齊魯醫(yī)學黃酮類化合物和腦健康

1、Flavonoids 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 pop

2、ulation.Ageing and Incidence of Neurodegenerative DiseasesLife Expectancyis increasing2Diet and brain functionMolecular Mechanisms?Flavonoids asneuroprotective agentsAnimal InvestigationsFlavonoid extracts from fruit and vegetables have been reported to attenuate cognitive decline and neuronal dysfu

3、nction 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.

4、Cardiovasc. Pharmacol. Fisher et al (2006) J. Cardiovasc. Pharmacol. Kuriyama et al (2006) AJCN3Flavonoids: sourceFruit and vegetables:(All classes)Red wine:(Flavanol, Flavonols)Cocoa:(Flavanols and procyanidins)Tea:(Flavanols)Berries:(Anthocyanins)Citrus:(Flavanone)4Flavonoids: structureFlavanolFla

5、vonolIsoflavoneFlavanoneAnthocyaninR2HOOR1R3OHOHOOR1R2R4R3R5O+OHHOOHOHR1R2OOHOOHOHR1R2R3OHOOHOR1R2R35Plant-derived flavonoids and brain function6Correct Choices (All trials)02468Baseline3 weeks6 weeks9 weeks12 weeksNumber correct (out of 8)YoungOld Effects of a Blueberry-rich diet on Spatial Working

6、 MemoryBlueberry*Williams et al: FRBM, 20087Effects of flavonoid supplementation on spatial memory in older animals8Human interventionCognitivetestsTest DrinkPlaceboDay 1Day 2Day 3Blood sampleBlood sampleBlood sampleBlood sampleBlood sampleBlood sampleUrine collected 09.00 - 13.00 hoursUrine collect

7、ed 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 3CognitivetestsCognitivetestsCognitivetestsCognitivetestsC

8、ognitivetests9 Memory:Working memory: Serial Sevens taskExplicit and implicit long-term memory: Immediate cued word recall and word-stem completion, respectivelySpatial memory: Brooks grid, computerised 3D mazeVisual memory: Face Recognition Test Executive Function: Computerised Stroop Test, Go-NoGo

9、 task Mood: Visual Analogue Scales. Motor skill: Static balance and Dynamic balanceCognitive Tests10Improvements in Human Executive Function (Attention)Mean no. of correctly detected targetsSustained ability to correctly detect target stimuli following flavonoid supplementation compared to the place

10、bo (* 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 targets11How are these effects mediated?12Propose

11、d mechanisms underlying the neuroprotective effects of flavonoidsAntioxidanteffectsModulation ofReceptor FunctionModulation ofNeuronal and glial signallingModulation ofMembrane FluidityInfluences on gene expressionInhibitors of Neuroinflammation13Biotransformation of flavonoidsOral Ingestionof flavo

12、noidMonomericunitsOligomericFlavonoidsStomachSmall IntestinejejunumileumColonLiverKidneyUrinePortalveinRenal excretionof glucuronides Oligomerscleaved cellsBlood-brainbarrierNeuronsgliaglucuronidesA-ring glucuronidesaglyconeO-methylated glucuronidesO-methylatedglucuronidesO-methylatedSulphatesFurthe

13、rmetabolismPhenolic acidsGut microfloraFlavonoidSpencer , et al: Antiox Redox Signal, 2001; J Nutr, 2003; Biochem J, 2003; ABB, 2004; Brit. J. Nutr. 2008143-O-methyl-epicatechinEpicatechin-7-sulphateEpicatechin-7-b-D-glucuronideEpicatechin0.1-30.9-250.1-80.9-5PlasmaconcentrationmMMajor Flavonoid Met

14、abolites15Brain Uptake of FlavonoidsAbd el Mohsen et al: FRBM, 2002; Free Radic Res., 2004 ; Br J Nutr., 2006 16Inhibition of Neuronal Injury by FlavonoidsControlOx. Stress (steady-state peroxide)EC + Ox. StressMe-EC + Ox. Stress% MTT reduction*020406080100120ControlOx. StressECMe-ECEC-GlucVehicleSp

15、encer et al: Biochem J, 2001; FRBM, 200417Neurotransmitter 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 &

16、Nutr, 2007; Brit J Nutr, 2008; Chem Soc Rev, 200918Flavonoid 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 mMOS: Peroxide: 50 mMH2O2H2O2ECbasalH2O23MECH2O

17、2H2O2ECSpencer et al: Biochem J, 2001; FRBM, 2004; Schroeter et al: Biochem J, 200119Flavonoid Activation of Pro-survival Signalling vehicle0.10.31.0mM4442pERK1/2Total ERK(15 min; 310 K; n=4)0.00.20.40.60.81.01.2vehicleEC 0.1mMEC 0.3EC 1EC 3EC 10Relative Band IntensitypERK2pERK1*20Flavonoids mediate

