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1、2021年7月26日星期一,黄酮类化合物和脑健康,1,Flavonoids and Brain Health: Multiple effects underpinned by common mechanisms,Dr. Jeremy P E Spencer,黄酮类化合物和脑健康,2,10.8,80-89,3.2,70-79,0.3,60-69,0.2,35-59,Prevalence of AD (%),Age (years),6.2,1.72,0.18,0.07,Prevalence of PD (%),Increased health care costs and general dema
2、nd on the NHS. Reduced quality of life for the elderly population.,Ageing and Incidence of Neurodegenerative Diseases,Life Expectancy is increasing,黄酮类化合物和脑健康,3,Diet and brain function,Molecular Mechanisms?,Flavonoids as neuroprotective agents,Animal Investigations,Human Studies,黄酮类化合物和脑健康,4,Flavono
3、ids: source,Fruit and vegetables: (All classes),Red wine: (Flavanol, Flavonols),Cocoa: (Flavanols and procyanidins),Tea: (Flavanols),Berries: (Anthocyanins),Citrus: (Flavanone),黄酮类化合物和脑健康,5,Flavonoids: structure,Flavanol,Flavonol,Isoflavone,Flavanone,Anthocyanin,O,O,R1,R2,R4,R3,R5,O,+,OH,HO,OH,OH,R1
4、,R2,O,O,HO,OH,OH,R1,R2,R3,O,HO,OH,O,R1,R2,R3,黄酮类化合物和脑健康,6,Plant-derived flavonoids and brain function,黄酮类化合物和脑健康,7,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
5、et al: FRBM, 2008,黄酮类化合物和脑健康,8,Effects of flavonoid supplementation on spatial memory in older animals,黄酮类化合物和脑健康,9,Human intervention,Cognitive,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 hour
6、s,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 - 17.00 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,tes
7、ts,Cognitive,tests,Cognitive,tests,Cognitive,tests,黄酮类化合物和脑健康,10,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
8、 Executive Function: Computerised Stroop Test, Go-NoGo task Mood: Visual Analogue Scales. Motor skill: Static balance and Dynamic balance,Cognitive Tests,黄酮类化合物和脑健康,11,Improvements in Human Executive Function (Attention),Mean no. of correctly detected targets,Sustained ability to correctly detect ta
9、rget 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 Executive function/attention,Pre-drink,1h post,5h post,Flavonoid,Placebo,*,36,40,44,48,52,56,60,Pre-drin
10、k,1h post,5h post,Mean no. of correctly detected targets,黄酮类化合物和脑健康,12,How are these effects mediated?,黄酮类化合物和脑健康,13,Proposed mechanisms underlying the neuroprotective effects of flavonoids,Antioxidant effects,Modulation of Receptor Function,Modulation of Neuronal and glial signalling,Modulation of
11、Membrane Fluidity,Influences on gene expression,Inhibitors of Neuroinflammation,黄酮类化合物和脑健康,14,Biotransformation of flavonoids,Spencer , et al: Antiox Redox Signal, 2001; J Nutr, 2003; Biochem J, 2003; ABB, 2004; Brit. J. Nutr. 2008,黄酮类化合物和脑健康,15,3-O-methyl-epicatechin,Epicatechin-7-sulphate,Epicatec
12、hin-7-b-D-glucuronide,Epicatechin,Major Flavonoid Metabolites,黄酮类化合物和脑健康,16,Brain Uptake of Flavonoids,Abd el Mohsen et al: FRBM, 2002; Free Radic Res., 2004 ; Br J Nutr., 2006,黄酮类化合物和脑健康,17,Inhibition of Neuronal Injury by Flavonoids,Control,Ox. Stress (steady-state peroxide),EC + Ox. Stress,Me-EC
13、+ Ox. Stress,Spencer et al: Biochem J, 2001; FRBM, 2004,黄酮类化合物和脑健康,18,Williams et al: FRBM, 2004 Spencer et al: Genes Chem Soc Rev, 2009,黄酮类化合物和脑健康,19,Flavonoid Attenuation of Death Signalling,Spencer et al: Biochem J, 2001; FRBM, 2004; Schroeter et al: Biochem J, 2001,黄酮类化合物和脑健康,20,Flavonoid Activa
