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Anti-inflammatory activity of Kyungok-go on Lipopolysaccharide-Stimulated BV-2 Microglia Cells

  • Hyun-Suk Song (Department of Pharmacology, School of Korean Medicine, Wonkwang University) ;
  • Ji-Yeong An (Department of Pharmacology, School of Korean Medicine, Wonkwang University) ;
  • Jin-Young Oh (Department of Pharmacology, School of Korean Medicine, Wonkwang University) ;
  • Dong-Uk Kim (Department of Pharmacology, School of Korean Medicine, Wonkwang University) ;
  • Bitna Kweon (Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University) ;
  • Sung-Joo Park (Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University) ;
  • Gi-Sang Bae (Department of Pharmacology, School of Korean Medicine, Wonkwang University)
  • Received : 2022.07.06
  • Accepted : 2022.09.08
  • Published : 2022.12.01

Abstract

Objectives: Kyungok-go (KOG) is a traditional multi-herbal medicine commonly used for enforcing weakened immunity for long time. Recently, there are several reports that KOG has anti-inflammatory and immuno-stimulatory activities in many experimental models. However, the protective effects of KOG on neuronal inflammation are still undiscovered. Thus, we investigated the neuro-protective activity of KOG on lipopolysaccharide (LPS)-stimulated mouse microglia cells. To find out KOG's anti-neuroinflammatory effects on microglial cells, we examined the production of nitrite using griess assay, and mRNA expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α using real time RT-PCR. In addition, to examine the regulating mechanisms of KOG, we investigated the protein expression of mitogen-activated protein kinases (MAPKs) and Iκ-Bα by western blot. KOG inhibited the elevation of nitrite, iNOS and COX-2 on LPS-stimulated BV2 cells. Also, KOG significantly inhibited the pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α on LPS-stimulated BV2 microglial cells. Moreover, KOG inhibited the activation of c-Jun N-terminal kinase (JNK), P38 and degradation of Iκ-Bα but not the activation of extracellular signal regulated kinase (ERK) on LPS-stimulated BV2 microglial cells. These results showed KOG has the anti-inflammatory effects through the inhibition on nitrite, iNOS, COX-2, IL-1β, IL-6, and TNF-α via the deactivation of JNK, p38 and nuclear factor (NF)-κB on LPS-stimulated BV2 microglial cells. Thereby, KOG could offer the new and promising treatment for neurodegenerative disease related to neuroinflammation.

Keywords

Acknowledgement

This paper was supported by the Wonkwang University in 2021.

