. Sci. USA. 100, 8514-8519. https://doi.org/10.1073/pnas.1432609100
  19. McGeer, P. L. and McGeer, E. G. (1995) The infl ammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res. Brain Res. Rev. 21, 195-218. https://doi.org/10.1016/0165-0173(95)00011-9
  20. Minghetti, L. (2004) Cyclooxygenase-2 (COX-2) in infl ammatory and degenerative brain diseases. J. Neuropathol. Exp. Neurol. 63, 901-910.
  21. Moon, D. O., Choi, Y. H., Kim, N. D., Park, Y. M. and Kim, G. Y. (2007) Anti-inflammatory effects of beta-lapachone in lipopolysaccharide-stimulated BV2 microglia. Int. Immunopharmacol. 7, 506-514. https://doi.org/10.1016/j.intimp.2006.12.006
  22. Peri, K. G., Hardy, P., Li, D. Y., Varma, D. R. and Chemtob, S. (1995) Prostaglandin G/H synthase-2 is a major contributor of brain prostaglandins in the newborn. J. Biol. Chem. 270, 24615-24620. https://doi.org/10.1074/jbc.270.41.24615
  23. Perry, V. H. and Gordon, S. (1988) Macrophages and microglia in the nervous system. Trends Neurosci. 11, 273-277. https://doi.org/10.1016/0166-2236(88)90110-5
  24. Pradelles, P., Grassi, J. and Maclouf, J. (1985) Enzyme immunoassays of eicosanoids using acetylcholine esterase as label: an alternative to radioimmunoassay. Anal. Chem. 57, 1170-1173. https://doi.org/10.1021/ac00284a003
  25. Ramachandran Nair, A. G., Ramesh, P., Sankara Subramanian, S. and Joshi, B. S. (1978) Rare methylated flavonols from Angelonia grandiflora. Phytochem. 17, 591-592. https://doi.org/10.1016/S0031-9422(00)89390-5
  26. Ryu, J. H., Son, H. J., Lee, S. H. and Sohn, D. H. (2002) Two neolignans from Perilla frutescens and their inhibition of nitric oxide synthase and tumor necrosis factor-alpha expression in murine macrophage cell line RAW 264.7. Bioorg. Med. Chem. Lett. 12, 649-651. https://doi.org/10.1016/S0960-894X(01)00812-5
  27. Wang, Y., Hamburger, M., Gueho, J. and Hostettmann, K. (1989) Antimicrobial flavonoids from Psiadia trinervia and their methylated and acetylated derivatives. Phytochem. 28, 2323-2327. https://doi.org/10.1016/S0031-9422(00)97976-7
  28. Ye, J., Ghosh, P., Cippitelli, M., Subleski, J., Hardy, K. J., Ortaldo, J. R. and Young, H. A. (1994) Characterization of a silencer regulatory element in the human interferon-gamma promoter. J. Biol. Chem. 269, 25728-25734.
  29. Yoon, J. H., Lim, H. J., Lee, H. J., Kim, H. D., Jeon, R. and Ryu, J. H. (2008) Inhibition of lipopolysaccharide-induced inducible nitric oxide synthase and cyclooxygenase-2 expression by xanthanolides isolated from Xanthium strumarium. Bioorg. Med. Chem. Lett. 18, 2179-2182. https://doi.org/10.1016/j.bmcl.2007.12.076
  30. Zielasek, J. and Hartung, H. P. (1996) Molecular mechanisms of microglial activation. Adv. Neuroimmunol. 6, 191-222. https://doi.org/10.1016/0960-5428(96)00017-4

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