FlavonoidsandBrainHealth:

Multipleeffectsunderpinnedbycommonmechanisms

Dr.JeremyPESpencer09/12/2024黃酮類(lèi)化合物和腦健康10.880-893.270-790.360-690.235-59PrevalenceofAD(%)Age(years)6.21.720.180.07PrevalenceofPD(%)IncreasedhealthcarecostsandgeneraldemandontheNHS.Reducedqualityoflifefortheelderlypopulation.AgeingandIncidenceofNeurodegenerativeDiseasesLifeExpectancyisincreasing黃酮類(lèi)化合物和腦健康DietandbrainfunctionMolecularMechanisms?FlavonoidsasneuroprotectiveagentsAnimalInvestigationsFlavonoidextractsfromfruitandvegetableshavebeenreportedtoattenuatecognitivedeclineandneuronaldysfunctioninanimalmodelsandhumans.Josephetal.(1998,1999)J.Neurosci.Unnoetal(2004)Exp.Gerontol.Haqueetal(2006)J.Nutr.Williamsetal(2008)FreeRadic.Biol.Med.HumanStudiesFlavonoids,inparticularflavanols,influenceneuralactivity,measuredwithfMRIFrancisetal(2006)J.Cardiovasc.Pharmacol.

Fisheretal(2006)J.Cardiovasc.Pharmacol.Kuriyamaetal(2006)AJCN黃酮類(lèi)化合物和腦健康Flavonoids:sourceFruitandvegetables:(Allclasses)Redwine:(Flavanol,Flavonols)Cocoa:(Flavanolsandprocyanidins)Tea:(Flavanols)Berries:(Anthocyanins)Citrus:(Flavanone)黃酮類(lèi)化合物和腦健康Flavonoids:structureFlavanolFlavonolIsoflavoneFlavanoneAnthocyaninR2HOOR1R3OHOHOOR1R2R4R3R5O+OHHOOHOHR1R2OOHOOHOHR1R2R3OHOOHOR1R2R3黃酮類(lèi)化合物和腦健康Plant-derivedflavonoidsandbrainfunction黃酮類(lèi)化合物和腦健康CorrectChoices(Alltrials)02468Baseline3weeks6weeks9weeks12weeksNumbercorrect(outof8)YoungOld

EffectsofaBlueberry-richdietonSpatialWorkingMemoryBlueberry****Williamsetal:FRBM,2008黃酮類(lèi)化合物和腦健康Effectsofflavonoidsupplementationonspatialmemoryinolderanimals黃酮類(lèi)化合物和腦健康HumaninterventionCognitivetestsTestDrinkPlaceboDay1Day2Day3BloodsampleBloodsampleBloodsampleBloodsampleBloodsampleBloodsampleUrinecollected09.00-13.00hoursUrinecollected13.00-17.00hoursUrinecollected17.00-09.00hoursthenextdayUrinecollected09.00-13.00hoursUrinecollected13.00-17.00hoursUrinecollected17.00-09.00hoursthenextdayBloodsampleCognitivetestsCognitivetestsDay1Day2Day3CognitivetestsCognitivetestsCognitivetestsCognitivetestsCognitivetests黃酮類(lèi)化合物和腦健康

Memory: Workingmemory:SerialSevenstask

Explicitandimplicitlong-termmemory:Immediatecuedwordrecall andword-stemcompletion,respectively

Spatialmemory:Brooksgrid,computerised3Dmaze

Visualmemory:FaceRecognitionTest

ExecutiveFunction:ComputerisedStroopTest,Go-NoGotask

Mood:VisualAnalogueScales.

Motorskill:StaticbalanceandDynamicbalanceCognitiveTests黃酮類(lèi)化合物和腦健康ImprovementsinHuman

ExecutiveFunction(Attention)Meanno.ofcorrectlydetectedtargetsSustainedabilitytocorrectlydetecttargetstimulifollowingflavonoidsupplementationcomparedtotheplacebo(*p<0.05;n=14).

