Archives of Biochemistry and Biophysics 492 (2009) 19

Contents lists available at ScienceDirect

Archives of Biochemistry and Biophysics

journal homepage: www.elsevier.com/locate/yabbi

Review

Flavonoids and cognition: The molecular mechanisms underlying their

behavioural effects
Jeremy P.E. Spencer *, David Vauzour, Catarina Rendeiro
Molecular Nutrition Group, Department of Food and Nutritional Sciences, School of Chemistry, Food and Pharmacy, University of Reading, Reading RG6 6AP, UK

a r t i c l e

i n f o

Article history:
Received 4 August 2009
and in revised form 5 October 2009
Available online 12 October 2009
Keywords:
Flavonoid
Brain
Memory
Signalling
Vascular system

a b s t r a c t
Evidence suggests that a group of phytochemicals known as avonoids are highly effective in reversing
age-related declines in neuro-cognitive performance through their ability to interact with the cellular and
molecular architecture of the brain responsible for memory and by reducing neuronal loss due to neurodegenerative processes. In particular, they may increase the number of, and strength of, connections
between neurons, via their specic interactions with the ERK and Akt signalling pathways, leading to
an increase in neurotrophins such as BDNF. Concurrently, their effects on the peripheral and cerebral vascular system may also lead to enhancements in cognitive performance through increased brain blood
ow and an ability to initiate neurogenesis in the hippocampus. Finally, they have also been shown to
reduce neuronal damage and losses induced by various neurotoxic species and neuroinammation.
Together, these processes act to maintain the number and quality of synaptic connections in the brain,
a factor known to be essential for efcient LTP, synaptic plasticity and ultimately the efcient working
of memory.
2009 Elsevier Inc. All rights reserved.

Introduction
Flavonoids comprise the most common group of polyphenolic
compounds in the human diet and are found ubiquitously in plants.
Major dietary sources of avonoids include fruits, vegetables, cereals, tea, wine and fruit juices [1]. Flavonoids consist of two aromatic
carbon rings, benzopyran (A and C rings) and benzene (B ring), and
may be divided into various sub-groups based on the degree of the
oxidation of the C-ring, the hydroxylation pattern of the ring structure and the substitution of the 3-position (Fig. 1). The main dietary
groups of avonoids are (1) avonols (e.g. kaempferol, quercetin),
which are found in onions, leeks, broccoli, (2) avones (e.g. apigenin, luteolin), which are found in parsley and celery, (3) isoavones
(e.g. daidzein, genistein), which are mainly found in soy and soy
products, (4) avanones (e.g. hesperetin, naringenin), which are
mainly found in citrus fruit and tomatoes, (5) avanols (e.g. (+)-catechin, ()-epicatechin, epigallocatechin, epigallocatechin gallate
(EGCG),1 which are abundant in green tea, red wine, chocolate and
(6) anthocyanidins (e.g. pelargonidin, cyanidin, malvidin), whose
sources include red wine and berry fruits (Fig. 1). Once ingested,
avonoids undergo extensive metabolism in the small and large

intestine, in the liver and in cells, resulting in very different forms

in the body to those found in foods [2,3].
Historically, the biological actions of avonoids, including those
on the brain, have been attributed to their ability to exert antioxidant
actions [4], through their ability to scavenge reactive species, or
through their possible inuences on intracellular redox status [5].
However, it has been speculated that this classical hydrogen-donating antioxidant activity cannot account for the bioactivity of avonoids in vivo, particularly in the brain, where they are found at only
very low concentrations [6]. Instead, it has been postulated that their
effects in the brain are mediated by an ability to protect vulnerable
neurons, enhance existing neuronal function, stimulate neuronal
regeneration and induce neurogenesis [7,8]. Indeed, it has become
evident that avonoids are able to exert neuroprotective actions
(at low concentration) via their interactions with critical neuronal
intracellular signalling pathways pivotal in controlling neuronal survival and differentiation, long-term potentiation (LTP) and memory
[911]. This review will examine the potential for avonoids to inuence memory, learning and neuro-cognitive performance through
specic activity on the hippocampus and will attempt to clarify the
probable mechanisms which underpin such actions.

* Corresponding author. Address: Molecular Nutrition Group, Department of Food and Nutritional Sciences, School of Chemistry, Food and Pharmacy, University of Reading,
Whiteknights Campus, Reading RG6 6AP, UK. Fax: +44 207 848 6143.
E-mail address: j.p.e.spencer@reading.ac.uk (J.P.E. Spencer).
1
Abbreviations used: EGCG, epigallocatechin gallate; LTP, long-term potentiation; MMSE, Mini-Mental State Examination; DG, dentate gyrus; PKB, protein kinase B; PKC,
protein kinase C; CaMKIV, calcium-calmodulin kinase IV; ERK, extracellular signal regulated kinase; CREB, cAMP-response element-binding protein; BDNF, brain-derived
neurotrophic factor; ASK1, apoptosis signal-regulating kinase 1; eNOS, endothelial nitric oxide synthase; PI3K, PI3 kinase; TNF-a, tumour necrosis factor-a.
0003-9861/$ - see front matter 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.abb.2009.10.003

