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Flavonoids and Brain Health: Multiple effects underpinned by common mechanisms

Flavonoids and Brain Health: Multiple effects underpinned by common mechanisms. Dr. Jeremy P E Spencer. Ageing and Incidence of Neurodegenerative Diseases. Age (years). Prevalence of AD (%). Prevalence of PD (%). 35-59. 0.2. 0.07. 60-69. 0.3. 0.18. 70-79. 3.2. 1.72.

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Flavonoids and Brain Health: Multiple effects underpinned by common mechanisms

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  1. Flavonoids and Brain Health: Multiple effects underpinned by common mechanisms Dr. Jeremy P E Spencer

  2. Ageing and Incidence of Neurodegenerative Diseases Age (years) Prevalence of AD (%) Prevalence of PD (%) 35-59 0.2 0.07 60-69 0.3 0.18 70-79 3.2 1.72 Life Expectancy is increasing 80-89 6.2 10.8 • Increased health care costs and general demand on the NHS. • Reduced quality of life for the elderly population.

  3. 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. 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 Diet and brain function Human Studies Animal Investigations Molecular Mechanisms? Flavonoids as neuroprotective agents

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

  5. R1 R2 HO O R3 OH OH Flavonoids: structure R1 O R3 R1 O R2 R4 OH R5 HO O + Isoflavone Flavanol R2 OH OH Anthocyanin R1 R1 R2 R2 O HO HO O R3 R3 OH O OH O OH Flavonol Flavanone

  6. Plant-derived flavonoids and brain function

  7. * * * * Blueberry Effects of a Blueberry-rich diet on Spatial Working Memory Correct Choices (All trials) 8 6 4 Number correct (out of 8) 2 0 Baseline 3 weeks 6 weeks 9 weeks 12 weeks Young Old Williams et al: FRBM, 2008

  8. Effects of flavonoid supplementation on spatial memory in older animals

  9. Human intervention Cognitive Cognitive tests tests Blood sample Day 1 Day 1 Cognitive Cognitive Cognitive tests tests tests Test Drink Blood sample Blood sample Blood sample Day 2 Day 2 Urine collected 09.00 - 13.00 hours Urine collected 13.00 - 17.00 hours Urine collected 17.00 - 09.00 hours the next day Cognitive Cognitive Cognitive tests tests tests Placebo Blood sample Blood sample Blood sample Day 3 Day 3 Urine collected 09.00 - 13.00 hours Urine collected 13.00 - 17.00 hours Urine collected 17.00 - 09.00 hours the next day

  10. 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

  11. Improvements in Human Executive Function (Attention) Go-NoGo task: measures Executive function/attention Subjects : 18-30 yrs Subjects: 60-75 yrs 60 60 Flavonoid * 56 56 Placebo 52 52 * Mean no. of correctly detected targets Mean no. of correctly detected targets 48 48 Flavonoid 44 44 Placebo 40 40 36 36 Pre-drink Pre-drink 1h post 5h post 1h post 5h post Sustained ability to correctly detect target stimuli following flavonoid supplementation compared to the placebo (* p < 0.05; n=14).

  12. How are these effects mediated?

  13. Proposed mechanisms underlying the neuroprotective effects of flavonoids Antioxidant effects Modulation of Neuronal and glial signalling Modulation of Receptor Function Influences on gene expression Modulation of Membrane Fluidity Inhibitors of Neuroinflammation

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

  15. Major Flavonoid Metabolites Epicatechin 3’-O-methyl-epicatechin 0.1-3 0.9-5 PlasmaconcentrationmM Epicatechin-7-b-D-glucuronide Epicatechin-7-sulphate 0.1-8 0.9-25

  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 Ox. Stress (steady-state peroxide) Control 120 *** 100 *** 80 % MTT reduction 60 40 Me-EC + Ox. Stress EC + Ox. Stress 20 0 Vehicle Me-EC EC-Gluc EC Control Ox. Stress Spencer et al: Biochem J, 2001; FRBM, 2004

  18. Neurotransmitter Receptor Tyrosine kinase PI 3-kinase PKC MAP kinase cascades ERK1/2 Akt/PKB JNK p38 c-jun CREB Neuronal survival and Plasticity Neuronal Apoptosis Increases in cognition performance and memory Brain Ageing 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 active JNK H2O2 EC H2O2 3’MEC H2O2 basal Flavonoid: 0.3 mM OS: Peroxide: 50 mM 54 46 1.6 1.6 1.6 1.6 *** total JNK 1.2 1.2 1.2 1.2 Band intensity Band intensity Band intensity Band intensity 0.8 0.8 0.8 0.8 *** 0.4 0.4 0.4 0.4 0 0 0 0 H2O2 EC H2O2 3’MEC basal H2O2 Spencer et al: Biochem J, 2001; FRBM, 2004; Schroeter et al: Biochem J, 2001

