Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice through inducing apoptosis of CD4+ T cells

Abstract

Abstract Background: Multiple sclerosis (MS) is an autoimmune disease of central nervous system characterized by severe demyelination of white matter. There is still no definite cure for MS because of its complex pathogenesis. Experimental autoimmune encephalomyelitis (EAE) is an ideal animal model for the study of MS. Arsenic trioxide (ATO) is an ancient Chinese medicine that is used as a therapeutic application for many autoimmune diseases. It is also used to inhibit acute immune rejection because of its anti-inflammatory and immunosuppressive properties. However, it is unclear if ATO has a curative effect on EAE, and the underlying mechanisms have not been clearly elucidated. In this study, we attempted to explore the possibility of using ATO 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 proportion of CD4 + T cells. In vitro , to further investigate the mechanism that underly the ameliorating effects of ATO in EAE mice, CD4 + T cells were traeted with ATO and then used for apoptosis assay, JC-1 staining, transmission electron microscope, and western bloting. Results: We found that ATO alleviated the severity of EAE in mice. Treatment with ATO also attenuated demyelination, alleviated inflammation, reduced microglia activation and decreased the expression 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 cells apoptosis through the mitochondrial pathway both in vitro and in vivo . Additionally, the administration of ATO had no adverse effect on liver and kidney function and did not 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.