J.P.E. Spencer et al. / Archives of Biochemistry and Biophysics 492 (2009) 19

R2

OH
HO

O
R3

Ring B
HO

R1

O
2

4'

Ring A

OH

OH

Flavonols

OH

Ring C

Kaempferol
Quercetin
Myricetin
Isorhamnetin

R1

R2

R3

OH
OH
OH
OH

H
OH
OH
OCH3

H
H
OH
H

H
H

OH
H

H
H

Flavones
OH
3'

Luteolin
Apigenin

OH

2'
4'
1

HO

5'

6'

R4

R1

3
6
5

R1

OH

OH

HO

R2

Flavanols
R1
Catechin
Epicatechin
EGC
ECG
EGCG

R4

OH
OH
OH
gallate
gallate

OH
OH

H
H
OH
H
OH

Anthocyanidins

Pelargonidin
Cyanidin
Delphinidin
Paeonidin
Petunidin
Malvidin

R2
R3
HO

R1

R2

H
OH
OH
OCH3
OCH3
OCH3

H
H
OH
H
OH
OCH3

R1
OH

HO

Flavanones

Naringenin
Hesperetin

R1

R2

R3

H
H

H
OCH3

OH
H

Flavanonols
Taxifolin
Astilbin
Engeletin

R1

O
R2

Isoflavones

OH
O-rhamnosyl
O-rhamnosyl

OH
OH
H

OH
OH
OH

Genistein
Daidzein

R1

R2

OH
OH

OH
H

Fig. 1. The structures of the main classes of avonoids. The major differences between the individual groups reside in the hydroxylation pattern of the ring structure, the
degree of saturation of the C-ring and the substitution of the 3-position.

The impact of avonoids on neuro-cognitive performance

Early indications regarding the ability of avonoids to impact
upon brain function were reported in the 1950s, with avones re-

ported to act as novel brain-stem stimulants [12]. However, later

studies had suggested that avonoids, in particular isoavones
such as genistein (Fig. 1), might be detrimental to memory processes in the brain due to their ability to act as tyrosine kinase

J.P.E. Spencer et al. / Archives of Biochemistry and Biophysics 492 (2009) 19

inhibitors [13]. More recent work has revealed that dietary intervention with isoavones results in positive effects on neuro-cognitive function [14,15], which is particularly apparent in postmenopausal women [1619]. However, other large intervention
trials have reported that dietary isoavone supplementation is
ineffective at improving cognitive function [2022]. The rationale
behind the potential of isoavones to exert positive effects on cognitive function is believed to lie primarily in their potential to mimic the actions of oestrogens in the brain [23]. Indeed, animal
behavioural studies have indicated that ovariectomy results in
the development of cognitive dysfunction and is elevated by oestrogen-replacement [23]. However, whilst epidemiological evidence exists to support a lower onset of Alzheimers disease in
post-menopausal women undertaking oestrogen-replacement
therapy [24], more recent evidence suggests oestrogen-containing
hormone therapy initiated during late post-menopause does not
improve episodic memory (an important early symptom of Alzheimers disease), and may increase dementia risk [25]. Therefore,
although the use of selective oestrogen receptor modulators may
have the potential to affect cognitive outcomes, further information from improved animal models, carefully designed cohort studies and randomized controlled trials in midlife women are required
before a nal conclusion can be made [25,26].
Other avonoid sub-groups, avanols, avonols, avanones,
avones and anthocyanins (Fig. 1), do not exert oestrogen-like effects and thus cannot inuence memory and cognition via a similar
mechanism. Nevertheless, there is much evidence to suggest that
they also have the capacity to improve memory [6,7,27,28]. A recent prospective study has provided strong evidence that dietary
avonoid intake is associated with better cognitive evolution, i.e.
the preservation of cognitive performance with ageing [29]. A total
of 1640 subjects (aged 65 years or older) free from dementia at
baseline and with reliable dietary assessment data were examined
for their cognitive performance (Mini-Mental State Examination,
Bentons Visual Retention Test, Isaacs Set Test) four times over
a 10-year period. After adjustment for age, sex and educational level, avonoid intake (avonols: quercetin, kaempferol, myricetin;
avones: luteolin, apigenin) was found to be associated with signicantly better cognitive performance at baseline and with a signicantly better evolution of performance over time. In particular,
subjects included in the two highest quartiles of avonoid intake
had better cognitive evolution than subjects in the lowest quartile
and after 10 years follow-up, subjects with the lowest avonoid intake had lost on average 2.1 points on the Mini-Mental State Examination (MMSE), whereas subjects with the highest quartile had
lost only 1.2 points. Such data provides a strong indication that
regular long-term avonoid consumption may have a positive effect on memory and neuro-cognitive performance as we age [29].
Animal intervention studies have indicated that avonoid-rich
foods (tea, grape juice, pomegranate juice, blueberry and Gingko
Biloba) and pure avonoids (epicatechin and quercetin) are able
to affect several different aspects of learning and memory, notably
rapid [30] and slow [3134] memory acquisition, short-term working memory [3539], long-term reference memory [40,41], reversal learning [30,35] and retention/retrieval [42]. For example,
phytochemicals present in foods such as spinach, strawberry and
blueberry have been shown to be benecial in retarding functional
age-related CNS and cognitive behavioural decits [31,43]. As the
major phytochemicals present in these foods are avonoids, this
led to further studies aimed at examining the relationships between the intake of specic avonoid-rich foods and behavioural
measures of memory. For example, the avanol ()-epicatechin,
especially in combination with exercise, has been shown to enhance the retention of rat spatial memory in water maze tasks
[42]. This improvement was associated with increased angiogenesis and neuronal spine density in the dentate gyrus (DG) of the hip-

