Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Vaccinium bracteatum Thunb. Exerts Anti-Inflammatory Activity by Inhibiting NF-κB Activation in BV-2 Microglial Cells

  • Kwon, Seung-Hwan (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Ma, Shi-Xun (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Ko, Yong-Hyun (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Seo, Jee-Yeon (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Lee, Bo-Ram (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Lee, Taek Hwan (College of Pharmacy, Yonsei University) ;
  • Kim, Sun Yeou (College of Pharmacy, Gachon University) ;
  • Lee, Seok-Yong (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Jang, Choon-Gon (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University)
  • Received : 2015.12.14
  • Accepted : 2016.03.08
  • Published : 2016.09.01
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Abstract

This study was designed to evaluate the pharmacological effects of Vaccinium bracteatum Thunb. methanol extract (VBME) on microglial activation and to identify the underlying mechanisms of action of these effects. The anti-inflammatory properties of VBME were studied using lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. We measured the production of nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase (COX)-2, prostaglandin $E_2$ ($PGE_2$), tumor necrosis factor-alpha (TNF-${\alpha}$), interleukin-1 beta (IL-$1{\beta}$), and interleukin-6 (IL-6) as inflammatory parameters. We also examined the effect of VBME on intracellular reactive oxygen species (ROS) production and the activity of nuclear factor-kappa B p65 (NF-${\kappa}B$ p65). VBME significantly inhibited LPS-induced production of NO and $PGE_2$ and LPS-mediated upregulation of iNOS and COX-2 expression in a dose-dependent manner; importantly, VBME was not cytotoxic. VBME also significantly reduced the generation of the pro-inflammatory cytokines TNF-${\alpha}$, IL-$1{\beta}$, and IL-6. In addition, VBME significantly dampened intracellular ROS production and suppressed NF-${\kappa}B$ p65 translocation by blocking $I{\kappa}B-{\alpha}$ phosphorylation and degradation in LPS-stimulated BV2 cells. Our findings indicate that VBME inhibits the production of inflammatory mediators in BV-2 microglial cells by suppressing NF-${\kappa}B$ signaling. Thus, VBME may be useful in the treatment of neurodegenerative diseases due to its ability to inhibit inflammatory mediator production in activated BV-2 microglial cells.

