The effect of STA-21, a STAT3 inhibitor and All Trans Retinoic Acid (ATRA) combinational therapy on Experimental autoimmune encephalomyelitis (EAE) as a muose model of Multiple sclerosis (MS)

Abstract

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE) are a chronic inflammatory and myelin-destroying disease of the central nervous system (CNS), the former due to immune system disorders in people with sensitive genetic backgrounds and the latter to immunization by myelin proteins. Th-17 / Treg balance plays an important role in autoimmune diseases, including MS, and in this study we examined the concomitant therapeutic effect of two compounds; STA-21 and ATRA that are able to alter this balance in EAE mice. Materials and Methods: In order to induce EAE, MOG peptide along with complete freunds adjuvant and pertussis toxin (PTX) was injected into 50 C57BL / 6 mice and then mice were randomly divided into 5 groups. They received the medications according to the protocol for two weeks. After 24 days of induction and treatment, the mice were killed and the spleen, spinal cord, and brain samples were removed for testing. In the next steps, pathology, flowcytometry, Realtime PCR and ELISA tests were performed. Findings: The results showed that combination therapy of STA-21 and ATRA reduced the symptoms of the disease in the group of mice treated with both drugs compared with the control group (p< 0.0001). Also, the percentage of immune cell accumulation and demyelination rate in the group receiving combination therapy was significantly lower than the control group (p=0.0003) and (p=0.002), respectively. Our results also showed that the percentage of Th-17 cells in CNS decreased significantly in the group treated with combination therapy compared with the control group (p<0.0001) while the percentage of Treg cells increased (p=0.0007). IL-17 inflammatory cytokine values in the supernatant of spleen cells culture in group mice with combination therapy was significantly lower than values in the control group (p <0.001) but the IFN-γ value did not decrease significantly (p = 0.1), while the IL-10 anti-inflammatory cytokine values were higher than in the control group (p <0.001).