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01 August 2024Flavonoids and Brain Health:Multiple effects underpinned by common mechanismsDr.Jeremy P E Spencer10.880-893.270-790.360-690.235-59Prevalenceof AD(%)Age(years)6.21.720.180.07Prevalenceof PD(%)Increased health care costs and general demand on the NHS.Reduced quality of life for the elderly population.Ageing and Incidence of Neurodegenerative DiseasesLife Expectancyis increasingDiet and brain functionMolecular Mechanisms?Flavonoids asneuroprotective agentsAnimal InvestigationsFlavonoid extracts from fruit and vegetables have been reported to attenuate cognitive decline and neuronal dysfunction in animal models and humans.Joseph et al.(1998,1999)J.Neurosci.Unno et al(2004)Exp.Gerontol.Haque et al(2006)J.Nutr.Williams et al(2008)Free Radic.Biol.Med.Human StudiesFlavonoids,in particular flavanols,influenceneural activity,measured with fMRI Francis et al(2006)J.Cardiovasc.Pharmacol.Fisher et al(2006)J.Cardiovasc.Pharmacol.Kuriyama et al(2006)AJCNFlavonoids:sourceFruit and vegetables:(All classes)Red wine:(Flavanol,Flavonols)Cocoa:(Flavanols and procyanidins)Tea:(Flavanols)Berries:(Anthocyanins)Citrus:(Flavanone)Flavonoids:structureFlavanolFlavonolIsoflavoneFlavanoneAnthocyaninR2HOOR1R3OHOHOOR1R2R4R3R5O+OHHOOHOHR1R2OOHOOHOHR1R2R3OHOOHOR1R2R3Plant-derived flavonoids and brain functionCorrect Choices(All trials)02468Baseline3 weeks6 weeks9 weeks12 weeksNumber correct(out of 8)YoungOld Effects of a Blueberry-rich diet on Spatial Working MemoryBlueberry*Williams et al:FRBM,2008Effects of flavonoid supplementation on spatial memory in older animalsHuman interventionCognitivetestsTest DrinkPlaceboDay 1Day 2Day 3Blood sampleBlood sampleBlood sampleBlood sampleBlood sampleBlood sampleUrine collected 09.00-13.00 hoursUrine collected 13.00-17.00 hoursUrine collected 17.00-09.00 hours the next dayUrine collected 09.00-13.00 hoursUrine collected 13.00-17.00 hoursUrine collected 17.00-09.00 hours the next dayBlood sampleCognitivetestsCognitivetestsDay 1Day 2Day 3CognitivetestsCognitivetestsCognitivetestsCognitivetestsCognitivetests Memory:Working memory:Serial Sevens task Explicit and implicit long-term memory:Immediate cued word recall and word-stem completion,respectively Spatial memory:Brooks grid,computerised 3D maze Visual memory:Face Recognition Test Executive Function:Computerised Stroop Test,Go-NoGo task Mood:Visual Analogue Scales.Motor skill:Static balance and Dynamic balanceCognitive TestsImprovements in Human Executive Function(Attention)Mean no.of correctly detected targetsSustained ability to correctly detect target stimuli following flavonoid supplementation compared to the placebo(*p 0.05;n=14).Subjects:18-30 yrsSubjects:60-75 yrs36404448525660FlavonoidPlacebo*Go-NoGo task:measures Executive function/attentionPre-drink1h post5h postFlavonoidPlacebo*36404448525660 Pre-drink1h post5h postMean no.of correctly detected targetsHow are these effects mediated?Proposed mechanisms underlying the neuroprotective effects of flavonoidsAntioxidanteffectsModulation ofReceptor FunctionModulation ofNeuronal and glial signallingModulation ofMembrane FluidityInfluences on gene expressionInhibitors of NeuroinflammationBiotransformation of flavonoidsOral Ingestionof flavonoidMonomericunitsOligomericFlavonoidsStomachSmall