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Hydrogen-Rich Saline Ameliorates Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice Via the Nrf2-ARE Signaling Pathway

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Abstract

Multiple sclerosis (MS) is a chronic and inflammatory disease of the central nervous system that is associated with demyelination, neurodegeneration, and sensitivity to oxidative stress. Hydrogen-rich saline (HRS) is efficacious in preventive and therapeutic applications for many disorders because of its antioxidant and anti-inflammatory properties. Here, we determined the effect of HRS in experimental autoimmune encephalomyelitis (EAE), which is a generally accepted model of the immuno-pathogenic mechanisms underlying MS. We found that HRS reduced the severity of EAE in mice and alleviated inflammation and demyelination. Furthermore, treatment with HRS attenuated oxidative stress in EAE mice. Finally, the results of our study suggest that activation of the Nrf2-ARE pathway plays a critical role in the protective effects of HRS in EAE mice.

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References

  1. Milo, R., and E. Kahana. 2010. Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmunity Reviews 9 (5): A387–A394.

    Article  CAS  PubMed  Google Scholar 

  2. Multiple Sclerosis Therapy Consensus Group, H. Wiendl, K.V. Toyka, P. Rieckmann, R. Gold, H.P. Hartung, and R. Hohlfeld. 2008. Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations. Journal of Neurology 255 (10): 1449–1463.

    Article  CAS  Google Scholar 

  3. Miron, V.E., T. Kuhlmann, and J.P. Antel. 2011. Cells of the oligodendroglial lineage, myelination, and remyelination. Biochimica et Biophysica Acta 1812 (2): 184–193.

    Article  CAS  PubMed  Google Scholar 

  4. Ding, L., H. Gu, X. Gao, S. Xiong, and B. Zheng. 2015. Aurora kinase a regulates m1 macrophage polarization and plays a role in experimental autoimmune encephalomyelitis. Inflammation 38 (2): 800–811.

    Article  CAS  PubMed  Google Scholar 

  5. Hainz, N., S. Wolf, T. Tschernig, and C. Meier. 2016. Probenecid application prevents clinical symptoms and inflammation in experimental autoimmune encephalomyelitis. Inflammation 39 (1): 123–128.

    Article  CAS  PubMed  Google Scholar 

  6. Cai, Y., H. Shen, C. Qin, J. Zhou, W. Lai, J. Pan, and C. Du. 2017. The spatio-temporal expression profiles of CD4 + T cell differentiation and function-related genes during EAE pathogenesis. Inflammation 40 (1): 195–204.

    Article  CAS  PubMed  Google Scholar 

  7. Schreibelt, G., J. van Horssen, S. van Rossum, C.D. Dijkstra, B. Drukarch, and H.E. de Vries. 2007. Therapeutic potential and biological role of endogenous antioxidant enzymes in multiple sclerosis pathology. Brain Research Reviews 56 (2): 322–330.

    Article  CAS  PubMed  Google Scholar 

  8. van Meeteren, M.E., J.J. Hendriks, C.D. Dijkstra, and E.A. van Tol. 2004. Dietary compounds prevent oxidative damage and nitric oxide production by cells involved in demyelinating disease. Biochemical Pharmacology 67 (5): 967–975.

    Article  CAS  PubMed  Google Scholar 

  9. Xie, K., L. Liu, Y. Yu, and G. Wang. 2014. Hydrogen gas presents a promising therapeutic strategy for sepsis. BioMed Research International 2014: 807635.

    PubMed  PubMed Central  Google Scholar 

  10. Sun, Q., J. Cai, J. Zhou, H. Tao, J.H. Zhang, W. Zhang, and X.J. Sun. 2011. Hydrogen-rich saline reduces delayed neurologic sequelae in experimental carbon monoxide toxicity. Critical Care Medicine 39 (4): 765–769.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang, Y., H. Li, C. Yang, D.F. Fan, D.Z. Guo, H.J. Hu, X.E. Meng, and S.Y. Pan. 2016. Treatment with hydrogen-rich saline delays disease progression in a mouse model of amyotrophic lateral sclerosis. Neurochemical Research 41 (4): 770–778.

    Article  CAS  PubMed  Google Scholar 

  12. Zhao, M., M.D. Liu, Y.Y. Pu, D. Wang, Y. Xie, G.C. Xue, Y. Jiang, Q.Q. Yang, X.J. Sun, and L. Cao. 2016. Hydrogen-rich water improves neurological functional recovery in experimental autoimmune encephalomyelitis mice. Journal of Neuroimmunology 294: 6–13.