pocampus, and with the up-regulation of genes associated with

learning in the hippocampus. There is also extensive evidence that
anthocyanin- and avanol-rich berries, in particular blueberries,
are highly effective at reversing age-related decits in spatial
working memory [37,39,41,4447]. The effects of blueberry appear
to be most pronounced in terms of short-term memory, suggesting
that these improvements are, in part, dependent on CA3CA3
excitatory connections [48]. Interestingly, the effects of ageing on
the CA3 region are rather different from that seen in the CA1 region
[49]. For example, in the context of spatial working memory, spatial representations which are encoded in the CA3 region, are found
to switch when young animals are moved to a different environment, whilst aged animals fail to rapidly encode new spatial information when moved to a different environment [49,50].
Accordingly, ageing appears to impair new learning as the existing
associations in the CA3CA3 network tend to dominate cell ring
[51]. As such, it seems possible that the improvements in spatial
memory induced by blueberry interventions may be acting by
assisting the CA3 network to make the spatial representations in
that region more plastic.
Alternatively, the blueberry avonoids may act to enhance the
efciency of spatial memory indirectly, by acting on the DG, the
hippocampal sub-region most sensitive to the effects of ageing
[52]. DG granule cells are particularly vulnerable to the ageing process [53,54], with age-dependent degeneration resulting in an
impairment of information transfer between DG and CA3, thus
resulting in an inability of CA3 networks to build new spatial representations [52]. This is supported by observations that DG lesioned animals exhibit marked difculties in acquiring spatial
representations [55]. Blueberry supplementation has been shown
to signicantly increase the proliferation of precursor cells in the
DG of aged rats [41]. This link between DG neurogenesis, cognitive
performance and ageing is well documented [5659], and may represent another mechanism by which avonoids may improve
memory by acting on the hippocampus. Ultimately, the effects of
avonoids on the hippocampus are likely to be very dependent
on local avonoid/metabolite concentration and, at present, it remains unclear whether as to whether avonoids induce global
changes in hippocampal (and other brain region) morphology/
function, or are capable of inducing changes within specic hippocampal sub-regions. In the next section we will examine the mechanisms by which avonoids induce such morphological change by
interactions with neurons at the molecular level.

Cellular and molecular interactions underpinning the cognitive

effects of avonoids
There is strong evidence that avonoids may exert benecial effects on memory via an ability to modulate the cellular and molecular architecture involved in the processes of memory [6,7,11,60].
The concentrations of avonoids in the brain are thought to be sufciently high to exert pharmacological activity at receptors, kinases and transcription factors. Although the precise site of their
interaction with signalling pathways is unclear, evidence indicates
that they are capable of acting in a number of ways: (1) by binding
to ATP sites on enzymes and receptors; (2) by modulating the
activity of kinases directly, i.e. MAPKKK, MAPKK or MAPK; (3) by
affecting the function of important phosphatases, which act in
opposition to kinases; (4) by preserving Ca2+ homeostasis, thereby
preventing Ca2+-dependent activation of kinases in neurons; and
(5) by modulating signalling cascades lying downstream of kinases,
i.e. transcription factor activation and binding to promoter sequences [6,10]. The effects of avonoids on neuronal signalling
pathways are highly concentration-dependent and are likely to
be related to their ability to exert high afnity receptor agonist-like

J.P.E. Spencer et al. / Archives of Biochemistry and Biophysics 492 (2009) 19

actions at low concentrations (low to mid nanomolar) and direct

enzyme inhibition at higher concentrations (high nanomolar to
micromolar) [61,62]. Potential avonoid-binding sites on neurons
include adenosine [63], GABAA [64,65] and testosterone receptors
[66] and a specic brain plasma membrane binding site for polyphenols has been proposed [67]. By affecting such pathways they
have the potential to induce new protein synthesis in neurons
and thus an ability to induce morphological changes which have
a direct inuence on memory acquisition, consolidation and storage. Alternatively, their well established effects on the vascular
system may also induce increases in cerebral blood ow capable
of impacting on acute cognitive performance, or may lead to an increase hippocampal vascularisation capable of inducing new neuronal growth.