18、 CREB ActivationpCREB (Ser-133)total CREBbasal0.10.31310Epicatechin mMEpicatechin: 300 nM; 15 min;O126: 10 mM; LY294002: 35 mM 00.40.81.21.6basalEC 300 nMEC 300 nMUO126EC 300 nMLY294002EC 300 nMLY294003UO126Relative band intensitypCREB (Ser-133)MEK inhibitorPI3K inhibitor21LY294002PD98059Epicatechin

19、PI3 KinaseInhibitorMEK InhibitorQuercetinSimilarity between flavonoids and kinase inhibitors22Flavonoid interactions with neuronal and glial signallingIFNIL-1bTNF-aCD23p38STAT-1iNOSNOTNF-aCaspase-8Caspase-9Caspase-3NeuronalApoptosis ROS/RNSMicroglia/AstrocyteNeuronASK1JNK1/2BADBcl-xLDHBT-1ERK1/2AktM

20、EK1/2PI3KCREBActivation by FlavonoidsScavenging by FlavonoidsInhibition byFlavonoidsActivationInhibitionCysDAVafeiadou et al: EMID Drug Targets, 2007; ABB, 2009Vauzour et al: J Neurochem, 2007; Genes & Nutr, 2008; ABB, 2008 23Lee et al (2006)FRBM 40, 323-334Flavonoid-Induced Signalling in Cancer Pre

21、ventionLee et al: FRBM, 2006Nguyen et al: FRBM, 2006Vauzour et al: ABB, 200724Interaction of Flavonoids with the brains architecture of memory25The Sensory Input to the HippocampusRendeiro et al: Genes & Nutr, 200926Newly acquiredSensory informationShort-termmemoryConsolidationLong-termmemoryMemoryR

22、ecallSlower RetrievalRapid RetrievalTraining/PracticeMemoryLossAcquisitionPost-translationalmodification ofproteinsDe Novo protein synthesisHippocampusCortexStorageSpencer et al: Proceed Nutr Soc, 2006;Chem Soc Rev, 200927ERK1/2/5CREBCaMK II/IVPKAPKB/AktPKCNeurotrophinsi.e. BDNFeNOSNOAngiogenesismTO

23、RArc/Arg3.1B-actinSynaptic plasticityMemory and LearningNeurogenesisSynapse re-modellingTranslationEfficiencyControl of Memory at the Molecular LevelSpencer et al: Chem Soc Rev, 200928Changes in Hippocampal CREBpCREB1 (Ser 133) CREB1YYOBOBHippocampusCortexpCREB1 (Ser 133) CREB101234HippocampusCortex

24、a*Relative BandIntensitypCREB/CREBAgedYoungAged + BBa = p 0.001* = p 0.001Williams et al: FRBM, 200829 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 hippo

25、campal function in humans Hippocampal changes in pro- and mature BDNFYYOBOBPro-BDNFBDNFGAPDH*aYOBRelativeBandIntensity0.00.51.01.5*bPro-BDNFMature DDNFa/b = p 0.001* = p 0.00130Changes in Hippocampal ERK1/2pERK 44pERK 42YYOBOBERK2pERK 44pERK 42a*b*RelativeBandIntensitypERK/ERK0.00.51.01.52.0AgedYoun

26、gAged + BBa/b = p 0.001* = p 0.001* = p 0.01ERKPKCCREBPKACaMK31Hippocampal 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 0.001PI3KTrkBAktBDNF32Enhancement of Hippo

27、campal 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 + BB33ERKPKCCREBPI3KBDNFTrkBmTORHomer2PostsynapticNMDA-RPKACaMKArc/Arg3.1AktBDNFE

28、nhancementof Protein SynthesisPresynapticGlutamateReleaseAMPA-R(1)(2)(3)Proposed mechanism of action ISpencer et al: Chem Soc Rev, 200934PostsynapticPresynapticTrkBNMDA-RAMPA-RIncreased Synaptic Receptor DensityDendritic spinal growth- mushroom spinesSynapse following LTPERKPI3KmTORHomer2Arc/Arg3.1A

29、ktGlutamateReleaseF-actinExpansionCofilinSustainedActivation of Arc, mTORProposed mechanism of action II35Interactions with the architecture of memory and cognitionNew nerve cell growth (neurogenesis)Increased neuronal communication(synaptic plasticity)Plant BioactivesCell Signalling and Gene ExpressionVascular EffectsNeuronal Morphology36Flavonoids improve Peripheral and Cerebral Blood FlowNitric oxide-dependentVasodilatation Acute changes in brain blood flowModulation of vascular signalling and factors linked with neurogenesisAcute improvements in vas