    Article  CAS  PubMed  Google Scholar 

  13. Zhu, W., Y. Ding, W. Kong, T. Li, and H. Chen. 2018. Docosahexaenoic acid (DHA) provides neuroprotection in traumatic brain injury models via activating Nrf2-ARE signaling. Inflammation 41 (4): 1182–1193.

    Article  CAS  PubMed  Google Scholar 

  14. Kawamura, T., C.S. Huang, X. Peng, K. Masutani, N. Shigemura, T.R. Billiar, M. Okumura, Y. Toyoda, and A. Nakao. 2011. The effect of donor treatment with hydrogen on lung allograft function in rats. Surgery 150 (2): 240–249.

    Article  PubMed  Google Scholar 

  15. Kawamura, T., N. Wakabayashi, N. Shigemura, C.S. Huang, K. Masutani, Y. Tanaka, K. Noda, X. Peng, T. Takahashi, T.R. Billiar, M. Okumura, Y. Toyoda, T.W. Kensler, and A. Nakao. 2013. Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo. American Journal of Physiology. Lung Cellular and Molecular Physiology 304 (10): L646–L656.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dong, F., S. Wang, Y. Wang, X. Yang, J. Jiang, D. Wu, X. Qu, H. Fan, and R. Yao. 2017. Quercetin ameliorates learning and memory via the Nrf2-ARE signaling pathway in d-galactose-induced neurotoxicity in mice. Biochemical and Biophysical Research Communications 491 (3): 636–641.

    Article  CAS  PubMed  Google Scholar 

  17. Kim, J., Y.N. Cha, and Y.J. Surh. 2010. A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutation Research 690 (1–2): 12–23.

    Article  CAS  PubMed  Google Scholar 

  18. Johnson, D.A., S. Amirahmadi, C. Ward, Z. Fabry, and J.A. Johnson. 2010. The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis. Toxicological Sciences 114 (2): 237–246.

    Article  CAS  PubMed  Google Scholar 

  19. Cai, J., Z. Kang, K. Liu, W. Liu, R. Li, J.H. Zhang, X. Luo, and X. Sun. 2009. Neuroprotective effects of hydrogen saline in neonatal hypoxia-ischemia rat model. Brain Research 1256: 129–137.

    Article  CAS  PubMed  Google Scholar 

  20. Ohsawa, I., M. Ishikawa, K. Takahashi, M. Watanabe, K. Nishimaki, K. Yamagata, K. Katsura, Y. Katayama, S. Asoh, and S. Ohta. 2007. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nature Medicine 13 (6): 688–694.

    Article  CAS  PubMed  Google Scholar 

  21. Chen, C., Q. Chen, Y. Mao, S. Xu, C. Xia, X. Shi, J.H. Zhang, H. Yuan, and X. Sun. 2010. Hydrogen-rich saline protects against spinal cord injury in rats. Neurochemical Research 35 (7): 1111–1118.

    Article  CAS  PubMed  Google Scholar 

  22. Zhang, G.X., B. Gran, S. Yu, J. Li, I. Siglienti, X. Chen, M. Kamoun, and A. Rostami. 2003. Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-beta 2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system. Journal of Immunology 170 (4): 2153–2160.

    Article  CAS  Google Scholar 

  23. Qu, X., D. Qi, F. Dong, B. Wang, R. Guo, M. Luo, and R. Yao. 2014. Quercetin improves hypoxia-ischemia induced cognitive deficits via promoting remyelination in neonatal rat. Brain Research 1553: 31–40.

    Article  CAS  PubMed  Google Scholar 

  24. Qu, X., R. Guo, Z. Zhang, L. Ma, X. Wu, M. Luo, F. Dong, and R. Yao. 2015. bFGF protects pre-oligodendrocytes from oxygen/glucose deprivation injury to ameliorate demyelination. Cellular and Molecular Neurobiology 35 (7): 913–920.

    Article  CAS  PubMed  Google Scholar 

  25. Dong, F., Y. Liu, Z. Zhang, R. Guo, L. Ma, X. Qu, H. Yu, H. Fan, and R. Yao. 2017. Postnatal alteration of monocarboxylate transporter 1 expression in the rat corpus callosum. Physiological Research 66 (2): 345–355.

    CAS  PubMed  Google Scholar 

  26. Dong, F., R. Yao, H. Yu, and Y. Liu. 2017. Neuroprotection of Ro25-6981 against ischemia/reperfusion-induced brain injury via inhibition of autophagy. Cellular and Molecular Neurobiology 37 (4): 743–752.