Whereas short-term memory involves covalent modications of

pre-existing proteins, long-term memory requires the synthesis
of new mRNAs and proteins [7880]. The activation of various signalling pathways have been linked with the control of de novo protein synthesis in the context of LTP, synaptic plasticity and
memory (Fig. 3): (i) cAMP-dependent protein kinase (protein kinase A) [81], (ii) protein kinase B (PKB) or Akt [82,83], (iii) protein
kinase C (PKC) [84], (iv) calcium-calmodulin kinase IV (CaMKIV)
[85] and (v) extracellular signal regulated kinase (ERK) [86,87]
(Fig. 2). The activation of all ve pathways converge to signal to
the cAMP-response element-binding protein (CREB), a transcription factor which binds to the promoter regions of many genes
associated with synapse re-modelling, increases in neuronal spine
density and synaptic plasticity [8891] (Fig. 2). Changes in spine
density, morphology and motility have been shown to occur with
paradigms that induce synaptic, as well as altered sensory experience, and lead to alterations in synaptic connectivity and strength
between neuronal partners, affecting the efcacy of synaptic communication [90].
There is much evidence to support the actions of nanomolar
concentrations of avonoids, in particular avanols and avanones,
on the ERK pathway [9294], which appear to be mediated by
interactions with MEK1 and MEK2, and potentially membrane
receptors [95,96]. Indeed, the avone backbone (2-phenyl-1,4benzopyrone) has close structural homology to specic pharmacological modulators of ERK signalling, such as PD98059 (20 -amino30 -methoxyavone). Fisetin, a avonoid found in strawberries,
has been shown to improve long-term potentiation and to enhance

Stimulation of synaptic plasticity

Long-term potentiation (LTP) is widely considered to be one of
the major mechanisms by which the brain acquires and stores
information [68,69]. LTP refers to a persistent increase in the
chemical strength of a synapse that can last from minutes to several days. LTP is known to contribute to synaptic plasticity or
the increased strength of the connection, or synapse, between
two neurons, a process thought to underlie memory [70,71]. Studies into human mental retardation syndromes have led to new insights into the molecular underpinnings of human cognitive
processing [7274] and have indicated that both short-term and
long-term memory is controlled at the molecular level [7577].

Kinase

Transcription
Factor

Protein

Function

CaMKII/IV

PKA

PKC

eNOS

CREB
ER, Elk-1

mTOR
ASK1, Chk1,

Stat 1/3

Neurotrophins
i.e. BDNF

Synapse
re-modelling

NMDA-R, AMPA-R

Translation
Efficiency

Synaptic plasticity

Outcome

pAkt/PKB

ERK1/2

LTP, Memory, Learning &

Cognitive Performance

Arc/Arg3.1
-actin

Growth
Differentiation
Cell Cycle Control

Nitric Oxide
VEGF-B, TGF-

Angiogenesis
Neurogenesis

New Nerve Cell Growth

Repair of Brain Injury

Fig. 2. Signalling pathways underlying neuronal survival and cognitive performance. Flavonoids activate ERKCREB pathway and the PI3 kinasemTOR cascade leading to
changes in synaptic plasticity. They are also capable of inuencing neurogenesis through the activation of PI3 kinaseAkteNOS.

J.P.E. Spencer et al. / Archives of Biochemistry and Biophysics 492 (2009) 19

object recognition in mice by a mechanism dependent on the activation of ERK and CREB [97]. Similarly, the avanol ()-epicatechin
(100300 nM) induces both ERK1/2 and CREB activation in cortical
neurons and subsequently increases CREB regulated gene expression [98], whilst nanomolar concentrations of quercetin are effective at enhancing CREB activation [99]. Blueberry (2% w/w diet;
12 weeks)-induced improvements in memory have been shown
to be mediated by increases in the phosphorylation state of
ERK1/2, but not via the activation of calcium-calmodulin kinase
(CaMKIV) or protein kinase A [39]. Other avonoids have also been
found to inuence the ERK pathway, with the citrus avanone hesperetin capable of activating ERK1/2 signalling in cortical neurons
at nanomolar concentrations [93] and avanols such as ECGC
restoring both protein kinase C and ERK1/2 activities in 6-hydroxydopamine treated and serum deprived neurons [100,101]. Furthermore, this ability to activate the ERK pathway is not restricted to
neurons and has also been observed in broblasts exposed to
nanomolar concentrations of epicatechin [102].
CREB activation downstream of ERK appears critical in the
induction of long-lasting changes in synaptic plasticity and memory [103105] and disruption of CREB activity specically blocks
the formation of long-term memory [106], whereas agents that increase the amount or activity of CREB accelerate the process [107].
CREB is known to be a critical transcription factor linking the actions of neurotrophins, such as BDNF, to neuronal survival, differentiation and synaptic function [108110] (Fig. 3). Consequently,
the central role of CREB in these processes has led to considerable
interest in identifying safe effective agents that may enhance the
activity of CREB in specic regions of the brain, as these may lead
to an improvement in memory [107]. Recent studies have shown
that spatial memory performance in rats supplemented with blueberry, correlates well with the activation of cAMP-response element-binding protein (CREB) and with increases in both pro- and
mature levels of hippocampal brain-derived neurotrophic factor
(BDNF) [39]. Regulation of BDNF is interesting as this neurotrophin
has been linked with the control of synaptic plasticity and longterm memory [111] and decreases in BDNF and pro-BDNF have
been reported in Alzheimers disease [112,113]. Furthermore, a
polymorphism that replaces valine for methionine at position 66