  20. mM vehicle 0.1 0.3 1.0 44 pERK1/2 42 Total ERK Flavonoid Activation of Pro-survival Signalling 1.2 pERK2 pERK1 1.0 *** *** 0.8 ( 15 min; 310 K; n=4) 0.6 Relative Band Intensity 0.4 0.2 0.0 mM vehicle EC 0.1 EC 0.3 EC 1 EC 3 EC 10

  21. Epicatechin [mM] basal 0.1 0.3 1 3 10 pCREB (Ser-133) total CREB Flavonoids mediate CREB Activation Epicatechin: 300 nM; 15 min; O126: 10 mM; LY294002: 35 mM 1.6 pCREB (Ser-133) 1.2 MEK inhibitor Relative band intensity 0.8 PI3K inhibitor 0.4 0 basal EC 300 nM EC 300 nM EC 300 nM EC 300 nM UO126 LY294002 LY294003 UO126

  22. Quercetin Similarity between flavonoids and kinase inhibitors PI3 Kinase Inhibitor MEK Inhibitor PD98059 LY294002 Epicatechin

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

  24. Flavonoid-Induced Signalling in Cancer Prevention Lee et al (2006) FRBM 40, 323-334 Nguyen et al: FRBM, 2006 Vauzour et al: ABB, 2007 Lee et al: FRBM, 2006

  25. Interaction of Flavonoids with the brains architecture of memory

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

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

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

  29. Changes in Hippocampal CREB Y Y O O B B pCREB1 (Ser 133) Hippocampus CREB1 pCREB1 (Ser 133) *** Cortex CREB1 4 Relative Band Intensity pCREB/ CREB 3 Young 2 Aged a Aged + BB 1 a = p  0.001 *** = p  0.001 0 Hippocampus Cortex Williams et al: FRBM, 2008

  30. Hippocampal changes in pro- and mature BDNF Y Y O O B B Pro-BDNF BDNF GAPDH • 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 *** *** 1.5 Relative Band Intensity 1.0 0.5 a b Pro-BDNF a/b = p  0.001 *** = p  0.001 Mature DDNF 0.0 Y O B

  31. Changes in Hippocampal ERK1/2 CREB Y Y O O B B pERK 44 ERK pERK 42 PKC PKA CaMK ERK2 *** 2.0 Relative Band Intensity pERK/ERK Young 1.5 Aged Aged + BB ** 1.0 0.5 b a/b = p  0.001 *** = p  0.001 ** = p  0.01 a 0.0 pERK 44 pERK 42

  32. Y Y O O B B CaMKIV (Thr 196) CaMKIV pAkt (Ser 473) Akt PKA C Hippocampal changes in Akt *** 2.0 Relative Band Intensity Young BDNF 1.5 Aged TrkB Aged + BB PI3K 1.0 b Akt 0.5 a a 0.0 a/b = p  0.001 *** = p  0.001 CaMKIV (Thr 196) pAkt (Ser 473) PKA (Thr 197)

  33. Enhancement of Hippocampal Protein Synthesis 1.2 *** 1.0 Relative Band Intensity Phospho-mTOR/ Total mTOR 0.8 0.6 0.4 a 0.2 BDNF TrkB 0.0 mTOR (Ser 2448) mTOR (Ser 2481) *** PI3K 2.5 Young Band Intensity Akt 2.0 Aged ERK Aged + BB 1.5 mTOR a Arc/Arg3.1 1.0 Homer2 0.5 0.0 Arc/Arg3.1 NR4A2

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

  35. Proposed mechanism of action II Synapse following LTP ‘Glutamate Release’ Presynaptic ‘Increased Synaptic Receptor Density’ AMPA-R NMDA-R TrkB Postsynaptic PI3K ERK ‘F-actin Expansion’ Akt Cofilin Arc/Arg3.1 ‘Sustained Activation of Arc, mTOR’ mTOR Homer2 ‘Dendritic spinal growth’ - mushroom spines

  36. Interactions with the architecture of memory and cognition Plant Bioactives Cell Signalling and Gene Expression Neuronal Morphology Vascular Effects Increased neuronal communication (synaptic plasticity) New nerve cell growth (neurogenesis)

  37. Heiss et al. JAMA, 2003 Flavonoids improve Peripheral and Cerebral Blood Flow Acute improvements in vascular responsiveness Nitric oxide-dependent Vasodilatation Acute changes in brain blood flow Modulation of vascular signalling and factors linked with neurogenesis

  38. Neurogenesis? 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 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 of the age-associated cognitive decline might be mediated through modifications of CREB and CREB-dependant gene expression

  41. 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

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