Presentation is loading. Please wait.

Presentation is loading. Please wait.

© University of Reading 2008 Molecular Nutrition Group School of Chemistry, Food and Pharmacy 20 April 2014 Flavonoids and Brain Health:

Similar presentations

Presentation on theme: "© University of Reading 2008 Molecular Nutrition Group School of Chemistry, Food and Pharmacy 20 April 2014 Flavonoids and Brain Health:"— Presentation transcript:

1 © University of Reading Molecular Nutrition Group School of Chemistry, Food and Pharmacy 20 April 2014 Flavonoids and Brain Health: Multiple effects underpinned by common mechanisms Dr. Jeremy P E Spencer

2 Prevalence of AD (%) Age (years) 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

3 Diet and brain function Molecular Mechanisms? Flavonoids as neuroprotective agents Animal Investigations Flavonoid extracts from fruit and vegetables have been reported to attenuate cognitive decline and neuronal dysfunction 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 Studies Flavonoids, in particular flavanols, influence neural activity, measured with fMRI Francis et al (2006) J. Cardiovasc. Pharmacol. Fisher et al (2006) J. Cardiovasc. Pharmacol. Kuriyama et al (2006) AJCN

4 Flavonoids: source Fruit and vegetables: (All classes) Red wine: (Flavanol, Flavonols) Cocoa: (Flavanols and procyanidins) Tea: (Flavanols) Berries: (Anthocyanins) Citrus: (Flavanone)

5 Flavonoids: structure Flavanol Flavonol Isoflavone Flavanone Anthocyanin R2R2 HO O R1R1 R3R3 OH O O R1R1 R2R2 R4R4 R3R3 R5R5 O + HO OH R1R1 R2R2 O O HO OH R1R1 R2R2 R3R3 O HO OH O R1R1 R2R2 R3R3

6 Plant-derived flavonoids and brain function

7 Correct Choices (All trials) Baseline3 weeks6 weeks9 weeks12 weeks Number correct (out of 8) YoungOld Effects of a Blueberry-rich diet on Spatial Working Memory Blueberry * * * * Williams et al: FRBM, 2008

8 Effects of flavonoid supplementation on spatial memory in older animals

9 Human intervention Cognitive tests Test Drink Placebo Day 1 Day 2 Day 3 Blood sample Urine collected hoursUrine collected hoursUrine collected hours the next day Urine collected hoursUrine collected hoursUrine collected 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

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 Executive Function: Computerised Stroop Test, Go-NoGo task Mood: Visual Analogue Scales. Motor skill: Static balance and Dynamic balance Cognitive Tests

11 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 : yrsSubjects: yrs Flavonoid Placebo * Go-NoGo task: measures Executive function/attention Pre-drink 1h post 5h post Flavonoid Placebo * Pre-drink 1h post 5h post Mean no. of correctly detected targets

12 How are these effects mediated?

13 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

14 Biotransformation of flavonoids Oral Ingestion of flavonoid Monomeric units Oligomeric Flavonoids Stomach Small Intestine jejunum ileum Colon Liver Kidney Urine Portal vein Renal excretion of glucuronides Oligomers cleaved cells Blood-brain barrier Neurons glia glucuronides A-ring glucuronides aglycone O-methylated glucuronides O-methylated glucuronides O-methylated Sulphates Further metabolism Phenolic acids Gut microflora Flavonoid Spencer, et al: Antiox Redox Signal, 2001; J Nutr, 2003; Biochem J, 2003; ABB, 2004; Brit. J. Nutr. 2008

15 3- O -methyl-epicatechin Epicatechin-7-sulphateEpicatechin-7-b-D- glucuronide Epicatechin Plasma concentration M Major Flavonoid Metabolites

16 Brain Uptake of Flavonoids Abd el Mohsen et al: FRBM, 2002; Free Radic Res., 2004 ; Br J Nutr., 2006

17 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

18 Neurotransmitter Receptor PKC PI 3-kinase Tyrosine kinase MAP kinase cascades JNKp38 ERK1/2 Akt/PKB Neuronal survival and Plasticity Neuronal Apoptosis CREB c-jun Brain Ageing Increases in cognition performance and memory Williams et al: FRBM, 2004 Spencer et al: Genes & Nutr, 2007; Brit J Nutr, 2008; Chem Soc Rev, 2009

19 Flavonoid Attenuation of Death Signalling Spencer et al: Biochem J, 2001; FRBM, 2004; Schroeter et al: Biochem J, 2001

20 Flavonoid Activation of Pro-survival Signalling vehicle M pERK1/2 Total ERK (15 min; 310 K; n=4) vehicleEC 0.1 M EC 0.3EC 1EC 3EC 10 Relative Band Intensity pERK2 pERK1 ***