Subjects:18-30yrsSubjects:60-75yrs36404448525660FlavonoidPlacebo*Go-NoGotask:measuresExecutivefunction/attentionPre-drink1hpost5hpostFlavonoidPlacebo*36404448525660

Pre-drink1hpost5hpostMeanno.ofcorrectlydetectedtargets黃酮類(lèi)化合物和腦健康Howaretheseeffectsmediated?黃酮類(lèi)化合物和腦健康ProposedmechanismsunderlyingtheneuroprotectiveeffectsofflavonoidsAntioxidanteffectsModulationofReceptorFunctionModulationofNeuronalandglialsignallingModulationofMembraneFluidityInfluencesongeneexpressionInhibitorsofNeuroinflammation黃酮類(lèi)化合物和腦健康BiotransformationofflavonoidsOralIngestionofflavonoidMonomericunitsOligomericFlavonoidsStomachSmallIntestinejejunumileumColonLiverKidneyUrinePortalveinRenalexcretionofglucuronidesOligomerscleavedcellsBlood-brainbarrierNeuronsgliaglucuronidesA-ringglucuronidesaglyconeO-methylatedglucuronidesO-methylatedglucuronidesO-methylatedSulphatesFurthermetabolismPhenolicacidsGutmicrofloraFlavonoidSpencer,etal:AntioxRedoxSignal,2001;JNutr,2003;BiochemJ,2003;ABB,2004;Brit.J.Nutr.2008黃酮類(lèi)化合物和腦健康3’-O-methyl-epicatechinEpicatechin-7-sulphateEpicatechin-7-b-D-

glucuronideEpicatechin0.1-30.9-250.1-80.9-5Plasma

concentration

mMMajorFlavonoidMetabolites黃酮類(lèi)化合物和腦健康BrainUptakeofFlavonoidsAbdelMohsenetal:FRBM,2002;FreeRadicRes.,2004;BrJNutr.,2006黃酮類(lèi)化合物和腦健康InhibitionofNeuronalInjurybyFlavonoidsControlOx.Stress(steady-stateperoxide)EC+Ox.StressMe-EC+Ox.Stress%MTTreduction******020406080100120ControlOx.StressECMe-ECEC-GlucVehicleSpenceretal:BiochemJ,2001;FRBM,2004黃酮類(lèi)化合物和腦健康NeurotransmitterReceptorPKCPI3-kinaseTyrosinekinaseMAPkinasecascadesJNKp38ERK1/2Akt/PKBNeuronalsurvivalandPlasticityNeuronalApoptosisCREBc-junBrainAgeingIncreasesincognitionperformanceandmemoryWilliamsetal:FRBM,2004Spenceretal:Genes&Nutr,2007;BritJNutr,2008;ChemSocRev,2009 黃酮類(lèi)化合物和腦健康FlavonoidAttenuationofDeathSignalling***00.40.81.21.6Bandintensity***00.40.81.21.6Bandintensity00.40.81.21.6Bandintensity00.40.81.21.6Bandintensitybasal54H2O23’MEC46activeJNKtotalJNKFlavonoid:0.3mMOS:Peroxide:50mMH2O2H2O2ECbasalH2O23’MECH2O2H2O2ECSpenceretal:BiochemJ,2001;FRBM,2004; Schroeteretal:BiochemJ,2001黃酮類(lèi)化合物和腦健康FlavonoidActivationofPro-survivalSignallingvehicle0.10.31.0mM4442pERK1/2TotalERK(15min;310K;n=4)0.00.20.40.60.81.01.2vehicleEC0.1mMEC0.3EC1EC3EC10RelativeBandIntensitypERK2pERK1******黃酮類(lèi)化合物和腦健康FlavonoidsmediateCREBActivationpCREB(Ser-133)totalCREBbasal0.10.31310Epicatechin[mM]Epicatechin:300nM;15min;O126:10mM;LY294002:35mM00.40.81.21.6basalEC300nMEC300nMUO126EC300nMLY294002EC300nMLY294003UO126RelativebandintensitypCREB(Ser-133)MEKinhibitorPI3Kinhibitor黃酮類(lèi)化合物和腦健康LY294002PD98059EpicatechinPI3KinaseInhibitorMEKInhibitorQuercetinSimilaritybetweenflavonoidsandkinaseinhibitors黃酮類(lèi)化合物和腦健康FlavonoidinteractionswithneuronalandglialsignallingIFN

