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1、27 October 2023,Flavonoids and Brain Health:Multiple effects underpinned by common mechanisms,Dr.Jeremy P E Spencer,10.8,80-89,3.2,70-79,0.3,60-69,0.2,35-59,Prevalenceof AD(%),Age(years),6.2,1.72,0.18,0.07,Prevalenceof PD(%),Increased health care costs and general demand on the NHS.Reduced quality o
2、f life for the elderly population.,Ageing and Incidence of Neurodegenerative Diseases,Life Expectancyis increasing,Diet and brain function,Molecular Mechanisms?,Flavonoids asneuroprotective agents,Animal Investigations,Human Studies,Flavonoids:source,Fruit and vegetables:(All classes),Red wine:(Flav
3、anol,Flavonols),Cocoa:(Flavanols and procyanidins),Tea:(Flavanols),Berries:(Anthocyanins),Citrus:(Flavanone),Flavonoids:structure,Flavanol,Flavonol,Isoflavone,Flavanone,Anthocyanin,O,O,R1,R2,R4,R3,R5,O,+,OH,HO,OH,OH,R1,R2,O,O,HO,OH,OH,R1,R2,R3,O,HO,OH,O,R1,R2,R3,Plant-derived flavonoids and brain fu
4、nction,Correct Choices(All trials),0,2,4,6,8,Baseline,3 weeks,6 weeks,9 weeks,12 weeks,Number correct(out of 8),Young,Old,Effects of a Blueberry-rich diet on Spatial Working Memory,Williams et al:FRBM,2008,Effects of flavonoid supplementation on spatial memory in older animals,Human intervention,Cog
5、nitive,tests,Test Drink,Placebo,Day 1,Day 2,Day 3,Blood sample,Blood sample,Blood sample,Blood sample,Blood sample,Blood sample,Urine collected 09.00-13.00 hours,Urine collected 13.00-17.00 hours,Urine collected 17.00-09.00 hours the next day,Urine collected 09.00-13.00 hours,Urine collected 13.00-1
6、7.00 hours,Urine collected 17.00-09.00 hours the next day,Blood sample,Cognitive,tests,Cognitive,tests,Day 1,Day 2,Day 3,Cognitive,tests,Cognitive,tests,Cognitive,tests,Cognitive,tests,Cognitive,tests,Memory:Working memory:Serial Sevens taskExplicit and implicit long-term memory:Immediate cued word
7、recall and word-stem completion,respectivelySpatial memory:Brooks grid,computerised 3D mazeVisual memory:Face Recognition Test Executive Function:Computerised Stroop Test,Go-NoGo task Mood:Visual Analogue Scales.Motor skill:Static balance and Dynamic balance,Cognitive Tests,Improvements in Human Exe
8、cutive Function(Attention),Mean no.of correctly detected targets,Sustained ability to correctly detect target stimuli following flavonoid supplementation compared to the placebo(*p 0.05;n=14).,Subjects:18-30 yrs,Subjects:60-75 yrs,36,40,44,48,52,56,60,Flavonoid,Placebo,*,Go-NoGo task:measures Execut
9、ive function/attention,Pre-drink,1h post,5h post,Flavonoid,Placebo,*,36,40,44,48,52,56,60,Pre-drink,1h post,5h post,Mean no.of correctly detected targets,How are these effects mediated?,Proposed mechanisms underlying the neuroprotective effects of flavonoids,Antioxidanteffects,Modulation ofReceptor
10、Function,Modulation ofNeuronal and glial signalling,Modulation ofMembrane Fluidity,Influences on gene expression,Inhibitors of Neuroinflammation,Biotransformation of flavonoids,Spencer,et al:Antiox Redox Signal,2001;J Nutr,2003;Biochem J,2003;ABB,2004;Brit.J.Nutr.2008,3-O-methyl-epicatechin,Epicatec
11、hin-7-sulphate,Epicatechin-7-b-D-glucuronide,Epicatechin,Major Flavonoid Metabolites,Brain Uptake of Flavonoids,Abd el Mohsen et al:FRBM,2002;Free Radic Res.,2004;Br J Nutr.,2006,Inhibition of Neuronal Injury by Flavonoids,Control,Ox.Stress(steady-state peroxide),EC+Ox.Stress,Me-EC+Ox.Stress,Spencer