BDNF
TrkB

BDNF

PI3K

CREB

Akt

PKC PKA CaMK ERK

Arc/Arg3.1

mTOR
Homer2

Enhancement
of Protein
Synthesis
Fig. 3. Activation of ERK, Akt and CREB in neuronal synapses. Flavonoid activation
of ERK and Akt leads to increased expression and release of BDNF from the synapse
through enhanced CREB activation. Akt is further modied via the binding of newly
synthesised BDNF to pre- and post-synaptic TrkB receptors and activation of the
PI3K/mTOR signalling pathway. Sustained activation of mTOR leads to enhanced
translational efciency whilst activation of Arc leads to expansion and synapse
growth.

of the pro-domain of BDNF is associated with memory defects

and abnormal hippocampal function in humans [114].
Blueberry avonoid-induced activation of CREB and BDNF
expression has also been shown to lead to the activation of the
PI3 kinase/Akt signalling pathway [39], via the binding of BDNF
to pre- or post-synaptic TrkB receptors (Fig. 3). In addition, avonoids have long been known to modulate PI3K, via direct interactions with its ATP binding site [115]. Indeed, a number of studies
have demonstrated that the structure of avonoids determines
whether or not they act as potent inhibitors of PI3K [61,116].
One of the most selective PI3K inhibitors available, LY294002,
was modelled on the structure of quercetin [62,117,118]. Quercetin and some of its in vivo metabolites have been shown to inhibit
pro-survival Akt/PKB signalling pathways by a mechanism of action consistent with quercetin and its metabolites acting at and
inhibiting PI3K activity [99]. However, other avonoids such as
the citrus avanone hesperetin (100300 nM) cause the activation
of Akt/PKB and the inhibition of pro-apoptotic proteins such as
apoptosis signal-regulating kinase 1 (ASK1), Bad, caspase-9 and
caspase-3 in cortical neurons [93]. The activation of Akt by avonoids in hippocampal neurons may trigger the activation of the
mTOR (the mammalian target of rapamycin) pathway and the increased translation of specic mRNA subpopulations [119], including the activity-regulated cytoskeleton-associated protein (Arc/
Arg3.1) [39] (Fig. 3). Arc is known to be important in LTP and has
been proposed to be under regulatory control of both BDNF [120]
and the ERK signalling [121] (Fig. 3). Increased Arc expression
may facilitate changes in synaptic strength, and the induction of
morphological changes, such as that observed when small spines
are converted into large mushroom-shaped spines through a
mechanism dependent on actin polymerization [122]. In support
of this, studies have indicated that changes in neuronal morphology occur in response to avonoid supplementation [42] and that
certain avonoids can inuence neuronal dendrite outgrowth
in vitro [101].
Flavonoid-induced changes in vascular function
There is strong evidence to suggest that avonoid-rich foods, in
particular those containing avanols, such as cocoa, tea and soy,
can improve peripheral blood ow and surrogate markers of cardiovascular function in humans [123126]. Epidemiological studies have highlighted that diets rich in cocoa avanols are capable
of reducing cardiovascular risk by increasing nitric oxide bioavailability and lowering blood pressure [127,128]. These investigations
have been supported by human intervention studies which show
that oral intake of a avanol-rich diet leads to increases in owmediated dilatation of the brachial artery and increases in plasma
levels of nitric oxide metabolites [123,129,130]. Indeed, these effects were mimicked by the ingestion of a pure avanol (epicatechin) strengthening the hypothesis that it is the avanols which
exert these vascular effects [123]. In the context of the CNS, brain
imaging studies in humans have also demonstrated that the consumption of avanol-rich cocoa may enhance cortical blood ow
[131133]. Improvements in blood ow in the brain may impact
on memory in a number of ways. As well as increasing the delivery
of oxygen to specic brain regions, newly formed hippocampal
neurons are often found in dense clusters associated with the vasculature [134]. Indeed, many of the newly formed neurons are also
immune-reactive for endothelial markers, tend to be clustered near
blood vessels and proliferate in response to vascular growth factors, suggesting that adult neurogenesis occurs in parallel with
angiogenesis, or new blood vessel growth [135,136]. A recent
meta-analysis has indicated that, at present, it is not clear whether
other avonoid sub-groups also exert such effects on the vascular
system [137]. Therefore, future studies are required to investigate

