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1、09 January 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 q
2、uality 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),Re
3、d 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 flav
4、onoids 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
5、,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 - 13.0
6、0 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
7、 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
8、 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
9、,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 eff
10、ects 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; B
11、iochem 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 Fl
12、avonoids,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:
13、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 inhib
14、itor,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 architec