21 Flavonoids mediate CREB Activation pCREB (Ser-133) total CREB basal Epicatechin [ M] Epicatechin: 300 nM; 15 min; O126: 10 M; LY294002: 35 M basalEC 300 nM UO126 EC 300 nM LY EC 300 nM LY UO126 Relative band intensity pCREB (Ser-133) MEK inhibitor PI3K inhibitor

22 LY PD98059 Epicatechin PI3 Kinase Inhibitor MEK Inhibitor Quercetin Similarity between flavonoids and kinase inhibitors

23 Flavonoid interactions with neuronal and glial signalling IFN IL-1 TNF- CD23 p38 STAT-1 iNOS NO TNF- Caspase-8 Caspase-9 Caspase-3 Neuronal Apoptosis ROS/RNS Microglia/Astrocyte Neuron ASK1 JNK1/2 BAD Bcl-xL DHBT-1 ERK1/2 Akt MEK1/2 PI3K CREB Activation by Flavonoids Scavenging by Flavonoids Inhibition by Flavonoids Activation Inhibition CysDA Vafeiadou et al: EMID Drug Targets, 2007; ABB, 2009 Vauzour et al: J Neurochem, 2007; Genes & Nutr, 2008; ABB, 2008

24 Lee et al (2006) FRBM 40, Flavonoid-Induced Signalling in Cancer Prevention Lee et al: FRBM, 2006 Nguyen et al: FRBM, 2006 Vauzour et al: ABB, 2007

25 Interaction of Flavonoids with the brains architecture of memory

26 26 The Sensory Input to the Hippocampus Rendeiro et al: Genes & Nutr, 2009

27 Newly acquired Sensory information Short-term memory Consolidation Long-term memory Memory Recall Slower Retrieval Rapid Retrieval Training/ Practice Memory Loss Acquisition Post-translational modification of proteins De Novo protein synthesis Hippocampus Cortex Storage Spencer et al: Proceed Nutr Soc, 2006;Chem Soc Rev, 2009

28 ERK1/2/5 CREB CaMK II/IVPKAPKB/Akt PKC Neurotrophins i.e. BDNF eNOS NO Angiogenesis mTOR Arc/Arg3.1 B-actin Synaptic plasticity Memory and Learning Neurogenesis Synapse re-modelling Translation Efficiency Control of Memory at the Molecular Level Spencer et al: Chem Soc Rev, 2009

29 Changes in Hippocampal CREB pCREB1 (Ser 133) CREB1 YYOBOB Hippocampus Cortex pCREB1 (Ser 133) CREB Hippocampus Cortex a *** Relative Band Intensity pCREB/ CREB Aged Young Aged + BB a = p *** = p Williams et al: FRBM, 2008

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 abnormal hippocampal function in humans Hippocampal changes in pro- and mature BDNF YYOBOB Pro-BDNF BDNF GAPDH *** a YOB Relative Band Intensity *** b Pro-BDNF Mature DDNF a/b = p *** = p 0.001

31 Changes in Hippocampal ERK1/2 pERK 44 pERK 42 YYOBOB ERK2 pERK 44 pERK 42 a *** b ** Relative Band Intensity pERK/ERK Aged Young Aged + BB a/b = p *** = p ** = p 0.01 ERK PKC CREB PKACaMK

32 Hippocampal changes in Akt pAkt (Ser 473) Akt PKA C CaMKIV (Thr 196) CaMKIV YYOBOB pAkt (Ser 473) CaMKIV (Thr 196) PKA (Thr 197) *** b Relative Band Intensity a a Aged Young Aged + BB a/b = p *** = p PI3K TrkB Akt BDNF

33 Enhancement of Hippocampal Protein Synthesis ERK PI3K TrkB mTOR Homer2 Arc/Arg3.1 Akt BDNF

34 ERK PKC CREB PI3K BDNF TrkB mTOR Homer2 Postsynaptic NMDA-R PKACaMK Arc/Arg3.1 Akt BDNF Enhancement of Protein Synthesis Presynaptic Glutamate Release AMPA-R (1) (2) (3) Proposed mechanism of action I Spencer et al: Chem Soc Rev, 2009

35 Postsynaptic Presynaptic TrkB NMDA-RAMPA-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

36 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 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

38 Neurogenesis? 38 Neurogenesis

39 39 The Future: Brain Imaging, morphology and Networks

40 40

41 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 might be mediated through modifications of CREB and CREB-dependant gene expression

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

43 43

Download ppt "© University of Reading 2008 Molecular Nutrition Group School of Chemistry, Food and Pharmacy 20 April 2014 Flavonoids and Brain Health:"

Similar presentations

Ads by Google