Chlorzoxazone Alleviates Experimental Autoimmune Encephalomyelitis via Inhibiting IL-6 Secretion of Dendritic Cells.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease with chronic inflammatory demyelination of the CNS. Experimental autoimmune encephalomyelitis (EAE) is an important animal model to study MS, with many pathological phenomena similar to MS. Th17 cells are important regulators of EAE and MS pathogenesis. Most cytokines needed for Th cell development are secreted by APCs, such as dendritic cells (DCs). Consequently, MS could be improved by inhibiting cytokine secretion from DCs. In this study, we reported that chlorzoxazone could ameliorate EAE pathogenesis via inhibiting IL-6 production by DCs. The EAE signs in the chlorzoxazone-treated group of mice were relieved, which was mainly manifested as lower clinical scores, a decrease in the number of immune cells, and a reduction of demyelination in the CNS. Moreover, the proportion of Th17 cells in the spleen and CNS decreased significantly. In vitro experiments showed that chlorzoxazone treatment significantly reduced DC-derived IL-6 production. In the DC-T cell coculture experiment, significantly decreased Th17 differentiation was observed after chlorzoxazone treatment. In addition, mass spectrometric analysis was performed to elucidate the mechanism by which chlorzoxazone affected EAE and DC function. We showed that the effect of chlorzoxazone on inhibiting the secretion of IL-6 by DCs may be mediated via the AMP-activated protein kinase pathway. Overall, our study elucidated the key role of chlorzoxazone in regulating EAE pathogenesis and suggested that it might be used as a new drug for MS patients.

9,10-Anhydrodehydroartemisinin Attenuates Experimental Autoimmune Encephalomyelitis by Inhibiting Th1 and Th17 Cell Differentiation.

Human inflammatory disease, multiple sclerosis (MS), is a demyelinating disease of central nervous system (CNS). The experimental autoimmune encephalomyelitis (EAE) is the most commonly used as experimental model because of its key pathological features' approximation of MS. The interaction between complex elements in immune system and in the CNS determines the MS pathogenesis. However, there is no cure for MS and the treatment for MS still encounters great challenges. Thus, finding a more effective disease-modifying treatment is imminent. In the present study, we investigated whether 9,10-Anhydrodehydroartemisin (ADART), a compound derived from artemisinin, could decrease demyelination in EAE and the underlying mechanisms. In established EAE mice, 100 mg/kg 9,10-Anhydrodehydroartemisinin (ADART) effectively reduced CNS and peripheral immune system infiltration inflammatory cells including CD4+ IFN-γ+ Th1 cells and CD4+ IL-17A+ Th17 cells. Correspondingly, the serum level of IFN-γ and IL-17A was also reduced. In vitro, ADART almost completely inhibited Th17 differentiation, and partially inhibited Th1 differentiation in 10 µM. This research revealed that ADART could be a great promising avenue among current therapies for MS.