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PLoS One ; 5(7): e11769, 2010 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-20668697


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. METHODOLOGY/PRINCIPAL FINDINGS: 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.

Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Cuprizona/toxicidade , Doenças Desmielinizantes/tratamento farmacológico , Fumaratos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Fumarato de Dimetilo , Imuno-Histoquímica , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Maleatos/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley
Neurochem Res ; 35(9): 1422-33, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20544279


In this study, we investigated the potential of minocycline to influence cuprizone induced demyelination in the grey and white matter. To induce demyelination C57BL/6 mice were fed with cuprizone for up to 6 weeks and were analysed at different timepoints (week 0, 4, 5, 6). Mice treated with minocycline had less demyelination of the cortex and corpus callosum compared with sham treated animals. In the cortex decreased numbers of activated and proliferating microglia were found after 6 weeks of cuprizone feeding, while there were no significant effects for microglial infiltration of the corpus callosum. In addition to the beneficial effects on demyelination, minocycline prevented from motor coordination disturbance as shown in the beam walking test. For astrogliosis and the numbers of OPC and oligodendrocytes no treatment effects were found. In summary, minocycline treatment diminished the course of demyelination in the grey and white matter and prevented disturbances in motor coordination.

Córtex Cerebral , Cuprizona/farmacologia , Doenças Desmielinizantes/induzido quimicamente , Minociclina/farmacologia , Fibras Nervosas Mielinizadas , Animais , Antibacterianos/farmacologia , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Quelantes/farmacologia , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/patologia , Oligodendroglia/citologia , Oligodendroglia/efeitos dos fármacos