fumarates and Demyelinating-Diseases

In this study we examined the role of fumaric acid esters (FAE) in a spontaneous and chronic animal model, the opticospinal EAE (OSE). Preventive treatment of dimethylfumarate (DMF) promotes onset of disease in animals treated with high dose DMF. This group also exhibited a significantly exacerbated disease course in a therapeutic treatment as compared to the low dose DMF approach, where less demyelination, macrophage infiltration, and increased Nrf2 expression in the spinal cord were observed. We conclude that low dose DMF treatment is effective in the therapy of the spontaneous opticospinal EAE model and mediates neuroprotective effects via the oxidative stress response pathway.

Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Esters; Fumarates; Mice; Mice, Inbred C57BL; Mice, Transgenic; T-Lymphocytes

Topics: Adult; Antiviral Agents; Demyelinating Diseases; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Interferons; Magnetic Resonance Imaging; Male; Psoriasis

Fumaric acid esters (FAE) are a group of compounds which are currently under investigation as an oral treatment for relapsing-remitting multiple sclerosis. One of the suggested modes of action is the potential of FAE to exert a neuroprotective effect.. We have investigated the impact of monomethylfumarate (MMF) and dimethylfumaric acid (DMF) on de- and remyelination using the toxic cuprizone model where the blood-brain-barrier remains intact and only scattered T-cells and peripheral macrophages are found in the central nervous system (CNS), thus excluding the influence of immunomodulatory effects on peripheral immune cells. FAE showed marginally accelerated remyelination in the corpus callosum compared to controls. However, we found no differences for demyelination and glial reactions in vivo and no cytoprotective effect on oligodendroglial cells in vitro. In contrast, DMF had a significant inhibitory effect on lipopolysaccharide (LPS) induced nitric oxide burst in microglia and induced apoptosis in peripheral blood mononuclear cells (PBMC).. These results contribute to the understanding of the mechanism of action of fumaric acids. Our data suggest that fumarates have no or only little direct protective effects on oligodendrocytes in this toxic model and may act rather indirectly via the modulation of immune cells.

Topics: Animals; Apoptosis; Cells, Cultured; Central Nervous System; Cuprizone; Demyelinating Diseases; Dimethyl Fumarate; Fumarates; Immunohistochemistry; Leukocytes, Mononuclear; Male; Maleates; Mice; Mice, Inbred C57BL; Rats; Rats, Sprague-Dawley