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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

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

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.


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


Flavonoids: source

Fruit and vegetables:

(All classes)

Tea:

(Flavanols)

Citrus:

(Flavanone)

Red wine:

(Flavanol, Flavonols)

Cocoa:

(Flavanols

and procyanidins)

Berries:

(Anthocyanins)


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



*

*

*

*

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



Human older animals

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


Cognitive Tests older animals

  • 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


Improvements in human executive function attention
Improvements in Human older animalsExecutive 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).



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


Biotransformation of flavonoids 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


Major Flavonoid Metabolites of flavonoids

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


Brain Uptake of Flavonoids of flavonoids

Abd el Mohsen et al: FRBM, 2002; Free Radic Res., 2004 ; Br J Nutr., 2006


Inhibition of Neuronal Injury of flavonoids

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


Neurotransmitter Receptor of flavonoids

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


Flavonoid Attenuation of of flavonoids

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


m of flavonoidsM

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


Epicatechin [ of flavonoidsmM]

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


Quercetin of flavonoids

Similarity between flavonoids

and kinase inhibitors

PI3 Kinase

Inhibitor

MEK Inhibitor

PD98059

LY294002

Epicatechin


Flavonoid interactions with of flavonoids

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


Flavonoid-Induced Signalling of flavonoids

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



The Sensory Input to the Hippocampus memory

Rendeiro et al: Genes & Nutr, 2009


Newly acquired memory

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


Control of Memory at the Molecular Level memory

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


Changes in Hippocampal CREB memory

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


Hippocampal changes in memorypro- 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


Changes in Hippocampal ERK1/2 memory

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


Y memory

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)


Enhancement of memoryHippocampal 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


Proposed mechanism of action I memory

‘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


Proposed mechanism of action II memory

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


Interactions with the architecture of memory and cognition memory

Plant Bioactives

Cell Signalling and Gene Expression

Neuronal Morphology

Vascular Effects

Increased neuronal communication

(synaptic plasticity)

New nerve cell growth

(neurogenesis)


Heiss et al. memoryJAMA, 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


Neurogenesis
Neurogenesis? memory

Neurogenesis


The Future: memory

Brain Imaging, morphology and Networks


Summary memory

  • 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


Acknowledgements memory

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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