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References

  1. Ahmad, A., Khan, M. M., Hoda, M. N., Raza, S. S., Khan, M. B., Javed, H., Ishrat, T., Ashafaq, M., Ahmad, M. E., Safhi, M. M. and Islam, F. (2011) Quercetin protects against oxidative stress associated damages in a rat model of transient focal cerebral ischemia and reperfusion. Neurochem. Res. 36, 1360-1371. https://doi.org/10.1007/s11064-011-0458-6
  2. Amor, S., Puentes, F., Baker, D. and van der Valk, P. (2010) Inflammation in neurodegenerative diseases. Immunology 129, 154-169. https://doi.org/10.1111/j.1365-2567.2009.03225.x
  3. Bauer, M. and Bauer, I. (2002) Heme oxygenase-1: redox regulation and role in the hepatic response to oxidative stress. Antioxid. Redox. Signal. 4, 749-758. https://doi.org/10.1089/152308602760598891
  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. Cunningham, C. (2013) Microglia and neurodegeneration: the role of systemic inflammation. Glia 61, 71-90. https://doi.org/10.1002/glia.22350
  6. Dajas, F., Rivera, F., Blasina, F., Arredondo, F., Echeverry, C., Lafon, L., Morquio, A. and Heinzen, H. (2003) Cell culture protection and in vivo neuroprotective capacity of flavonoids. Neurotox. Res. 5, 425-432. https://doi.org/10.1007/BF03033172
  7. Jayasooriya, R. G., Lee, K. T., Lee, H. J., Choi, Y. H., Jeong, J. W. and Kim, G. Y. (2014) Anti-inflammatory effects of ${\beta}$-hydroxyisovaleryl-shikonin in BV2 microglia are mediated through suppression of the PI3K/Akt/NF-${\kappa}B$ pathway and activation of the Nrf2/HO-1 pathway. Food Chem. Toxicol. 65, 82-89. https://doi.org/10.1016/j.fct.2013.12.011
  8. Kim, B. W., Koppula, S., Park, S. Y., Hwang, J. W., Park, P. J., Lim, J. H. and Choi, D. K. (2014) Attenuation of inflammatory-mediated neurotoxicity by Saururus chinensis extract in LPS-induced BV-2 microglia cells via regulation of NF-${\kappa}B$ signaling and anti-oxidant properties. BMC Complement. Altern. Med. 14, 502. https://doi.org/10.1186/1472-6882-14-502
  9. Kim, S., Kim, J. I., Choi, J. W., Kim, M., Yoon, N. Y., Choi, C. G., Choi, J. S. and Kim, H. R. (2013) Anti-inflammatory effect of hexane fraction from Myagropsis myagroides ethanolic extract in lipopolysaccharide-stimulated BV-2 microglial cells. J. Pharm. Pharmacol. 65, 895-906. https://doi.org/10.1111/jphp.12049
  10. Kim, S. H., Smith, C. J. and Van Eldik, L. J. (2004) Importance of MAPK pathways for microglial pro-inflammatory cytokine IL-1 beta production. Neurobiol. Aging 25, 431-439. https://doi.org/10.1016/S0197-4580(03)00126-X
  11. Ko, C. Y., Wang, W. L., Wang, S. M., Chu, Y. Y., Chang, W. C. and Wang, J. M. (2014) Glycogen synthase kinase-$3{\beta}$-mediated CCAAT/enhancer-binding protein delta phosphorylation in astrocytes promotes migration and activation of microglia/macrophages. Neurobiol. Aging 35, 24-34. https://doi.org/10.1016/j.neurobiolaging.2013.07.021
  12. Ko, H. M., Koppula, S., Kim, B. W., Kim, I. S., Hwang, B. Y., Suk, K., Park, E. J. and Choi, D. K. (2010) Inflexin attenuates proinflammatory responses and nuclear factor-kappaB activation in LPS-treated microglia. Eur. J. Pharmacol. 633, 98-106. https://doi.org/10.1016/j.ejphar.2010.02.011
  13. Kwon, S. H., Hong, S. I., Ma, S. X., Lee, S. Y. and Jang, C. G. (2015a) 3',4',7-Trihydroxyflavone prevents apoptotic cell death in neuronal cells from hydrogen peroxide-induced oxidative stress. Food Chem. Toxicol. 80, 41-51. https://doi.org/10.1016/j.fct.2015.02.014
  14. Kwon, S. H., Ma, S. X., Hong, S. I., Lee, S. Y. and Jang, C. G. (2015b) Lonicera japonica THUNB. Extract Inhibits Lipopolysaccharide-Stimulated Inflammatory Responses by Suppressing NF-${\kappa}B$ Signaling in BV-2 Microglial Cells. J. Med. Food 18, 762-775. https://doi.org/10.1089/jmf.2014.3341
  15. Lee, K., Lee, J. S., Jang, H. J., Kim, S. M., Chang, M. S., Park, S. H., Kim, K. S., Bae, J., Park, J. W., Lee, B., Choi, H. Y., Jeong, C. H. and Bu, Y. (2012) Chlorogenic acid ameliorates brain damage and edema by inhibiting matrix metalloproteinase-2 and 9 in a rat model of focal cerebral ischemia. Eur. J. Pharmacol. 689, 89-95. https://doi.org/10.1016/j.ejphar.2012.05.028
