Abstract
Microglia are considered as a major target in the prevention of neuroinflammation by modulating the production of pro-inflammatory mediators. Artesunate, a water-soluble artemisinin derivative, exerts an anti-inflammatory effect. In the present study, we showed artesunate dose-dependently suppressed the lipopolysaccharide (LPS)-induced production of nitric oxide (NO), inducible nitric oxide synthase (iNOS), and interleukin-1beta (IL-1β) in BV2 microglial cells. In addition, artesunate inhibited LPS-induced expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and activation of nuclear factor kappa B (NF-κB) by blockade of inhibitor of NF-κB (IκB) degradation. This data indicate that artesunate attenuates the generation of proinflammatory mediators on LPS-stimulated BV-2 microglial cells. And this effect may be associated with the suppression of TLR4/MyD88/NF-κB signaling pathways. Therefore, artesunate may be a potential anti-neuroinflammatory agent.
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Ransohoff, R.M., and V.H. Perry. 2009. Microglial physiology: unique stimuli, specialized responses. Annual Review of Immunology 27: 119–145.
Brown, G.C., and J.J. Neher. 2010. Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Molecular Neurobiology 41: 242–247.
Nelson, P.T., L.A. Soma, and E. Lavi. 2002. Microglia in diseases of the central nervous system. Annals of Medicine 34: 491–500.
Meshnick, S.R., T.E. Taylor, and S. Kamchonwongpaisan. 1996. Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiological Reviews 60: 301–315.
Xu, H., Y. He, X. Yang, L. Liang, Z. Zhan, Y. Ye, X. Yang, F. Lian, and L. Sun. 2007. Anti-malarial agent artesunate inhibits TNF-alpha-induced production of proinflammatory cytokines via inhibition of NF-kappaB and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes. Rheumatology 46: 920–926.
Chen, H.H., H.J. Zhou, G.D. Wu, and X.E. Lou. 2004. Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGF receptor KDR/flk-1. Pharmacology 71: 1–9.
Efferth, T., H. Dunstan, A. Sauerbrey, H. Miyachi, and C.R. Chitambar. 2001. The anti-malarial artesunate is also active against cancer. International Journal of Oncology 18: 767–773.
Li, B., R. Zhang, J. Li, L. Zhang, G. Ding, P. Luo, S. He, Y. Dong, W. Jiang, Y. Lu, H. Cao, J. Zheng, and H. Zhou. 2008. Antimalarial artesunate protects sepsis model mice against heat-killed Escherichia coli challenge by decreasing TLR4, TLR9 mRNA expressions and transcription factor NF-kappa B activation. International Immunopharmacology 8: 379–389.
Wang, X., L. Stridh, W. Li, J. Dean, A. Elmgren, L. Gan, K. Eriksson, H. Hagberg, and C. Mallard. 2009. Lipopolysaccharide sensitizes neonatal hypoxic-ischemic brain injury in a MyD88-dependent manner. The Journal of Immunology: Official Journal of the American Association of Immunologists 183: 7471–7477.
Okorji, U.P., and O.A. Olajide. 2014. A semi-synthetic derivative of artemisinin, artesunate inhibits prostaglandin E2 production in LPS/IFNgamma-activated BV2 microglia. Bioorganic & Medicinal Chemistry 22: 4726–4734.
Zhu, C., Z. Xiong, X. Chen, F. Peng, X. Hu, Y. Chen, and Q. Wang. 2012. Artemisinin attenuates lipopolysaccharide-stimulated proinflammatory responses by inhibiting NF-kappaB pathway in microglia cells. PLoS ONE 7: e35125.
Lee, I.S., D.K. Ryu, J. Lim, S. Cho, B.Y. Kang, and H.J. Choi. 2012. Artesunate activates Nrf2 pathway-driven anti-inflammatory potential through ERK signaling in microglial BV2 cells. Neuroscience Letters 509: 17–21.
Gonzalez, H., D. Elgueta, A. Montoya, and R. Pacheco. 2014. Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases. Journal of Neuroimmunology 274: 1–13.
Pais, T.F., E.M. Szego, O. Marques, L. Miller-Fleming, P. Antas, P. Guerreiro, R.M. de Oliveira, B. Kasapoglu, and T.F. Outeiro. 2013. The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation. The EMBO Journal 32: 2603–2616.
Zhang, L., J. Zhang, L. Yang, Y. Dong, Y. Zhang, and Z. Xie. 2013. Isoflurane and sevoflurane increase interleukin-6 levels through the nuclear factor-kappa B pathway in neuroglioma cells. British Journal of Anaesthesia 110(Suppl 1): i82–91.
