Diazoxide Promotes Oligodendrocyte Precursor Cell Proliferation and Myelination 英文参考文献.docVIP

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Diazoxide Promotes Oligodendrocyte Precursor Cell Proliferation and Myelination 英文参考文献.doc

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Diazoxide Promotes Oligodendrocyte Precursor Cell Proliferation and Myelination 英文参考文献

DiazoxidePromotesOligodendrocytePrecursorCell ProliferationandMyelination BirgitFogal,CarolynMcClaskey,ShaYan,HenglinYan,ScottA.Rivkees* Department of Pediatrics, Section of Developmental Biology and Endocrinology, Yale Child Health Research Center, Yale University School of Medicine, New Haven, Connecticut,UnitedStatesofAmerica Abstract Background:Severalclinicalconditionsareassociatedwithwhitematterinjury,includingperiventricularwhitematterinjury (PWMI),whichisaformofbraininjurysustainedbypreterminfants.Ithasbeensuggestedthatwhitematterinjuryinthis condition is due to altered oligodendrocyte (OL) development or death, resulting in OL loss and hypomyelination. At present drugs are not available that stimulate OL proliferation and promote myelination. Evidence suggests that depolarizing stimuli reduces OL proliferation and differentiation, whereas agents that hyperpolarize OLs stimulate OL proliferation and differentiation. Considering that the drug diazoxide activates KATP channels to hyperpolarize cells, we testedifthiscompoundcouldinfluenceOLproliferationandmyelination. Methodology/Findings: Studies were performed using rat oligodendrocyte precursor cell (OPC) cultures, cerebellar slice cultures,andaninvivomodelofPWMIinwhichnewbornmicewereexposedtochronicsublethalhypoxia(10%O2).Wefound thatKATPchannelcomponentsKir6.1and6.2andSUR2wereexpressedinoligodendrocytes.Additionally,diazoxidepotently stimulatedOPCproliferation,asdidotherKATPactivators.Diazoxidealsostimulatedmyelinationincerebellarslicecultures.We alsofoundthatdiazoxidepreventedhypomyelinationandventriculomegalyfollowingchronicsublethalhypoxia. Conclusions: These results identify KATP channel components in OLs and show that diazoxide can stimulate OL proliferation in vitro. Importantly we find that diazoxide can promote myelination in vivo and prevent hypoxia-induced PWMI. Citation:FogalB,McClaskeyC,YanS,YanH,RivkeesSA(2010)DiazoxidePromotesOligodendrocytePrecursorCellProliferationandMyelination.PLoSONE5(