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.

中文翻译：

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三氧化二砷通过诱导 CD4+ T 细胞凋亡改善 C57BL/6 小鼠实验性自身免疫性脑脊髓炎。


背景技术多发性硬化症(MS)是一种免疫介导的中枢神经系统疾病，其特征在于严重的白质脱髓鞘。由于其复杂的发病机制，多发性硬化症尚无明确的治愈方法。实验性自身免疫性脑脊髓炎（EAE）是研究多发性硬化症的理想动物模型。三氧化二砷（ATO）是一种古老的中药，具有治疗多种自身免疫性疾病的功效。由于其抗炎和免疫抑制特性，它还用于抑制急性免疫排斥。然而，ATO是否对EAE具有治疗作用尚不清楚，其潜在机制尚未明确阐明。在这项研究中，我们试图评估 ATO 是否可以用于改善小鼠的 EAE。方法 免疫后 10 天，对 EAE 小鼠腹膜内施用 ATO（0.5 mg/kg/天），持续 8 天。免疫后第22天，收集脊髓、脾脏和血液，分析脱髓鞘、炎症、小胶质细胞活化和CD4+ T细胞比例。在体外，为了进行机制研究，从初始 C57BL/6 小鼠的脾脏中分选 CD4+ T 细胞，并用 ATO 处理，然后用于细胞凋亡测定、JC-1 染色、透射电子显微镜下成像和蛋白质印迹。结果 ATO 延迟了小鼠 EAE 的发作并减轻了 EAE 的严重程度。 ATO 治疗还可以减轻 EAE 小鼠的脱髓鞘、减轻炎症、减少小胶质细胞活化，并降低 IL-2、IFN-γ、IL-1β、IL-6 和 TNF-α 的表达水平。此外，ATO治疗的EAE小鼠脊髓、脾脏和外周血中CD4+ T细胞的数量和比例均减少。 最后，ATO 在体外和体内均通过线粒体途径诱导 CD4+ T 细胞凋亡。此外，给予ATO对心脏、肝脏或肾脏功能没有不良影响，也不会诱导脊髓细胞凋亡。结论 总体而言，我们的研究结果表明，ATO 在 EAE 的发生和进展中发挥保护作用，并有潜力成为治疗 MS 的新药。