  16. Liu, H. T., Du, Y. G., He, J. L., Chen, W. J., Li, W. M., Yang, Z., Wang, Y. X. and Yu, C. (2010) Tetramethylpyrazine inhibits production of nitric oxide and inducible nitric oxide synthase in lipopolysaccharideinduced N9 microglial cells through blockade of MAPK and PI3K/Akt signaling pathways, and suppression of intracellular reactive oxygen species. J. Ethnopharmacol. 129, 335-343. https://doi.org/10.1016/j.jep.2010.03.037
  17. Lue, L. F., Walker, D. G. and Rogers, J. (2001) Modeling microglial activation in Alzheimer's disease with human postmortem microglial cultures. Neurobiol. Aging 22, 945-956. https://doi.org/10.1016/S0197-4580(01)00311-6
  18. Lull, M. E. and Block, M. L. (2010) Microglial activation and chronic neurodegeneration. Neurotherapeutics 7, 354-365. https://doi.org/10.1016/j.nurt.2010.05.014
  19. Park, S. Y., Jin, M. L., Kim, Y. H., Kim, Y. and Lee, S. J. (2012) Antiinflammatory effects of aromatic-turmerone through blocking of NF-${\kappa}$B, JNK, and p38 MAPK signaling pathways in amyloid ${\beta}$-stimulated microglia. Int. Immunopharmacol. 14, 13-20. https://doi.org/10.1016/j.intimp.2012.06.003
  20. Prasad, R. G., Choi, Y. H. and Kim, G. Y. (2015) Shikonin Isolated from Lithospermum erythrorhizon Downregulates Proinflammatory Mediators in Lipopolysaccharide-Stimulated BV2 Microglial Cells by Suppressing Crosstalk between Reactive Oxygen Species and NF-${\kappa}B$. Biomol.Ther. (Seoul) 23, 110-118. https://doi.org/10.4062/biomolther.2015.006
  21. Richetti, S. K., Blank, M., Capiotti, K. M., Piato, A. L., Bogo, M. R., Vianna, M. R. and Bonan, C. D. (2011) Quercetin and rutin prevent scopolamine-induced memory impairment in zebrafish. Behav. Brain Res. 217, 10-15. https://doi.org/10.1016/j.bbr.2010.09.027
  22. Schwartz, M. (2003) Macrophages and microglia in central nervous system injury: are they helpful or harmful? J. Cereb. Blood Flow Metab. 23, 385-394. https://doi.org/10.1097/01.WCB.0000061881.75234.5E
  23. Tansey, M. G., McCoy, M. K. and Frank-Cannon, T. C. (2007) Neuroinflammatory mechanisms in Parkinson's disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp. Neurol. 208, 1-25. https://doi.org/10.1016/j.expneurol.2007.07.004
  24. Teismann, P., Tieu, K., Cohen, O., Choi, D. K., Wu, D. C., Marks, D., Vila, M., Jackson-Lewis, V. and Przedborski, S. (2003) Pathogenic role of glial cells in Parkinson's disease. Mov. Disord. 18, 121-129. https://doi.org/10.1002/mds.10332
  25. Wang, L., Zhang, X. T., Zhang, H. Y., Yao, H. Y. and Zhang, H. (2010) Effect of Vaccinium bracteatum Thunb. leaves extract on blood glucose and plasma lipid levels in streptozotocin-induced diabetic mice. J. Ethnopharmacol. 130, 465-469. https://doi.org/10.1016/j.jep.2010.05.031
  26. Wang, L., Zhang, Y., Xu, M., Wang, Y., Cheng, S., Liebrecht, A., Qian, H., Zhang, H. and Qi, X. (2013) Anti-diabetic activity of Vaccinium bracteatum Thunb. leaves' polysaccharide in STZ-induced diabetic mice. Int. J. Biol. Macromol. 61, 317-321. https://doi.org/10.1016/j.ijbiomac.2013.07.028
  27. Wang, M. J., Lin, W. W., Chen, H. L., Chang, Y. H., Ou, H. C., Kuo, J. S., Hong, J. S. and Jeng, K. C. (2002) Silymarin protects dopaminergic neurons against lipopolysaccharide-induced neurotoxicity by inhibiting microglia activation. Eur. J. Neurosci. 16, 2103-2112. https://doi.org/10.1046/j.1460-9568.2002.02290.x
  28. Wilms, H., Zecca, L., Rosenstiel, P., Sievers, J., Deuschl, G. and Lucius, R. (2007) Inflammation in Parkinson's diseases and other neurodegenerative diseases: cause and therapeutic implications. Curr. Pharm. Des. 13, 1925-1928. https://doi.org/10.2174/138161207780858429
  29. Xi, J., Zhang, B., Luo, F., Liu, J. and Yang, T. (2012) Quercetin protects neuroblastoma SH-SY5Y cells against oxidative stress by inhibiting expression of Kruppel-like factor 4. Neurosci. Lett. 527, 115-120. https://doi.org/10.1016/j.neulet.2012.08.082
  30. Zbarsky, V., Datla, K. P., Parkar, S., Rai, D. K., Aruoma, O. I. and Dexter, D. T. (2005) Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson's disease. Free Radic. Res. 39, 1119-1125.
  31. Zhao, M., Zhou, A., Xu, L. and Zhang, X. (2014) The role of TLR4-mediated PTEN/PI3K/AKT/NF-${\kappa}B$ signaling pathway in neuroinflammation in hippocampal neurons. Neuroscience 269, 93-101. https://doi.org/10.1016/j.neuroscience.2014.03.039

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