Kingwell, K. 2012. Neurodegenerative disease: microglia in early disease stages. Nature Reviews. Neurology 8: 475.
Kang, C.H., R.G. Jayasooriya, M.G. Dilshara, Y.H. Choi, Y.K. Jeong, N.D. Kim, and G.Y. Kim. 2012. Caffeine suppresses lipopolysaccharide-stimulated BV2 microglial cells by suppressing Akt-mediated NF-kappaB activation and ERK phosphorylation. Food and Chemical Toxicology: an International Journal Published for the British Industrial Biological Research Association 50: 4270–4276.
Zhu, H.T., C. Bian, J.C. Yuan, W.H. Chu, X. Xiang, F. Chen, C.S. Wang, H. Feng, and J.K. Lin. 2014. Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-kappaB signaling pathway in experimental traumatic brain injury. Journal of Neuroinflammation 11: 59.
Zhong, L.M., Y. Zong, L. Sun, J.Z. Guo, W. Zhang, Y. He, R. Song, W.M. Wang, C.J. Xiao, and D. Lu. 2012. Resveratrol inhibits inflammatory responses via the mammalian target of rapamycin signaling pathway in cultured LPS-stimulated microglial cells. PLoS ONE 7: e32195.
de Vries, P.J., and T.K. Dien. 1996. Clinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malaria. Drugs 52: 818–836.
Kim, H.G., J.H. Yang, E.H. Han, J.H. Choi, T. Khanal, M.H. Jeong, T.C. Jeong, and H.G. Jeong. 2013. Inhibitory effect of dihydroartemisinin against phorbol ester-induced cyclooxygenase-2 expression in macrophages. Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association 56: 93–99.
Wang, Y., Z. Huang, L. Wang, S. Meng, Y. Fan, T. Chen, J. Cao, R. Jiang, and C. Wang. 2011. The anti-malarial artemisinin inhibits pro-inflammatory cytokines via the NF-kappaB canonical signaling pathway in PMA-induced THP-1 monocytes. International Journal of Molecular Medicine 27: 233–241.
Smith, J.A., A. Das, S.K. Ray, and N.L. Banik. 2012. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Research Bulletin 87: 10–20.
Crampton, S.J., L.M. Collins, A. Toulouse, Y.M. Nolan, and G.W. O’Keeffe. 2012. Exposure of foetal neural progenitor cells to IL-1beta impairs their proliferation and alters their differentiation—a role for maternal inflammation. Journal of Neurochemistry 120: 964–973.
Rothwell, N., S. Allan, and S. Toulmond. 1997. The role of interleukin 1 in acute neurodegeneration and stroke: pathophysiological and therapeutic implications. The Journal of Clinical Investigation 100: 2648–2652.
Yao, L., E.M. Kan, J. Lu, A. Hao, S.T. Dheen, C. Kaur, and E.A. Ling. 2013. Toll-like receptor 4 mediates microglial activation and production of inflammatory mediators in neonatal rat brain following hypoxia: role of TLR4 in hypoxic microglia. Journal of Neuroinflammation 10: 23.
Zhang, G., and S. Ghosh. 2001. Toll-like receptor-mediated NF-kappaB activation: a phylogenetically conserved paradigm in innate immunity. The Journal of Clinical Investigation 107: 13–19.
Zhang, P., X.M. Chen, B.D. Luo, Q. Tan, F. Zou, W.R. Wan, and J.Q. Guo. 2006. Effects of artesunate on CD14 and toll-like receptor 4 in peritoneal macrophages of mice with heat stroke endotoxemia. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi = Zhonghua Laodong Weisheng Zhiyebing Zazhi = Chinese Journal of Industrial Hygiene and Occupational Diseases 24: 226–228.
Mankan, A.K., M.W. Lawless, S.G. Gray, D. Kelleher, and R. McManus. 2009. NF-kappaB regulation: the nuclear response. Journal of Cellular and Molecular Medicine 13: 631–643.
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This research was funded by the affiliated hospital of Xuzhou Medical College (No. 2013104049). Additional support is provided by the neurobiology laboratory of Xuzhou Medical College.
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Wang, D., Shi, J., Lv, S. et al. Artesunate Attenuates Lipopolysaccharide-Stimulated Proinflammatory Responses by Suppressing TLR4, MyD88 Expression, and NF-κB Activation in Microglial Cells. Inflammation 38, 1925–1932 (2015). https://doi.org/10.1007/s10753-015-0172-7
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DOI: https://doi.org/10.1007/s10753-015-0172-7