IntestinejejunumileumColonLiverKidneyUrinePortalveinRenal excretionof glucuronides Oligomerscleaved cellsBlood-brainbarrierNeuronsgliaglucuronidesA-ring glucuronidesaglyconeO-methylated glucuronidesO-methylatedglucuronidesO-methylatedSulphatesFurthermetabolismPhenolic acidsGut microfloraFlavonoidSpencer,et al:Antiox Redox Signal,2001;J Nutr,2003;Biochem J,2003;ABB,2004;Brit.J.Nutr.20083-O-methyl-epicatechinEpicatechin-7-sulphateEpicatechin-7-b-D-glucuronideEpicatechin0.1-30.9-250.1-80.9-5Plasmaconcentrationm mMMajor Flavonoid MetabolitesBrain Uptake of FlavonoidsAbd el Mohsen et al:FRBM,2002;Free Radic Res.,2004;Br J Nutr.,2006 Inhibition of Neuronal Injury by FlavonoidsControlOx.Stress(steady-state peroxide)EC+Ox.StressMe-EC+Ox.Stress%MTT reduction*020406080100120ControlOx.StressECMe-ECEC-GlucVehicleSpencer et al:Biochem J,2001;FRBM,2004Neurotransmitter ReceptorPKCPI 3-kinaseTyrosine kinaseMAP kinase cascadesJNK p38ERK1/2Akt/PKBNeuronal survival and PlasticityNeuronal ApoptosisCREBc-junBrain AgeingIncreases in cognition performance and memoryWilliams et al:FRBM,2004Spencer et al:Genes&Nutr,2007;Brit J Nutr,2008;Chem Soc Rev,2009Flavonoid Attenuation of Death Signalling*00.40.81.21.6Band intensity*00.40.81.21.6Band intensity00.40.81.21.6Band intensity00.40.81.21.6Band intensitybasal54H2O23MEC46active JNKtotal JNKFlavonoid:0.3 m mMOS:Peroxide:50 m mMH2O2H2O2ECbasalH2O23MECH2O2H2O2ECSpencer et al:Biochem J,2001;FRBM,2004;Schroeter et al:Biochem J,2001Flavonoid Activation of Pro-survival Signalling vehicle0.10.31.0m mM4442pERK1/2Total ERK(15 min;310 K;n=4)0.00.20.40.60.81.01.2vehicleEC 0.1m mMEC 0.3EC 1EC 3EC 10Relative Band IntensitypERK2pERK1*Flavonoids mediate CREB ActivationpCREB(Ser-133)total CREBbasal0.10.31310Epicatechin m mMEpicatechin:300 nM;15 min;O126:10 m mM;LY294002:35 m mM 00.40.81.21.6basalEC 300 nMEC 300 nMUO126EC 300 nMLY294002EC 300 nMLY294003UO126Relative band intensitypCREB(Ser-133)MEK inhibitorPI3K inhibitorLY294002PD98059EpicatechinPI3 KinaseInhibitorMEK InhibitorQuercetinSimilarity between flavonoids and kinase inhibitorsFlavonoid interactions with neuronal and glial signallingIFN IL-1b bTNF-a aCD23p38STAT-1iNOSNOTNF-a aCaspase-8Caspase-9Caspase-3NeuronalApoptosis ROS/RNSMicroglia/AstrocyteNeuronASK1JNK1/2BADBcl-xLDHBT-1ERK1/2AktMEK1/2PI3KCREBActivation by FlavonoidsScavenging by FlavonoidsInhibition byFlavonoidsActivationInhibitionCysDAVafeiadou et al:EMID Drug Targets,2007;ABB,2009Vauzour et al:J Neurochem,2007;Genes&Nutr,2008;ABB,2008 Lee et al(2006)FRBM 40,323-334Flavonoid-Induced Signalling in Cancer PreventionLee et al:FRBM,2006Nguyen et al:FRBM,2006Vauzour et al:ABB,2007Interaction of Flavonoids with the brains architecture of memory26The Sensory Input to the HippocampusRendeiro et al:Genes&Nutr,2009Newly acquiredSensory informationShort-termmemoryConsolidationLong-termmemoryMemoryRecallSlower RetrievalRapid RetrievalTraining/PracticeMemoryLossAcquisitionPost-translationalmodification ofproteinsDe Novo protein synthesisHippocampusCortexStorageSpencer et al:Proceed Nutr Soc,2006;Chem Soc Rev,2009ERK1/2/5CREBCaMK II/IVPKAPKB/AktPKCNeurotrophinsi.e.BDNFeNOSNOAngiogenesismTORArc/Arg3.1B-actinSynaptic plasticityMemory and LearningNeurogenesisSynapse re-modellingTranslationEfficiencyControl of Memory at the Molecular LevelSpencer et al:Chem Soc Rev,2009Changes