IL-1bTNF-aCD23p38STAT-1iNOSNO?TNF-aCaspase-8Caspase-9Caspase-3NeuronalApoptosisROS/RNSMicroglia/AstrocyteNeuronASK1JNK1/2BADBcl-xLDHBT-1ERK1/2AktMEK1/2PI3KCREBActivationbyFlavonoidsScavengingbyFlavonoidsInhibitionbyFlavonoidsActivationInhibitionCysDAVafeiadouetal:EMIDDrugTargets,2007;ABB,2009Vauzouretal:JNeurochem,2007;Genes&Nutr,2008;ABB,2008黃酮類(lèi)化合物和腦健康Leeetal(2006)FRBM40,323-334Flavonoid-InducedSignallinginCancerPreventionLeeetal:FRBM,2006Nguyenetal:FRBM,2006Vauzouretal:ABB,2007黃酮類(lèi)化合物和腦健康InteractionofFlavonoidswiththebrainsarchitectureofmemory黃酮類(lèi)化合物和腦健康TheSensoryInputtotheHippocampusRendeiroetal:Genes&Nutr,200926黃酮類(lèi)化合物和腦健康NewlyacquiredSensoryinformationShort-termmemoryConsolidationLong-termmemoryMemoryRecallSlowerRetrievalRapidRetrievalTraining/PracticeMemoryLossAcquisitionPost-translationalmodificationofproteinsDeNovoproteinsynthesisHippocampusCortexStorageSpenceretal:ProceedNutrSoc,2006; ChemSocRev,2009黃酮類(lèi)化合物和腦健康ERK1/2/5CREBCaMKII/IVPKAPKB/AktPKCNeurotrophinsi.e.BDNFeNOSNOAngiogenesismTORArc/Arg3.1B-actinSynapticplasticityMemoryandLearningNeurogenesisSynapsere-modellingTranslationEfficiencyControlofMemoryattheMolecularLevelSpenceretal:ChemSocRev,2009黃酮類(lèi)化合物和腦健康ChangesinHippocampalCREBpCREB1(Ser133)CREB1YYOBOBHippocampusCortexpCREB1(Ser133)CREB101234HippocampusCortexa***RelativeBandIntensitypCREB/CREBAgedYoungAged+BBa=p0.001***=p0.001Williamsetal:FRBM,2008黃酮類(lèi)化合物和腦健康Pro-neurotrophinprecursorsalsomediatebiologicalfunctionsPolymorphismthatreplacesvalineformethionineatposition66oftheprodomain,isassociatedwithmemorydefectsandabnormalhippocampalfunctioninhumansHippocampalchangesin

pro-andmatureBDNFYYOBOBPro-BDNFBDNFGAPDH***aYOBRelativeBandIntensity0.00.51.01.5***bPro-BDNFMatureDDNFa/b=p0.001***=p0.001黃酮類(lèi)化合物和腦健康

ChangesinHippocampalERK1/2pERK44pERK42YYOBOBERK2pERK44pERK42a***b**RelativeBandIntensitypERK/ERK0.00.51.01.52.0AgedYoungAged+BBa/b=p0.001***=p0.001**=p0.01ERKPKCCREBPKACaMK黃酮類(lèi)化合物和腦健康Hippocampal

changesinAktpAkt(Ser473)AktPKACCaMKIV(Thr196)CaMKIVYYOBOBpAkt(Ser473)CaMKIV(Thr196)PKA(Thr197)***bRelativeBandIntensity0.00.51.01.52.0aaAgedYoungAged+BBa/b=p0.001***=p0.001PI3KTrkBAktBDNF黃酮類(lèi)化合物和腦健康Enhancementof

Hippocampal

ProteinSynthesisERKPI3KTrkBmTORHomer2Arc/Arg3.1AktBDNFmTOR(Ser2448)0.00.20.40.60.81.01.2***aRelativeBandIntensityPhospho-mTOR/TotalmTORmTOR(Ser2481)Arc/Arg3.1NR4A20.00.51.01.52.02.5BandIntensity***aAgedYoungAged+BB黃酮類(lèi)化合物和腦健康ERKPKCCREBPI3KBDNFTrkBmTORHomer2PostsynapticNMDA-RPKACaMKArc/Arg3.1AktBDNF‘EnhancementofProteinSynthesis’Presynaptic‘GlutamateRelease’AMPA-R(1)(2)(3)ProposedmechanismofactionISpenceretal:ChemSocRev,2009黃酮類(lèi)化合物和腦健康PostsynapticPresynapticTrkBNMDA-RAMPA-R‘IncreasedSynapticReceptorDensity’‘Dendriticspinalgrowth’-mushroomspinesSynapsefollowingLTPERKPI3KmTORHomer2Arc/Arg3.1Akt‘GlutamateRelease’‘F-actinExpansion’Cofilin‘SustainedActivationofArc,mTOR’ProposedmechanismofactionII黃酮類(lèi)化合物和腦健康InteractionswiththearchitectureofmemoryandcognitionNewnervecellgrowth(neurogenesis)Increasedneuronalcommunication(synapticplasticity)PlantBioactivesCellSignallingandGeneExpressionVascularEffectsNeuronalMorphology黃酮類(lèi)化合物和腦健康FlavonoidsimprovePeripheralandCerebralBloodFlowNitricoxide-dependentVasodilatationAcutechangesinbrainbloodflowModulationofvascularsignallingandfactorslinkedwithneurogenesisAcute