14、tion of Pro-survival Signalling,黄酮类化合物和脑健康,21,Flavonoids mediate CREB Activation,Epicatechin: 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 inhibito
15、r,黄酮类化合物和脑健康,22,LY294002,PD98059,Epicatechin,PI3 Kinase Inhibitor,MEK Inhibitor,Similarity between flavonoids and kinase inhibitors,黄酮类化合物和脑健康,23,Flavonoid interactions with neuronal and glial signalling,Vafeiadou et al: EMID Drug Targets, 2007; ABB, 2009 Vauzour et al: J Neurochem, 2007; Genes ABB,
16、 2008,黄酮类化合物和脑健康,24,Lee et al (2006) FRBM 40, 323-334,Flavonoid-Induced Signalling in Cancer Prevention,Lee et al: FRBM, 2006,Nguyen et al: FRBM, 2006 Vauzour et al: ABB, 2007,黄酮类化合物和脑健康,25,Interaction of Flavonoids with the brains architecture of memory,黄酮类化合物和脑健康,26,The Sensory Input to the Hippoc
17、ampus,Rendeiro et al: Genes Chem Soc Rev, 2009,黄酮类化合物和脑健康,28,Control of Memory at the Molecular Level,Spencer et al: Chem Soc Rev, 2009,黄酮类化合物和脑健康,29,Changes in Hippocampal 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 Ban
18、d Intensity pCREB/ CREB,Aged,Young,Aged + BB,a = p 0.001 * = p 0.001,Williams et al: FRBM, 2008,黄酮类化合物和脑健康,30,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 abnorma
19、l 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,Relative Band Intensity,0.0,0.5,1.0,1.5,*,b,Pro-BDNF,Mature DDNF,a/b = p 0.001 * = p 0.001,黄酮类化合物和脑健康,31,Changes in Hippocampal ERK1/2,ERK,PKC,CREB,PKA,CaMK,黄酮类化合物和脑健康,32,Hippocampa
20、l changes in Akt,黄酮类化合物和脑健康,33,Enhancement of Hippocampal Protein Synthesis,ERK,PI3K,TrkB,mTOR,Homer2,Arc/Arg3.1,Akt,BDNF,黄酮类化合物和脑健康,34,Proposed mechanism of action I,Spencer et al: Chem Soc Rev, 2009,黄酮类化合物和脑健康,35,Postsynaptic,Presynaptic,TrkB,NMDA-R,AMPA-R,Increased Synaptic Receptor Density,Dendr
21、itic spinal growth - mushroom spines,Synapse following LTP,ERK,PI3K,mTOR,Homer2,Arc/Arg3.1,Akt,Glutamate Release,F-actin Expansion,Cofilin,Sustained Activation of Arc, mTOR,Proposed mechanism of action II,黄酮类化合物和脑健康,36,Interactions with the architecture of memory and cognition,New nerve cell growth
22、(neurogenesis),Increased neuronal communication (synaptic plasticity),Plant Bioactives,Cell Signalling and Gene Expression,Vascular Effects,Neuronal Morphology,黄酮类化合物和脑健康,37,Flavonoids improve Peripheral and Cerebral Blood Flow,Nitric oxide-dependent Vasodilatation,Acute changes in brain blood flow,
23、Modulation of vascular signalling and factors linked with neurogenesis,Acute improvements in vascular responsiveness,Heiss et al. JAMA, 2003,黄酮类化合物和脑健康,38,Neurogenesis?,Neurogenesis,黄酮类化合物和脑健康,39,The Future: Brain Imaging, morphology and Networks,黄酮类化合物和脑健康,40,黄酮类化合物和脑健康,41,Summary,Flavonoid-rich di
24、ets 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
25、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 expression,黄酮类化合物和脑健康,42,Acknowledgements,Dr. Manal Abd El Mohsen Dr. Giulia Corona Dr. Ana Rodriquez-Mateos Dr. Maria-Jose Oruna-Concha Dr. Katerina Vafeiadou Dr. David Vauzour Prof. Judi Ellis Dr. Laurie Butler Dr. Claire Williams Vanessa Collins Georgina Dodd Eva Hernandez Pauline How Susie Jennings Sara Neshatdoust Catarina Rendeiro Caroline Saunders Setarah Tabatabaee Xenofon Tzounis,黄酮类化合物和脑健康,43,