J.P.E. Spencer et al. / Archives of Biochemistry and Biophysics 492 (2009) 19

the vascular effects of other commonly consumed subclasses (e.g.

anthocyanins and avanones), examine doseresponse effects,
and be of long enough duration to allow assessment of clinically
relevant endpoints.
Angiogenesis is known to be accompanied by the production of
endothelium-derived nitric oxide and vasodilatation and many
angiogenesis effectors also possess vasodilating properties
[138,139]. Vascular nitric oxide is generated by endothelial nitric
oxide synthase (eNOS) and is a key regulator of vascular re-modelling and angiogenesis, as well as blood pressure [140]. As discussed, avanols are able to induce nitric oxide production in the
endothelium along with rapid vasodilatation [123,130]. They do
this through their ability to activate eNOS by inducing its phosphorylation at Ser1177 [141143]. Several protein kinases including
Akt, PKA and AMPK are capable of activating eNOS by phosphorylating Ser1177 and avonoids are well reported to activate Akt at
Ser473 in a dose-dependent manner (Fig. 3). Therefore, avonoidinduced activation of Akt is likely to lead to increased nitric oxide
bioavailability in the vasculature of the hippocampus and subsequent angiogenesis and neurogenesis (Fig. 4). In addition, the presence of increased vascularisation in the hippocampus is likely to
stabilise the presence of the new neurons [136]. In this way avonoids have much in common with exercise, which is known to promote adaptive mechanisms in both the peripheral and cerebral
vasculature, such as improved organ blood ow, induction of antioxidant pathways, and enhanced angiogenesis and vascular regeneration [144,145]. In addition, it may also increase levels of BDNF,
suggesting that there appear to be common mechanisms by which
both exercise and avonoids lead to an improve learning and mental performance [146].

Inhibition of neurodegeneration and neuroinammation

The underlying neurodegeneration observed in Parkinsons, Alzheimers, and other neurodegenerative diseases is believed to be
triggered by multi-factorial processes, including neuroinammation [147,148], glutamatergic excitotoxicity and increases in iron
and/or depletion of endogenous antioxidants [149151]. There is
a growing body of evidence to suggest that avonoids and other
polyphenols may be capable of counteracting such neuronal injury,
thereby delaying the progression of disease pathologies
[6,10,152,153]. For example, a Ginkgo biloba extract has been
shown to protect hippocampal neurons against nitric oxide- and
b-amyloid-induced neurotoxicity [154] and studies have demonstrated that the consumption of green tea may have a benecial effect in reducing the risk of Parkinsons disease [155158]. In
agreement with the latter study, tea extracts and pure ()-epigallocatechin-3-gallate (EGCG) have been shown to attenuate 6hydroxydopamine-induced toxicity [159], to protect against hippocampal injury during transient global ischaemia [160] and to
prevent nigral damage induced by MPTP [161].
The death of nigral neurons in Parkinsons disease is thought to
involve the formation of the endogenous neurotoxin, 5-S-cysteinyl-dopamine (5-S-cys-DA) and its oxidation product,
dihydrobenzothiazine (DHBT-1) [162165]. However, the generation of 5-S-cysteinyldopamine [166] and neuronal injury induced
by it is effectively counteracted by a range of avonoids and other
polyphenols [164]. There is also evidence that avonoids are effective in blocking oxidant-induced neuronal injury [167,168]
through an ability to modulate a number of protein kinase and lipid kinase signalling cascades, such as the PI3 kinase (PI3K)/Akt,

Sensory Information (Experience)

Afferent Nerve Input

Increased
Blood Flow

Flavonoids

Angiogenesis

Neurogenesis

Old Neurons

Neuronal
Maturation

Immature Neurons

Synaptic Activity

Functional
Integration
New Synapses

Synaptic plasticity

Memory

Fig. 4. Overview of the functions of avonoids on the memory system. Activation of both synaptic plasticity and new neural growth may act together to enhance memory and
cognition.

