Effects of fumaric acids on cuprizone induced central nervous system de- and remyelination in the mouse.
BACKGROUND
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.


RESULTS
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).


CONCLUSIONS
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.
Moharregh-Khiabani
Darius
D
Department of Neurology, Hannover Medical School, Hannover, Germany.
Blank
Alexander
A
Skripuletz
Thomas
T
Miller
Elvira
E
Kotsiari
Alexandra
A
Gudi
Viktoria
V
Stangel
Martin
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism*; D003471:Cuprizone / Q000633:toxicity*; D003711:Demyelinating Diseases / Q000188:drug therapy*; D000069462:Dimethyl Fumarate; D005650:Fumarates / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008297:Male; D008298:Maleates / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley
D005650:Fumarates; D008298:Maleates; C073341:citraconic acid; D003471:Cuprizone; D000069462:Dimethyl Fumarate