Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Galangin Suppresses Pro-Inflammatory Gene Expression in Polyinosinic-Polycytidylic Acid-Stimulated Microglial Cells

  • Choi, Min-Ji (Department of Molecular Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University) ;
  • Park, Jin-Sun (Department of Molecular Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University) ;
  • Park, Jung-Eun (Department of Molecular Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University) ;
  • Kim, Han Su (Department of Otorhinolaryngology, School of Medicine, Ewha Womans University) ;
  • Kim, Hee-Sun (Department of Molecular Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University)
  • Received : 2017.09.01
  • Accepted : 2017.09.19
  • Published : 2017.11.01
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Abstract

Galangin (3,5,7-trihydroxyflavone) is a polyphenolic compound abundant in honey and medicinal herbs, such as Alpinia officinarum. In this study, we investigated the anti-inflammatory effects of galangin under in vitro and in vivo neuroinflammatory conditions caused by polyinosinic-polycytidylic acid (poly(I:C)), a viral mimic dsRNA analog. Galangin suppressed the production of nitric oxide, reactive oxygen species, and pro-inflammatory cytokines in poly(I:C)-stimulated BV2 microglia. On the other hand, galangin enhanced anti-inflammatory interleukin (IL)-10 production. Galangin also suppressed the expression of pro-inflammatory markers in poly(I:C)-injected mouse brains. Further mechanistic studies showed that galangin inhibited poly(I:C)-induced nuclear factor (NF)-${\kappa}B$ activity and phosphorylation of Akt without affecting MAP kinases. Interestingly, galangin increased the expression and transcriptional activity of peroxisome proliferator-activated receptor (PPAR)-${\gamma}$, known to play an anti-inflammatory role. To investigate whether PPAR-${\gamma}$ is involved in the anti-inflammatory function of galangin, BV2 cells were pre-treated with PPAR-${\gamma}$ antagonist before treatment of galangin. We found that PPAR-${\gamma}$ antagonist significantly blocked galangin-mediated upregulation of IL-10 and attenuated the inhibition of tumor necrosis factor (TNF)-${\alpha}$ and IL-6 in poly(I:C)-stimulated microglia. In conclusion, our data suggest that PI3K/Akt, NF-${\kappa}B$, and PPAR-${\gamma}$ play a pivotal role in mediating the anti-inflammatory effects of galangin in poly(I:C)-stimulated microglia.

