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Attenuation of Experimental Autoimmune Encephalomyelitis and Nonimmune Demyelination by IFN- plus Vitamin B₁₂: Treatment to Modify Notch-1/Sonic Hedgehog Balance ¹

Fabrizio G. Mastronardi^*, Weixian Min^*, Huimin Wang, Shawn Winer, Michael Dosch, Joan M. Boggs^* and Mario A. Moscarello^2,*

Departments of ^* Structural Biology and Biochemistry, Neuropathology, and Infection, Immunity, Injury, and Repair, Hospital for Sick Children, Toronto, Ontario, Canada

Interferon- is a mainstay therapy of demyelinating diseases, but its effects are incomplete in human multiple sclerosis and several of its animal models. In this study, we demonstrate dramatic improvements of clinical, histological, and laboratory parameters in in vivo mouse models of demyelinating disease through combination therapy with IFN- plus vitamin B₁₂ cyanocobalamin {B₁₂CN) in nonautoimmune primary demyelinating ND4 (DM20) transgenics, and in acute and chronic experimental autoimmune encephalomyelitis in SJL mice. Clinical improvement (p values <0.0001) was paralleled by near normal motor function, reduced astrocytosis, and reduced demyelination. IFN- plus B₁₂CN enhanced in vivo and in vitro oligodendrocyte maturation. In vivo and in vitro altered expression patterns of reduced Notch-1 and enhanced expression of sonic hedgehog and its receptor were consistent with oligodendrocyte maturation and remyelination. IFN--B₁₂CN combination therapy may be promising for the treatment of multiple sclerosis.

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