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Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory infiltration in association with demyelination in the central nervous system. Among the factors involved in the immunological mechanisms of MS, Th1, Th17, and Th22 cells play a critical role. In the present study, we investigated the role of CA-074, a potent Cathepsin B inhibitor, in MS progression, using the SJL/J mouse model of experimental autoimmune encephalomyelitis (EAE). Following induction of EAE, mice were administered CA-074 (10 mg/kg) intraperitoneally each day, beginning on day 14 and continuing until day 28, and were evaluated for clinical signs. We further investigated the effect of CA-074 on Th1 (T-bet/STAT4), Th17 (IL-17A/RORγT), Th22 (TNF-α/IL-22), and regulatory T (Treg/Foxp3) cells in the spleen, using flow cytometry. We also analyzed the effect of CA-074 on T-bet, IL-17A, RORγT, IL-22, and mRNA and protein levels using RT-PCR and western blot analysis for brain tissues. Cathepsin B expression were also assessed by western blot in the brain tissues. The severity of clinical scores decreased significantly in CA-074-treated mice compared with that in EAE control mice. Moreover, the percentage of CD4+T-bet+, CXCR5+T-bet+, CD4+STAT4+, CD4+IL-17A+, CXCR5+IL-17A+, CD4+RORγT+, CCR6+RORγT+, CD4+TNF-α+, CD4+IL-22+, and CCR6+IL-22+ cells decreased while CD25+Foxp3+ increased in CA-074-treated EAE mice as compared to vehicle-treated EAE mice. Further, CA-074-treated EAE mice had downregulated Cathepsin B protein expression which was associated with decreased T-bet, IL-17A, RORγT, and IL-22 mRNA/protein expression. These results suggest that Cathepsin B could be a novel therapeutic candidate against for the treatment of MS. • We investigated the possible neuroprotective effects of Cathepsin B inhibitor. • CA-074 ameliorates disease severity by relapsing-remitting in EAE. • CA-074 reduces Th1 transcription factor signaling. • CA-074 downregulated Th17/Th22 signaling in EAE mice. • CA-074 could be used as a novel candidate for MS treatment. [ABSTRACT FROM AUTHOR]