    Article  CAS  PubMed  Google Scholar 

  27. Yin, L.L., L.L. Lin, L. Zhang, and L. Li. 2012. Epimedium flavonoids ameliorate experimental autoimmune encephalomyelitis in rats by modulating neuroinflammatory and neurotrophic responses. Neuropharmacology 63 (5): 851–862.

    Article  CAS  PubMed  Google Scholar 

  28. Mao, Y.F., X.F. Zheng, J.M. Cai, X.M. You, X.M. Deng, J.H. Zhang, L. Jiang, and X.J. Sun. 2009. Hydrogen-rich saline reduces lung injury induced by intestinal ischemia/reperfusion in rats. Biochemical and Biophysical Research Communications 381 (4): 602–605.

    Article  CAS  PubMed  Google Scholar 

  29. Domingues, H.S., C.C. Portugal, R. Socodato, and J.B. Relvas. 2016. Oligodendrocyte, astrocyte, and microglia crosstalk in myelin development, damage, and repair. Frontiers in Cell and Development Biology 4: 71.

    Google Scholar 

  30. Amorini, A.M., A. Petzold, B. Tavazzi, J. Eikelenboom, G. Keir, A. Belli, G. Giovannoni, V. di Pietro, C. Polman, S. D'Urso, R. Vagnozzi, B. Uitdehaag, and G. Lazzarino. 2009. Increase of uric acid and purine compounds in biological fluids of multiple sclerosis patients. Clinical Biochemistry 42 (10–11): 1001–1006.

    Article  CAS  PubMed  Google Scholar 

  31. Choi, I.Y., S.P. Lee, D.R. Denney, and S.G. Lynch. 2011. Lower levels of glutathione in the brains of secondary progressive multiple sclerosis patients measured by 1H magnetic resonance chemical shift imaging at 3 T. Multiple Sclerosis 17 (3): 289–296.

    Article  CAS  PubMed  Google Scholar 

  32. Shingu, C., H. Koga, S. Hagiwara, S. Matsumoto, K. Goto, I. Yokoi, and T. Noguchi. 2010. Hydrogen-rich saline solution attenuates renal ischemia-reperfusion injury. Journal of Anesthesia 24 (4): 569–574.

    Article  PubMed  Google Scholar 

  33. Ishii, T., K. Itoh, H. Sato, and S. Bannai. 1999. Oxidative stress-inducible proteins in macrophages. Free Radical Research 31 (4): 351–355.

    Article  CAS  PubMed  Google Scholar 

  34. Han, X., W. Yao, Z. Liu, H. Li, Z.J. Zhang, Z. Hei, and Z. Xia. 2016. Lipoxin A4 preconditioning attenuates intestinal ischemia reperfusion injury through Keap1/Nrf2 pathway in a lipoxin A4 receptor independent manner. Oxidative Medicine and Cellular Longevity 2016: 9303606.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We sincerely thank Professor Xuejun Sun from the Second Military Medical University for his help with hydrogen-rich saline preparation.

Funding

This work was supported by the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (15KJB180018, 18KJB180028) and the Science and Technology Project of Xuzhou City (KC16SH076).

Author information

Author notes

  1. Yaping Liu and Fuxing Dong contributed equally to this work.

Authors and Affiliations

  1. Laboratory of National Experimental Teaching and Demonstration Center of Basic Medicine, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu Province, China

    Yaping Liu

  2. Research Center for Neurobiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu Province, China

    Yaping Liu, Fuxing Dong, Rui Guo, Ying Zhang, Xuebin Qu, Xiuxiang Wu & Ruiqin Yao

  3. Research Facility Center for Morphology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu Province, China

    Fuxing Dong, Rui Guo & Ying Zhang

  4. Department of Cell Biology and Neurobiology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu Province, China

    Xuebin Qu, Xiuxiang Wu & Ruiqin Yao

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  1. Yaping Liu
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Corresponding author

Correspondence to Ruiqin Yao.

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All animal care and experimental procedures were carried out according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Bioethics Committee of Xuzhou Medical University.

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The authors declare that they have no conflicts of interest.

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Liu, Y., Dong, F., Guo, R. et al. Hydrogen-Rich Saline Ameliorates Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice Via the Nrf2-ARE Signaling Pathway. Inflammation 42, 586–597 (2019). https://doi.org/10.1007/s10753-018-0915-3

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  • DOI: https://doi.org/10.1007/s10753-018-0915-3

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