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References

  1. Ahmad, S. S., Akhtar, S., Jamal, Q. M., Rizvi, S. M., Kamal, M. A., Khan, M. K. and Siddiqui, M. H. (2016) Multiple targets for the management of Alzheimer's disease. CNS Neurol. Disord. Drug Targets 15, 1279-1289. https://doi.org/10.2174/1871527315666161003165855
  2. Bernado A. and Minghetti L. (2006) PPAR-${\gamma}$ agonists as regulators of microglial activation and brain inflammation. Curr. Pharm. Des. 12, 93-109. https://doi.org/10.2174/138161206780574579
  3. Bouhlel, M. A., Derudas, B., Rigamonti, E., Dievart, R., Brozek, J., Haulon, S. Zawadzki, C., Jude, B., Torpier, G., Marx, N., Staels, B. and Chinetti-Gbaguidi, G. (2007) PPAR${\gamma}$ activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab. 6, 137-143. https://doi.org/10.1016/j.cmet.2007.06.010
  4. Cherry, J. D., Olschowka, J. A. and O'Banion, M. K. (2014) Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J. Neuroinflammation 11, 98. https://doi.org/10.1186/1742-2094-11-98
  5. Chien, S. T., Shi, M. D., Lee, Y. C., Te, C. C. and Shih, Y. W. (2015) Galangin, a novel dietary flavonoid, attenuates metastatic feature via PKC/ERK signaling pathway in TPA-treated liver cancer HepG2 cells. Cancer Cell Int. 15, 15. https://doi.org/10.1186/s12935-015-0168-2
  6. Chung, J. H., Seo, A. Y., Chung, S. W., Kim, M. K., Leeuwenburgh, C., Yu, B. P. and Chung, H. Y. (2008) Molecular mechanism of PPAR in the regulation of age-related inflammation. Ageing Res. Rev. 7, 126-136. https://doi.org/10.1016/j.arr.2008.01.001
  7. Cunningham, C., Campion, S., Teeling, J., Felton, L. and Perry, V. H. (2007) The sickness behaviour and CNS inflammatory mediator profile induced by systemic challenge of mice with synthetic double-stranded RNA (poly I:C). Brain Behav. Immun. 21, 490-502. https://doi.org/10.1016/j.bbi.2006.12.007
  8. Cushnie, T. P., Hamilton, V. E., Chapman, D. G., Taylor, P. W. and Lam, A. J. (2007) Aggregation of Staphylococcus aureus following treatment with the antibacterial flavonol galangin. J. Appl. Microbiol. 103, 1562-1567. https://doi.org/10.1111/j.1365-2672.2007.03393.x
  9. Descamps, O., Spilman, P., Zhang, Q., Libeu, C. P., Poksay, K., Gorostiza, O., Campagna, J., Jagodzinska, B., Bredesen, D. E. and John, V. (2013) A${\beta}$PP-selective BACE inhibitors (ASBI): novel class of therapeutic agents for alzheimer's disease. J. Alzheimers Dis. 37, 343-355. https://doi.org/10.3233/JAD-130578
  10. 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
  11. 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
  12. Guo, A. J., Xie, H. Q., Choi, R. C., Zheng, K. Y., Bi, C. W., Xu, S. L., Dong, T. T. and Tsim, K. W. (2010) Galangin, a flavonol derived from Rhizoma Alpiniae Officinarum, inhibits acetylcholinesterase activity in vitro. Chem. Biol. Interact. 187, 246-248. https://doi.org/10.1016/j.cbi.2010.05.002
  13. Heo, M. Y., Sohn, S. J. and Au, W. W. (2001) Anti-genotoxicity of galangin as a cancer chemopreventive agent candidate. Mutat. Res. 488, 135-150. https://doi.org/10.1016/S1383-5742(01)00054-0
  14. Honmore, V. S., Kandhare, A. D., Kadam, P. P., Khedkar, V. M., Sarkar, D., Bodhankar, S. L., Zanwar, A. A., Rojatkar, S. R. and Natu, A. D. (2016) Isolates of Alpinia officinarum Hance as COX-2 inhibitors: Evidence from anti-inflammatory, antioxidant and molecular docking studies. Int. Immunopharmacol. 33, 8-17. https://doi.org/10.1016/j.intimp.2016.01.024
  15. Hoogland, I. C., Houbolt, C., van Westerloo, D. J., van Gool, W. A. and van de Beek, D. (2015) Systemic inflammation and microglial activation: systematic review of animal experiments. J. Neuroinflammation 12, 114. https://doi.org/10.1186/s12974-015-0332-6
  16. Huh, J., Jung, I., Choi, J., Baek, Y., Lee, J., Park, D. and Choi, D. (2013) The natural flavonoid galangin inhibits osteoclastic bone destruction and osteoclastogenesis by suppressing $NF-{\kappa}B$ in collagen-induced arthritis and bone marrow-derived macrophages. Eur. J. Pharmacol. 698, 57-66. https://doi.org/10.1016/j.ejphar.2012.08.013
  17. Jaganathan, S. K. and Mandal, M. (2009) Antiproliferative effects of honey and of its polyphenols: a review. J. Biomed. Biotechnol. 2009, 830616.
