Effects of Fumaric Acids on Cuprizone Induced Central Nervous System De- and Remyelination in the Mouse 英文参考文献.docVIP

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Effects of Fumaric Acids on Cuprizone Induced Central Nervous System De- and Remyelination in the Mouse 英文参考文献.doc

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Effects of Fumaric Acids on Cuprizone Induced Central Nervous System De- and Remyelination in the Mouse 英文参考文献

EffectsofFumaricAcidsonCuprizoneInducedCentral NervousSystemDe-andRemyelinationintheMouse DariusMoharregh-Khiabani1,AlexanderBlank1,ThomasSkripuletz1,ElviraMiller1,AlexandraKotsiari1, ViktoriaGudi1,2,MartinStangel1,2 * 1DepartmentofNeurology,HannoverMedicalSchool,Hannover,Germany,2CenterforSystemsNeuroscience,Hannover,Germany Abstract Background: Fumaric acid esters (FAE) are a group of compounds which are currently under investigation as an oral treatmentforrelapsing-remittingmultiplesclerosis.OneofthesuggestedmodesofactionisthepotentialofFAEtoexerta neuroprotectiveeffect. Methodology/PrincipalFindings:Wehaveinvestigatedtheimpactofmonomethylfumarate(MMF)anddimethylfumaric acid(DMF)onde-andremyelinationusingthetoxiccuprizonemodelwheretheblood-brain-barrierremainsintactandonly scatteredT-cellsandperipheralmacrophagesarefoundinthecentralnervoussystem(CNS),thusexcludingtheinfluenceof 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 andinduced apoptosis in peripheral blood mononuclear cells(PBMC). Conclusions:Theseresultscontributetotheunderstandingofthemechanismofactionoffumaricacids.Ourdatasuggest thatfumarateshavenooronlylittledirectprotectiveeffectsonoligodendrocytesinthistoxicmodelandmayactrather indirectlyviathemodulationofimmunecells. Citation:Moharregh-KhiabaniD,BlankA,SkripuletzT,MillerE,KotsiariA,etal.(2010)EffectsofFumaricAcidsonCuprizoneInducedCentralNervousSystemDe- andRemyelinationintheMouse.PLoSONE5(7):e11769.doi:10.1371/journal.pone.0011769 Editor:ChristophKleinschnitz,Julius-Maximilians-Universita¨t Wu¨rzburg,Germany ReceivedFebruary1,2010;AcceptedJune7,2010;PublishedJuly23,2010 Copyright:?201