Neuroprotective Actions of Methylene Blue and Its Derivatives 英文参考文献.docVIP

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Neuroprotective Actions of Methylene Blue and Its Derivatives 英文参考文献.doc

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Neuroprotective Actions of Methylene Blue and Its Derivatives 英文参考文献

NeuroprotectiveActionsofMethyleneBlueandIts Derivatives EthanPoteet1,AliWinters1,Liang-JunYan1,KyleShufelt2,KaylaN.Green2,JamesW.Simpkins1,YiWen1, Shao-HuaYang1* 1DepartmentofPharmacologyandNeuroscience,InstituteforAlzheimer’sDiseaseandAgingResearch,UniversityofNorthTexasHealthScienceCenteratFortWorth, FortWorth,Texas,UnitedStatesofAmerica,2DepartmentofChemistry,TexasChristianUniversity,FortWorth,Texas,UnitedStatesofAmerica Abstract Methylene blue (MB), the first lead chemical structure of phenothiazine and other derivatives, is commonly used in diagnostic procedures and as a treatment for methemoglobinemia. We have previously demonstrated that MB could function as an alternative mitochondrial electron transfer carrier, enhance cellular oxygen consumption, and provide protection invitro and in rodent models of Parkinson’s disease and stroke. In the present study, we investigated the structure-activityrelationshipsofMBinvitrousingMBandsixstructurallyrelatedcompounds.MBreducesmitochondrial superoxideproductionviaalternativeelectrontransferthatbypassesmitochondrialcomplexesI-III.MBmitigatesreactive freeradicalproductionandprovidesneuroprotectioninHT-22cellsagainstglutamate,IAAandrotenonetoxicity.Distinctly, MBprovidesnoprotectionagainstdirectoxidativestressinducedbyglucoseoxidase.SubstitutionofasidechainatMB’s 10-nitrogen rendered a 1000-fold reduction of the protective potency against glutamate neurototoxicity. Compounds withoutsidechainsatpositions3and7,chlorophenothiazineandphenothiazine,havedistinctredoxpotentialscompared toMBandareincapableofenhancingmitochondrialelectrontransfer,whileobtainingdirectantioxidantactionsagainst glutamate,IAA,androtenoneinsults.Chlorophenothiazineexhibiteddirectantioxidantactionsinmitochondrialysateassay comparedtoMB,whichrequiredreductionbyNADHandmitochondria.MBincreasedcomplexIVexpressionandactivity, while 2-chlorphenothiazine had no effect. Our study indicated that MB could attenuate superoxide production by functioningasanaltern