in Hippocampal CREBpCREB1(Ser 133)CREB1YYOBOBHippocampusCortexpCREB1(Ser 133)CREB101234HippocampusCortexa*Relative BandIntensitypCREB/CREBAgedYoungAged+BBa=p 0.001*=p 0.001Williams et al:FRBM,2008 Pro-neurotrophin precursors also mediate biological functions Polymorphism that replaces valine for methionine at position 66 of the pro domain,is associated with memory defects and abnormal hippocampal function in humans Hippocampal changes in pro-and mature BDNFYYOBOBPro-BDNFBDNFGAPDH*aYOBRelativeBandIntensity0.00.51.01.5*bPro-BDNFMature DDNFa/b=p 0.001*=p 0.001Changes in Hippocampal ERK1/2pERK 44pERK 42YYOBOBERK2pERK 44pERK 42a*b*RelativeBandIntensitypERK/ERK0.00.51.01.52.0AgedYoungAged+BBa/b=p 0.001*=p 0.001*=p 0.01ERKPKCCREBPKACaMKHippocampal changes in AktpAkt(Ser 473)AktPKA CCaMKIV(Thr 196)CaMKIVYYOBOBpAkt(Ser 473)CaMKIV(Thr 196)PKA(Thr 197)*bRelativeBandIntensity0.00.51.01.52.0aaAgedYoungAged+BBa/b=p 0.001*=p 0.001PI3KTrkBAktBDNFEnhancement of Hippocampal Protein SynthesisERKPI3KTrkBmTORHomer2Arc/Arg3.1AktBDNFmTOR(Ser 2448)0.00.20.40.60.81.01.2*aRelativeBandIntensityPhospho-mTOR/Total mTORmTOR(Ser 2481)Arc/Arg3.1NR4A20.00.51.01.52.02.5BandIntensity*aAgedYoungAged+BBERKPKCCREBPI3KBDNFTrkBmTORHomer2PostsynapticNMDA-RPKACaMKArc/Arg3.1AktBDNFEnhancementof Protein SynthesisPresynapticGlutamateReleaseAMPA-R(1)(2)(3)Proposed mechanism of action ISpencer et al:Chem Soc Rev,2009PostsynapticPresynapticTrkBNMDA-RAMPA-RIncreased Synaptic Receptor DensityDendritic spinal growth-mushroom spinesSynapse following LTPERKPI3KmTORHomer2Arc/Arg3.1AktGlutamateReleaseF-actinExpansionCofilinSustainedActivation of Arc,mTORProposed mechanism of action IIInteractions with the architecture of memory and cognitionNew nerve cell growth(neurogenesis)Increased neuronal communication(synaptic plasticity)Plant BioactivesCell Signalling and Gene ExpressionVascular EffectsNeuronal Morphology37Flavonoids improve Peripheral and Cerebral Blood FlowNitric oxide-dependentVasodilatation Acute changes in brain blood flowModulation of vascular signalling and factors linked with neurogenesisAcute improvements in vascular responsivenessHeiss et al.JAMA,2003Neurogenesis?38Neurogenesis39The Future:Brain Imaging,morphology and Networks 40Summary Flavonoid-rich diets are capable of reversing age-related declines in spatial working memory.The effects of dietary flavonoids/metabolites areseemingly independent of their antioxidant potential.Flavonoids appear to induce cellular effects via specific interactions within cell signalling cascades,such as the MAP kinase pathway.The beneficial effects of flavonoids on the reversal of the age-associated cognitive decline might be mediated through modifications of CREB and CREB-dependant gene expressionAcknowledgementsDr.Manal Abd El MohsenDr.Giulia CoronaDr.Ana Rodriquez-MateosDr.Maria-Jose Oruna-ConchaDr.Katerina VafeiadouDr.David VauzourProf.Judi EllisDr.Laurie ButlerDr.Claire WilliamsVanessa CollinsGeorgina DoddEva HernandezPauline HowSusie JenningsSara NeshatdoustCatarina RendeiroCaroline SaundersSetarah TabatabaeeXenofon Tzounis43后面内容直接删除就行资料可以编辑修改使用资料可以编辑修改使用资料仅供参考，实际情况实际分析主要经营：课件设计，文档制作，网络软件设计、图文设计制作、发布广告等秉着以优质的服务对待每一位客户，做到让客户满意！致力于数据挖掘，合同简历、论文写作、PPT设计、计划书、策划案、学习课件、各类模板等方方面面，打造全网一站式需求The user can demonstrate on a 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