methyl-4-(adenin-9-yl)-2-hydroxybutanoate and myelin-oligodendrocyte-glycoprotein-(35-55)

The reversible S-adenosyl-l-homocysteine hydrolase inhibitor DZ2002 [methyl 4-(adenin-9-yl)-2-hydroxybutanoate] suppresses antigen-induced-specific immune responses, particularly type 1 helper T cell (Th1)-type responses. Experimental autoimmune encephalomyelitis (EAE) is thought to be a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of human multiple sclerosis (MS). In this study, we examined the effects of DZ2002 on active EAE induced by myelin oligodendrocyte glycoprotein (MOG) 35-55 in female C57BL/6 mice. Administration of DZ2002 (50 mg/kg/day i.p.) significantly reduced the incidence and severity of EAE, which was associated with the inhibition of MOG35-55-specific T cell proliferation and Th1-type cytokine production. In vitro studies also demonstrated that DZ2002 inhibited anti-CD3/28-induced naive T cell activation concomitant with the down-regulation of cyclin-dependent kinase (CDK) 4, CDK6, cyclin D3, and the up-regulation or protection of the CDK inhibitor p27. These findings highlight the fact that DZ2002 likely prevents EAE by suppressing T cell activation and suggest its utility in the treatment of MS and other Th1-mediated inflammatory diseases.

Topics: Adenine; Adenosylhomocysteinase; Amino Acid Sequence; Animals; Antigen Presentation; Butyrates; CD3 Complex; Cell Cycle; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Enzyme Inhibitors; Female; Glycoproteins; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; T-Lymphocytes