  18. Jeong, Y. H., Park, J. S., Kim, D. H., Kang, J. L. and Kim, H. S. (2017) Anti-inflammatory mechanism of lonchocarpine in LPS- or poly(I:C)-induced neuroinflammation. Pharmacol. Res. 119, 431-442. https://doi.org/10.1016/j.phrs.2017.02.027
  19. Kim, W. K., Hwang, S. Y., Oh, E. S., Pia, H. Z., Kim, K. W. and Han, I. O. (2004) TGF-${\beta}1$ represses activation and resultant death of microglia via inhibition of phosphatidylinositol 3-kinase activity. J. Immunol. 172, 7015-7023. https://doi.org/10.4049/jimmunol.172.11.7015
  20. Lee, E. J., Ko, H. M., Jeong, Y. H., Park, E. M. and Kim, H. S. (2015) ${\beta}$-Lapachone suppresses neuroinflammation by modulating the expression of cytokines and matrix metalloproteinases in activated microglia. J. Neuroinflammation 12, 133. https://doi.org/10.1186/s12974-015-0355-z
  21. Li, S., Wu, C., Zhu, L., Gao, J., Fang, J., Li, D., Fu, M., Liang, R., Wang, L., Cheng, M. and Yang, H. (2012) By improving regional cortical blood flow, attenuating mitochondrial dysfunction and sequential apoptosis galangin acts as a potential neuroprotective agent after acute ischemic stroke. Molecules 17, 13403-13423. https://doi.org/10.3390/molecules171113403
  22. Liu, Y. N., Zha, W. J., Ma, Y., Chen, F. F., Zhu, W., Ge, A., Zeng, X. N. and Huang, M. (2015) Galangin attenuates airway remodelling by inhibiting TGF-${\beta}1$-mediated ROS generation and MAPK/Akt phosphorylation in asthma. Sci. Rep. 5, 11758. https://doi.org/10.1038/srep11758
  23. Meyer, J. J., Afolayan, A. J., Taylor, M. B. and Erasmus, D. (1997) Antiviral activity of galangin isolated from the aerial parts of Helichrysum aureonitens. J. Ethnopharmacol. 56, 165-169. https://doi.org/10.1016/S0378-8741(97)01514-6
  24. Moynagh, P. N. (2005) TLR signalling and activation of IRFs: revisiting old friends from the $NF-{\kappa}B$ pathway. Trends Immunol. 26, 469-476. https://doi.org/10.1016/j.it.2005.06.009
  25. Qin, L., Wu, X., Block, M. L., Liu, Y., Breese, G. R., Hong, J. S., Knapp, D. J. and Crews, F. T. (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55, 453-462. https://doi.org/10.1002/glia.20467
  26. Rüweler, M., Anker, A., Gülden, M., Maser, E. and Seibert, H. (2008) Inhibition of peroxide-induced radical generation by plant polyphenols in C6 astroglioma cells. Toxicol. In vitro 22, 1377-1381. https://doi.org/10.1016/j.tiv.2008.02.019
  27. Saijo, K., Crotti, A. and Glass, C. K. (2013) Regulation of microglia activation and deactivation by nuclear receptors. Glia 61, 104-111. https://doi.org/10.1002/glia.22423
  28. Sastre, M., Dewachter, I., Landreth, G. E., Willson, T. M., Klockgether, T., van Leuven, F. and Heneka, M. T. (2003) Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J. Neurosci. 23, 9796-9804. https://doi.org/10.1523/JNEUROSCI.23-30-09796.2003
  29. Saponaro, C., Cianciulli, A., Calvello, R., Dragone, T., Iacobazzi, F. and Panaro, M. A. (2012) The PI3K/Akt pathway is required for LPS activation of microglial cells. Immunopharmacol. Immunotoxicol. 34, 858-865. https://doi.org/10.3109/08923973.2012.665461
  30. Sen, G. C. and Sarkar, S. N. (2005) Transcriptional signaling by double-stranded RNA: role of TLR3. Cytokine Growth Factor Rev. 16, 1-14. https://doi.org/10.1016/j.cytogfr.2005.01.006
  31. Ulland, T. K., Wang, Y. and Colonna, M. (2015) Regulation of microglial survival and proliferation in health and diseases. Semin. Immunol. 27, 410-415. https://doi.org/10.1016/j.smim.2016.03.011
  32. Zeng, H., Huang, P., Wang, X., Wu, J., Wu, M. and Huang, J. (2015) Galangin-induced down-regulation of BACE1 by epigenetic mechanisms in SH-SY5Y cells. Neuroscience 294, 172-181. https://doi.org/10.1016/j.neuroscience.2015.02.054
  33. Zhao, X. R., Gonzales, N. and Aronowski, J. (2015) Pleiotropic role of $PPAR{\gamma}$ in intracerebral hemorrhage: an intricate system involving Nrf2, RXR, and $NF-{\kappa}B$. CNS Neurosci. Ther. 21, 357-366. https://doi.org/10.1111/cns.12350
  34. Zolezzi, J. M., Santos, M. J., Bastias-Candia, S., Pinto, C., Godoy, J. A. and Inestrosa, N. C. (2017) PPARs in the central nervous system: roles in neurodegeneration and neuroinflammation. Biol. Rev. Camb. Philos. Soc. 92, 2046-2069. https://doi.org/10.1111/brv.12320

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