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Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice by inducing CD4+ T cell apoptosis.
J Neuroinflammation. 2020 May 06; 17(1):147.JN

Abstract

BACKGROUND

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system characterized by severe white matter demyelination. Because of its complex pathogenesis, there is no definite cure for MS. Experimental autoimmune encephalomyelitis (EAE) is an ideal animal model for the study of MS. Arsenic trioxide (ATO) is an ancient Chinese medicine used for its therapeutic properties with several autoimmune diseases. It is also used to inhibit acute immune rejection due to its anti-inflammatory and immunosuppressive properties. However, it is unclear whether ATO has a therapeutic effect on EAE, and the underlying mechanisms have not yet been clearly elucidated. In this study, we attempted to assess whether ATO could be used to ameliorate EAE in mice.

METHODS

ATO (0.5 mg/kg/day) was administered intraperitoneally to EAE mice 10 days post-immunization for 8 days. On day 22 post-immunization, the spinal cord, spleen, and blood were collected to analyze demyelination, inflammation, microglia activation, and the proportion of CD4+ T cells. In vitro, for mechanistic studies, CD4+ T cells were sorted from the spleen of naïve C57BL/6 mice and treated with ATO and then used for an apoptosis assay, JC-1 staining, imaging under a transmission electron microscope, and western blotting.

RESULTS

ATO delayed the onset of EAE and alleviated the severity of EAE in mice. Treatment with ATO also attenuated demyelination, alleviated inflammation, reduced microglia activation, and decreased the expression levels of IL-2, IFN-γ, IL-1β, IL-6, and TNF-α in EAE mice. Moreover, the number and proportion of CD4+ T cells in the spinal cord, spleen, and peripheral blood were reduced in ATO-treated EAE mice. Finally, ATO induced CD4+ T cell apoptosis via the mitochondrial pathway both in vitro and in vivo. Additionally, the administration of ATO had no adverse effect on the heart, liver, or kidney function, nor did it induce apoptosis in the spinal cord.

CONCLUSIONS

Overall, our findings indicated that ATO plays a protective role in the initiation and progression of EAE and has the potential to be a novel drug in the treatment of MS.

Authors+Show Affiliations

Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China.Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China.Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China.Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China. Department of Obstetrics and Gynecology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, China.Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, Fujian, China.School of Medicine, Guangxi University, Nanning, Guangxi, China. yxyyz@gxu.edu.cn.Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China. xia@xmu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32375831

Citation

An, Ke, et al. "Arsenic Trioxide Ameliorates Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice By Inducing CD4+ T Cell Apoptosis." Journal of Neuroinflammation, vol. 17, no. 1, 2020, p. 147.
An K, Xue MJ, Zhong JY, et al. Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice by inducing CD4+ T cell apoptosis. J Neuroinflammation. 2020;17(1):147.
An, K., Xue, M. J., Zhong, J. Y., Yu, S. N., Lan, T. S., Qi, Z. Q., & Xia, J. J. (2020). Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice by inducing CD4+ T cell apoptosis. Journal of Neuroinflammation, 17(1), 147. https://doi.org/10.1186/s12974-020-01829-x
An K, et al. Arsenic Trioxide Ameliorates Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice By Inducing CD4+ T Cell Apoptosis. J Neuroinflammation. 2020 May 6;17(1):147. PubMed PMID: 32375831.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice by inducing CD4+ T cell apoptosis. AU - An,Ke, AU - Xue,Meng-Jiao, AU - Zhong,Jia-Ying, AU - Yu,Sheng-Nan, AU - Lan,Tian-Shu, AU - Qi,Zhong-Quan, AU - Xia,Jun-Jie, Y1 - 2020/05/06/ PY - 2020/01/12/received PY - 2020/04/27/accepted PY - 2020/5/8/entrez PY - 2020/5/8/pubmed PY - 2020/5/8/medline KW - Apoptosis KW - Arsenic trioxide KW - CD4+ T cells KW - Experimental autoimmune encephalomyelitis SP - 147 EP - 147 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 17 IS - 1 N2 - BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system characterized by severe white matter demyelination. Because of its complex pathogenesis, there is no definite cure for MS. Experimental autoimmune encephalomyelitis (EAE) is an ideal animal model for the study of MS. Arsenic trioxide (ATO) is an ancient Chinese medicine used for its therapeutic properties with several autoimmune diseases. It is also used to inhibit acute immune rejection due to its anti-inflammatory and immunosuppressive properties. However, it is unclear whether ATO has a therapeutic effect on EAE, and the underlying mechanisms have not yet been clearly elucidated. In this study, we attempted to assess whether ATO could be used to ameliorate EAE in mice. METHODS: ATO (0.5 mg/kg/day) was administered intraperitoneally to EAE mice 10 days post-immunization for 8 days. On day 22 post-immunization, the spinal cord, spleen, and blood were collected to analyze demyelination, inflammation, microglia activation, and the proportion of CD4+ T cells. In vitro, for mechanistic studies, CD4+ T cells were sorted from the spleen of naïve C57BL/6 mice and treated with ATO and then used for an apoptosis assay, JC-1 staining, imaging under a transmission electron microscope, and western blotting. RESULTS: ATO delayed the onset of EAE and alleviated the severity of EAE in mice. Treatment with ATO also attenuated demyelination, alleviated inflammation, reduced microglia activation, and decreased the expression levels of IL-2, IFN-γ, IL-1β, IL-6, and TNF-α in EAE mice. Moreover, the number and proportion of CD4+ T cells in the spinal cord, spleen, and peripheral blood were reduced in ATO-treated EAE mice. Finally, ATO induced CD4+ T cell apoptosis via the mitochondrial pathway both in vitro and in vivo. Additionally, the administration of ATO had no adverse effect on the heart, liver, or kidney function, nor did it induce apoptosis in the spinal cord. CONCLUSIONS: Overall, our findings indicated that ATO plays a protective role in the initiation and progression of EAE and has the potential to be a novel drug in the treatment of MS. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/32375831/Arsenic_trioxide_ameliorates_experimental_autoimmune_encephalomyelitis_in_C57BL/6_mice_by_inducing_CD4+_T_cell_apoptosis L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-020-01829-x DB - PRIME DP - Unbound Medicine ER -
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