References

  1. Kreutzberg G. W. (1996). Microglia: a sensor for pathological events in the CNS. Trends in neurosciences, 19(8), 312-318. https://doi.org/10.1016/0166-2236(96)10049-7
  2. Yang, I., Han, S. J., Kaur, G., Crane, C., & Parsa, A. T. (2010). The role of microglia in central nervous system immunity and glioma immunology. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 17(1), 6-10. https://doi.org/10.1016/j.jocn.2009.05.006
  3. Hansen, D. V., Hanson, J. E., & Sheng, M. (2018). Microglia in Alzheimer's disease. The Journal of cell biology, 217(2), 459-472. https://doi.org/10.1083/jcb.201709069
  4. Cai, Y., Liu, J., Wang, B., Sun, M., & Yang, H. (2022). Microglia in the Neuroinflammatory Pathogenesis of Alzheimer's Disease and Related Therapeutic Targets. Frontiers in immunology, 13, 856376. https://doi.org/10.3389/fimmu.2022.856376
  5. Kim, M.D. (2011) The literature study on the efficacy and manufacturing process of Gyeongoggo. J Oriental Medical Classics, 24(2), 51-64. https://doi.org/10.14369/SKMC.2011.24.2.051
  6. Park, MyungJae, Kim, Jeong-Soo, Lee, AhReum, Roh, Seong-Soo, Kwon, OJun, & Seo, Young-Bae. (2017). Inhibition of Inflammation by Kyeongok-go with Black ginseng in LPS-induced RAW 264.7 Macrophages. The Korea Journal of Herbology, 32(3), 19-27. https://doi.org/10.6116/KJH.2017.32.3.19
  7. Choi, J. H., Jang, M., Lee, J. I., Chung, W. S., & Cho, I. H. (2018). Neuroprotective Effects of a Traditional Multi-Herbal Medicine Kyung-Ok-Ko in an Animal Model of Parkinson's Disease: Inhibition of MAPKs and NF-κB Pathways and Activation of Keap1-Nrf2 Pathway. Frontiers in pharmacology, 9, 1444. https://doi.org/10.3389/fphar.2018.01444
  8. Lee, W., & Bae, J. S. (2019). Inhibitory effects of Kyung-Ok-Ko, traditional herbal prescription, on particulate matter-induced vascular barrier disruptive responses. International journal of environmental health research, 29(3), 301-311. https://doi.org/10.1080/09603123.2018.1542490
  9. Jang, M., Lee, M. J., Lee, J. M., Bae, C. S., Kim, S. H., Ryu, J. H., & Cho, I. H. (2014). Oriental medicine Kyung-Ok-Ko prevents and alleviates dehydroepiandrosterone-induced polycystic ovarian syndrome in rats. PloS one, 9(2), e87623. https://doi.org/10.1371/journal.pone.0087623
  10. Block, M. L., Zecca, L., & Hong, J. S. (2007). Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature reviews. Neuroscience, 8(1), 57-69. https://doi.org/10.1038/nrn2038
  11. Kim, W.K., Kim, L.H., & Jang, I.S. (2011) A Review Study of Scalp Acupuncture for Parkinson's Disease in China. J Oriental Neuropsychiatry, 22(4), 11-20. https://doi.org/10.7231/JON.2011.22.4.011
  12. Jeong, B.J., Kim, J.W., Kim, B.Y., Woo, S.H., Na, Y.J., Shim, H.J., Lee, W.H., Lee, J.Y., Seo, H.S., & Kim, Y.H. (2006) A case of tremor in Parkinson's disease treated with Korean medicine. J Int Korean Med, 27(4), 954-960. https://doi.org/10.22246/jikm.2017.38.2.103
  13. Heo. J. (1993) Donguibogam naegyeongpyeon. Seoul :Gyemyeong Publishing House. 78.
  14. Kim, H. J., Jung, S. W., Kim, S. Y., Cho, I. H., Kim, H. C., Rhim, H., Kim, M., & Nah, S. Y. (2018). Panax ginseng as an adjuvant treatment for Alzheimer's disease. Journal of ginseng research, 42(4), 401-411. https://doi.org/10.1016/j.jgr.2017.12.008
  15. Lee, B., Shim, I., Lee, H., & Hahm, D. H. (2011). Rehmannia glutinosa ameliorates scopolamine-induced learning and memory impairment in rats. Journal of microbiology and biotechnology, 21(8), 874-883. https://doi.org/10.4014/jmb.1104.04012
  16. Lee, Y., Gao, Q., Kim, E., Lee, Y., Park, S. J., Lee, H. E., Jang, D. S., & Ryu, J. H. (2015). Pretreatment with 5-hydroxymethyl-2-furaldehyde blocks scopolamine-induced learning deficit in contextual and spatial memory in male mice. Pharmacology, biochemistry, and behavior, 134, 57-64. https://doi.org/10.1016/j.pbb.2015.04.007
  17. Bae, E. A., Hyun, Y. J., Choo, M. K., Oh, J. K., Ryu, J. H., & Kim, D. H. (2004). Protective effect of fermented red ginseng on a transient focal ischemic rats. Archives of pharmacal research, 27(11), 1136-1140. https://doi.org/10.1007/BF02975119
  18. Cai, M., Shin, B. Y., Kim, D. H., Kim, J. M., Park, S. J., Park, C. S., Won, d., Hong, N. D., Kang, D. H., Yutaka, Y., & Ryu, J. H. (2011). Neuroprotective effects of a traditional herbal prescription on transient cerebral global ischemia in gerbils. Journal of ethnopharmacology, 138(3), 723-730. https://doi.org/10.1016/j.jep.2011.10.016
  19. Lull, M. E., & Block, M. L. (2010). Microglial activation and chronic neurodegeneration. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 7(4), 354-365. https://doi.org/10.1016/j.nurt.2010.05.014
  20. Lehnardt, S., Massillon, L., Follett, P., Jensen, F. E., Ratan, R., Rosenberg, P. A., Volpe, J. J., & Vartanian, T. (2003). Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proceedings of the National Academy of Sciences of the United States of America, 100(14), 8514-8519. https://doi.org/10.1073/pnas.1432609100
  21. Dawson, V. L., & Dawson, T. M. (1995). Physiological and toxicological actions of nitric oxide in the central nervous system. Advances in pharmacology (San Diego, Calif.), 34, 323-342. https://doi.org/10.1016/s1054-3589(08)61095-9
  22. Korhonen, R., Lahti, A., Hamalainen, M., Kankaanranta, H., & Moilanen, E. (2002). Dexamethasone inhibits inducible nitric-oxide synthase expression and nitric oxide production by destabilizing mRNA in lipopolysaccharide-treated macrophages. Molecular pharmacology, 62(3), 698-704. https://doi.org/10.1124/mol.62.3.698
  23. Bishop, A., & Anderson, J. E. (2005). NO signaling in the CNS: from the physiological to the pathological. Toxicology, 208(2), 193-205. https://doi.org/10.1016/j.tox.2004.11.034
  24. Williams, C. S., Mann, M., & DuBois, R. N. (1999). The role of cyclooxygenases in inflammation, cancer, and development. Oncogene, 18(55), 7908-7916. https://doi.org/10.1038/sj.onc.1203286
  25. Du, R. W., Du, R. H., & Bu, W. G. (2014). β-Arrestin 2 mediates the anti-inflammatory effects of fluoxetine in lipopolysaccharide-stimulated microglial cells. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 9(4), 582-590. https://doi.org/10.1007/s11481-014-9556-y
  26. Dong, C., Davis, R. J., & Flavell, R. A. (2002). MAP kinases in the immune response. Annual review of immunology, 20, 55-72. https://doi.org/10.1146/annurev.immunol.20.091301.131133
  27. Liu, Y., Shepherd, E. G., & Nelin, L. D. (2007). MAPK phosphatases--regulating the immune response. Nature reviews. Immunology, 7(3), 202-212. https://doi.org/10.1038/nri2035
  28. Viatour, P., Merville, M. P., Bours, V., & Chariot, A. (2005). Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. Trends in biochemical sciences, 30(1), 43-52. https://doi.org/10.1016/j.tibs.2004.11.009
  29. Kim, B. W., Koppula, S., Hong, S. S., Jeon, S. B., Kwon, J. H., Hwang, B. Y., Park, E. J., & Choi, D. K. (2013). Regulation of microglia activity by glaucocalyxin-A: attenuation of lipopolysaccharide-stimulated neuroinflammation through NF-κB and p38 MAPK signaling pathways. PloS one, 8(2), e55792. https://doi.org/10.1371/journal.pone.0055792