Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acute Disease
-
Animals
-
Brain / drug effects
-
Brain / metabolism
-
Cell Line
-
Chronic Disease
-
Demyelinating Diseases / genetics
-
Demyelinating Diseases / metabolism
-
Demyelinating Diseases / prevention & control*
-
Drug Synergism
-
Drug Therapy, Combination
-
Encephalomyelitis, Autoimmune, Experimental / genetics
-
Encephalomyelitis, Autoimmune, Experimental / metabolism
-
Encephalomyelitis, Autoimmune, Experimental / prevention & control*
-
Female
-
Hedgehog Proteins
-
Humans
-
Interferon-beta / therapeutic use*
-
Mice
-
Mice, Inbred Strains
-
Mice, Transgenic
-
Oligodendroglia / cytology
-
Oligodendroglia / drug effects
-
Oligodendroglia / metabolism
-
Peptide Fragments / biosynthesis
-
Receptor, Notch1
-
Receptors, Cell Surface / biosynthesis
-
Receptors, Cell Surface / metabolism*
-
Stem Cells / drug effects
-
Stem Cells / metabolism
-
Trans-Activators / biosynthesis
-
Trans-Activators / genetics
-
Trans-Activators / metabolism*
-
Transcription Factors*
-
Vitamin B 12 / therapeutic use*
Substances
-
Hedgehog Proteins
-
NOTCH1 protein, human
-
Notch1 protein, mouse
-
Peptide Fragments
-
Receptor, Notch1
-
Receptors, Cell Surface
-
SHH protein, human
-
Shh protein, mouse
-
Trans-Activators
-
Transcription Factors
-
Interferon-beta
-
Vitamin B 12