J.P.E. Spencer et al. / Archives of Biochemistry and Biophysics 492 (2009) 19

tyrosine kinase, protein kinase C (PKC) and mitogen-activated protein kinase (MAP kinase) signalling pathways [9,10]. Inhibitory or
stimulatory actions at these pathways are likely to profoundly affect neuronal function by altering the phosphorylation state of target molecules, leading to changes in caspase activity and/or by
gene expression. For example, avonoids have been observed to
block oxidant-induced neuronal damage by preventing the activation of caspase-3, providing evidence in support of their potent
anti-apoptotic action [167,168]. The avanols epicatechin and 30 O-methyl-epicatechin also protect neurons against oxidative damage via a mechanism involving the suppression of JNK, and downstream partners, c-jun and pro-caspase-3 [92]. Flavanones, such as
hesperetin and its metabolite, 5-nitro-hesperetin, have been observed to inhibit oxidant-induced neuronal apoptosis via a mechanism involving the activation/phosphorylation of signalling
proteins important in the pro-survival pathways [93]. Similarly,
the avone, baicalein, has been shown to signicantly inhibit 6hydroxydopamine-induced JNK activation and neuronal cell death
and quercetin may suppress JNK activity and apoptosis induced by
hydrogen peroxide [169,170], 4-hydroxy-2-nonenal [171] and tumour necrosis factor-a (TNF-a) [172].
Recent evidence suggests that non-steroidal anti-inammatory
drugs are effective in delaying the onset of neurodegenerative disorders, particularly Parkinsons disease [173]. As such, there has
been an interest in the development of new compounds with an
ability to counteract neuroinammatory injury to the brain. The
citrus avanone naringenin has recently been found to be highly
effective in reducing LPS/IFN-c-induced glial cell activation and
resulting neuronal injury, via an inhibition of p38 and STAT-1,
and a reduction in iNOS expression and other avonoids have been
shown to partially alleviate neuroinammation through the inhibition of TNF-a production [174]. Flavonoids present in blueberry
have also been shown to inhibit NO, IL-1b and TNF-a production
in activated microglia cells [175], whilst the avonol quercetin
[176], the avones wogonin and bacalein [177] and the avanols
catechin and epigallocatechin gallate (EGCG) [178] have all been
shown to attenuate microglia and/or astrocyte mediated neuroinammation. Their ability to exert such actions, again appear to rely
on their ability to directly modulate protein and lipid kinase signalling pathways [10,60,179,180], pro-inammatory transcription
factors (2335, 2430, 2590) and the downstream regulation of iNOS
and cyclooxygenase (COX-2) expression, NO production, cytokine
release, NADPH oxidase activation. For example, setin has been
shown to inhibit p38 MAP kinase phosphorylation in LPS-stimulated BV-2 microglial cells [181] and the avone luteolin inhibits
IL-6 production in activated microglia via inhibition of the JNK signalling pathway [182].

Summary
The actions of dietary avonoids on cognition appear to involve
a number of effects within the brain, including a potential to protect neurons against injury induced by neurotoxins and neuroinammation, a potential to activate synaptic signalling and an
ability to improve cerebrovascular blood ow. These effects appear
to be underpinned by an ability to interact with neuronal signalling
cascades in the brain, which leads a number of responses, including the inhibition of apoptosis triggered by neurotoxic species,
the promotion of neuronal survival and differentiation, and an
enhancement of peripheral and cerebral blood perfusion. With regards to the latter, future studies investigating whether such
changes in blood ow are also capable of inducing angiogenesis
and new nerve cell growth in the hippocampus would be of interest. Furthermore, the modulation of neuronal signalling and the
protection against neuronal losses induced by avonoids suggest

