Inflammation and oxidative stress are thought to promote tissue damage in
multiple sclerosis. Thus, novel
therapeutics enhancing cellular resistance to
free radicals could prove useful for
multiple sclerosis treatment.
BG00012 is an oral formulation of
dimethylfumarate. In a phase II
multiple sclerosis trial,
BG00012 demonstrated beneficial effects on relapse rate and magnetic resonance imaging markers indicative of
inflammation as well as axonal destruction. First we have studied effects of
dimethylfumarate on the disease course, central nervous system, tissue integrity and the molecular mechanism of action in an animal model of chronic
multiple sclerosis:
myelin oligodendrocyte glycoprotein induced
experimental autoimmune encephalomyelitis in C57BL/6 mice. In the chronic phase of
experimental autoimmune encephalomyelitis, preventive or therapeutic application of
dimethylfumarate ameliorated the disease course and improved preservation of myelin, axons and neurons. In vitro, the application of
fumarates increased murine neuronal survival and protected human or rodent astrocytes against oxidative stress. Application of
dimethylfumarate led to stabilization of the
transcription factor nuclear factor (erythroid-derived 2)-related factor 2, activation of nuclear factor (erythroid-derived 2)-related factor 2-dependent transcriptional activity and accumulation of
NADP(H)
quinoline oxidoreductase-1 as a prototypical target gene. Furthermore, the immediate metabolite of
dimethylfumarate,
monomethylfumarate, leads to direct modification of the inhibitor of nuclear factor (erythroid-derived 2)-related factor 2,
Kelch-like ECH-associated protein 1, at
cysteine residue 151. In turn, increased levels of nuclear factor (erythroid-derived 2)-related factor 2 and reduced
protein nitrosylation were detected in the central nervous sytem of
dimethylfumarate-treated mice. Nuclear factor (erythroid-derived 2)-related factor 2 was also upregulated in the spinal cord of autopsy specimens from untreated patients with
multiple sclerosis. In
dimethylfumarate-treated mice suffering from
experimental autoimmune encephalomyelitis, increased immunoreactivity for nuclear factor (erythroid-derived 2)-related factor 2 was detected by confocal microscopy in neurons of the motor cortex and the brainstem as well as in oligodendrocytes and astrocytes. In mice deficient for nuclear factor (erythroid-derived 2)-related factor 2 on the same genetic background, the
dimethylfumarate mediated beneficial effects on
clinical course, axon preservation and astrocyte activation were almost completely abolished thus proving the functional relevance of this
transcription factor for the neuroprotective mechanism of action. We conclude that the ability of
dimethylfumarate to activate nuclear factor (erythroid-derived 2)-related factor 2 may offer a novel cytoprotective modality that further augments the natural
antioxidant responses in
multiple sclerosis tissue and is not yet targeted by other
multiple sclerosis therapies.