课件：黄酮类化合物和脑健康.ppt

16 March 2019,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,Prevalence of AD (%),Age (years),6.2,1.72,0.18,0.07,Prevalence of PD (%),Increased health care costs and general demand on the NHS. Reduced quality of life for the elderly population.,Ageing and Incidence of Neurodegenerative Diseases,Life Expectancy is increasing,Diet and brain function,Molecular Mechanisms?,Flavonoids as neuroprotective agents,Animal Investigations,Human Studies,Flavonoids: source,Fruit and vegetables: (All classes),Red wine: (Flavanol, 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 function,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,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 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 - 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,tests,Cognitive,tests,Cognitive,tests,Cognitive,tests,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 balance,Cognitive Tests,Improvements in Human Executive 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 Executive 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,Antioxidant effects,Modulation of Receptor Function,Modulation of Neuronal and glial signalling,Modulation of Membrane 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,Epicatechin-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 et al: Biochem J, 2001; FRBM, 2004,Williams et al: FRBM, 2004 Spencer 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: 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 Kinase Inhibitor,MEK Inhibitor,Similarity between flavonoids and kinase inhibitors,Flavonoid interactions with neuronal and glial signalling,Vafeiadou et al: EMID Drug Targets, 2007; ABB, 2009 Vauzour 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, 2006 Vauzour 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 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 Band Intensity pCREB/ 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 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 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,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 Receptor Density,Dendritic 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,Interactions with the architecture of memory and cognition,New nerve cell growth (neurogenesis),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-dependent Vasodilatation,Acute changes in brain blood flow,Modulation of vascular 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 working memory. The effects of dietary flavonoids/metabolites are seemingly 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 mi