Attenuation of experimental autoimmune encephalomyelitis and nonimmune demyelination by IFN-beta plus vitamin B12: treatment to modify notch-1/sonic hedgehog balance.
Interferon-beta 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-beta plus vitamin B(12) cyanocobalamin (B(12)CN) 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-beta plus B(12)CN 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-beta-B(12)CN combination therapy may be promising for the treatment of multiple sclerosis.
Mastronardi
Fabrizio G
FG
Department of Structural Biology and Biochemistry, Hospital for Sick Children, Toronto, Ontario, Canada.
Min
Weixian
W
Wang
Huimin
H
Winer
Shawn
S
Dosch
Michael
M
Boggs
Joan M
JM
Moscarello
Mario A
MA
D000208:Acute Disease; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002908:Chronic Disease; D003711:Demyelinating Diseases / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D053823:Hedgehog Proteins; D006801:Humans; D016899:Interferon-beta / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014805:Vitamin B 12 / Q000627:therapeutic use*
D053823:Hedgehog Proteins; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D010446:Peptide Fragments; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; C509239:SHH protein, human; C465570:Shh protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016899:Interferon-beta; D014805:Vitamin B 12