12、 et al:Biochem J,2001;FRBM,2004,Williams et al:FRBM,2004Spencer et al:Genes Chem Soc Rev,2009,Flavonoid Attenuation of Death Signalling,Spencer et al:Biochem J,2001;FRBM,2004;Schroeter et al:Biochem J,2001,Flavonoid Activation of Pro-survival Signalling,Flavonoids mediate CREB Activation,Epicatechin
13、:300 nM;15 min;O126:10 mM;LY294002:35 mM,0,0.4,0.8,1.2,1.6,basal,EC 300 nM,EC 300 nM,UO126,EC 300 nM,LY294002,EC 300 nM,LY294003,UO126,Relative band intensity,pCREB(Ser-133),MEK inhibitor,PI3K inhibitor,LY294002,PD98059,Epicatechin,PI3 KinaseInhibitor,MEK Inhibitor,Similarity between flavonoids and
14、kinase inhibitors,Flavonoid interactions with neuronal and glial signalling,Vafeiadou et al:EMID Drug Targets,2007;ABB,2009Vauzour et al:J Neurochem,2007;Genes ABB,2008,Lee et al(2006)FRBM 40,323-334,Flavonoid-Induced Signalling in Cancer Prevention,Lee et al:FRBM,2006,Nguyen et al:FRBM,2006Vauzour
15、et al:ABB,2007,Interaction of Flavonoids with the brains architecture of memory,26,The Sensory Input to the Hippocampus,Rendeiro et al:Genes&Nutr,2009,Spencer et al:Proceed Nutr Soc,2006;Chem Soc Rev,2009,Control of Memory at the Molecular Level,Spencer et al:Chem Soc Rev,2009,Changes in Hippocampal
16、 CREB,pCREB1(Ser 133),CREB1,Y,Y,O,B,O,B,Hippocampus,Cortex,pCREB1(Ser 133),CREB1,0,1,2,3,4,Hippocampus,Cortex,a,*,Relative BandIntensitypCREB/CREB,Aged,Young,Aged+BB,a=p 0.001*=p 0.001,Williams et al:FRBM,2008,Pro-neurotrophin precursors also mediate biological functions Polymorphism that replaces v
17、aline 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 BDNF,Y,Y,O,B,O,B,Pro-BDNF,BDNF,GAPDH,*,a,Y,O,B,RelativeBandIntensity,0.0,0.5,1.0,1.5,*,b,Pro-BDNF,Mature DDNF,a/b=p 0.001*=p 0.001
18、,Changes in Hippocampal ERK1/2,ERK,PKC,CREB,PKA,CaMK,Hippocampal changes in Akt,Enhancement of Hippocampal Protein Synthesis,ERK,PI3K,TrkB,mTOR,Homer2,Arc/Arg3.1,Akt,BDNF,Proposed mechanism of action I,Spencer et al:Chem Soc Rev,2009,Postsynaptic,Presynaptic,TrkB,NMDA-R,AMPA-R,Increased Synaptic Rec
19、eptor Density,Dendritic spinal growth-mushroom spines,Synapse following LTP,ERK,PI3K,mTOR,Homer2,Arc/Arg3.1,Akt,GlutamateRelease,F-actinExpansion,Cofilin,SustainedActivation of Arc,mTOR,Proposed mechanism of action II,Interactions with the architecture of memory and cognition,New nerve cell growth(n
20、eurogenesis),Increased neuronal communication(synaptic plasticity),Plant Bioactives,Cell Signalling and Gene Expression,Vascular Effects,Neuronal Morphology,37,Flavonoids improve Peripheral and Cerebral Blood Flow,Nitric oxide-dependentVasodilatation,Acute changes in brain blood flow,Modulation of v
21、ascular signalling and factors linked with neurogenesis,Acute improvements in vascular responsiveness,Heiss et al.JAMA,2003,Neurogenesis?,38,Neurogenesis,39,The Future:Brain Imaging,morphology and Networks,40,Summary,Flavonoid-rich diets are capable of reversing age-related declines in spatial worki
22、ng 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 o
23、f the age-associated cognitive decline might be mediated through modifications of CREB and CREB-dependant gene expression,Acknowledgements,Dr.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 Tzounis,43,