that optimal maintenance of brain morphology may underpin their

effects of cognition. If so, this is particularly relevant as this innate
brain structure is known to deteriorate with ageing, with neuronal
populations or synaptic connections lost over time, leaving the system less efcient in the processing and storage of sensory
information.
The consumption of avonoid-rich foods, such as berries or cocoa, throughout life may have the potential to limit or even reverse
age-dependent deteriorations in memory and cognition. However,
there are a number of questions still to be resolved. Most notably,
at present there is no data in support of a causal relationship between the consumption of avonoids and behavioural outcomes.
In order to make such relationships, future intervention studies
will be required to utilise better characterised intervention materials, more appropriate controls and more rigorous clinical outcomes. Whilst cognitive behavioural testing in humans and
animals provides an appropriate way of assessing function,
in vivo structural and dynamic quantitative assessments will ultimately be required to provide hard evidence of effects in the brain.
For example, it would be highly advantageous to directly link
behavioural responses to changes in hippocampal volume and density, changes in neural stem cell and progenitor cells and alterations in brain blood ow using MRI and fMRI techniques.
Functional MRI measures may be used to assess changes in blood
ow that underlie improved cognitive functioning as a result of avonoid supplementation. In addition, such haemodynamic changes
may be further compared to changes in grey matter density and to
biomarkers of neural stem and progenitor cells using proton nuclear magnetic resonance spectroscopy (H-MRS). Such an approach
will be essential to provide links between avonoid intake and
brain function in a mechanistic, dynamic and quantitative way.
Taking such an approach one may also be able to assess other factors relating to intake such as what timeframe is required to gain
maximum benecial effects, which avonoids are most effective
in inducing these changes and in which doses?
Acknowledgments
Dr. Spencer is funded by the Biotechnology and Biological Sciences Research Council (BB/F008953/1; BB/C518222/1; BB/
G005702/1; BB/E023185/1) and the Medical Research Council
(G0400278/NI02).
References
[1] C. Manach, A. Scalbert, C. Morand, C. Remesy, L. Jimenez, Am. J. Clin. Nutr. 79
(2004) 727747.
[2] J.P.E. Spencer, M.M. Abd El Mohsen, C. Rice-Evans, Arch. Biochem. Biophys.
423 (2003) 148161.
[3] J.P.E. Spencer, M.M. Abd El Mohsen, A.M. Minihane, J.C. Mathers, Br. J. Nutr. 99
(2007) 1222.
[4] C.A. Rice-Evans, N.J. Miller, G. Paganga, Free Radic. Biol. Med. 20 (1996) 933
956.
[5] S.E. Pollard, G.G. Kuhnle, D. Vauzour, K. Vafeiadou, X. Tzounis, M. Whiteman,
C. Rice-Evans, J.P.E. Spencer, Biochem. Biophys. Res. Commun. 350 (2006)
960968.
[6] J.P.E. Spencer, Br. J. Nutr. 99E (Suppl. 1) (2008) ES60ES77.
[7] J.P.E. Spencer, Proc. Nutr. Soc. 67 (2008) 238252.
[8] J.A. Joseph, B. Shukitt-Hale, G. Casadesus, Am. J. Clin. Nutr. 81 (2005) 313S
316S.
[9] R.J. Williams, J.P.E. Spencer, C. Rice-Evans, Free Radic. Biol. Med. 36 (2004)
838849.
[10] J.P.E. Spencer, Gen. Nutr. 2 (2007) 257273.
[11] J.P. Spencer, Chem. Soc. Rev. 38 (2009) 11521161.
[12] R.P. Da, L. Verlicchi, I. Setnikar, W. Murmann, M.J. Magistretti, Nature 184
(Suppl. 6) (1959) 362363.
[13] T.J. ODell, E.R. Kandel, S.G. Grant, Nature 353 (1991) 558560.
[14] M.L. Casini, G. Marelli, E. Papaleo, A. Ferrari, F. DAmbrosio, V. Unfer, Fertil.
Steril. 85 (2006) 972978.
[15] S.E. File, D.E. Hartley, S. Elsabagh, R. Duffy, H. Wiseman, Menopause 12 (2005)
193201.

J.P.E. Spencer et al. / Archives of Biochemistry and Biophysics 492 (2009) 19

[16] D. Kritz-Silverstein, M.D. Von, E. Barrett-Connor, M.A. Bressel, Menopause 10

(2003) 196202.
[17] S.C. Ho, A.S. Chan, Y.P. Ho, E.K. So, A. Sham, B. Zee, J.L. Woo, Menopause 14
(2007) 489499.
[18] Y.B. Lee, H.J. Lee, H.S. Sohn, J. Nutr. Biochem. 16 (2005) 641649.
[19] S.E. File, N. Jarrett, E. Fluck, R. Duffy, K. Casey, H. Wiseman,
Psychopharmacology (Berl.) 157 (2001) 430436.
[20] S. Kreijkamp-Kaspers, L. Kok, D.E. Grobbee, E.H. De Haan, A. Aleman, Y.T. van
der Schouw, J. Gerontol. A Biol. Sci. Med. Sci. 62 (2007) 556562.
[21] S. Kreijkamp-Kaspers, L. Kok, D.E. Grobbee, E.H. de Haan, A. Aleman, J.W.
Lampe, Y.T. van der Schouw, JAMA 292 (2004) 6574.
[22] L.R. Fournier, T.A. Ryan Borchers, L.M. Robison, M. Wiediger, J.S. Park, B.P.
Chew, M.K. McGuire, D.A. Sclar, T.L. Skaer, K.A. Beerman, J. Nutr. Health Aging
11 (2007) 155164.
[23] S.J. Birge, J. Am. Geriatr. Soc. 44 (1996) 865870.
[24] V.W. Henderson, Neuroscience 138 (2006) 10311039.
[25] V.W. Henderson, Semin. Reprod. Med. 27 (2009) 283293.
[26] V.W. Henderson, Clin. Obstet. Gynecol. 51 (2008) 618626.
[27] B. Shukitt-Hale, F.C. Lau, J.A. Joseph, J. Agric. Food Chem. 56 (2008) 636641.
[28] B. Shukitt-Hale, A.N. Carey, D. Jenkins, B.M. Rabin, J.A. Joseph, Neurobiol.
Aging 28 (2007) 11871194.
[29] L. Letenneur, C. Proust-Lima, G.A. Le, J.F. Dartigues, P. Barberger-Gateau, Am. J.
Epidemiol. 165 (2007) 13641371.
[30] Y. Wang, L. Wang, J. Wu, J. Cai, Br. J. Pharmacol. 148 (2006) 147153.
[31] J.A. Joseph, B. Shukitt-Hale, N.A. Denisova, D. Bielinski, A. Martin, J.J. McEwen,
P.C. Bickford, J. Neurosci. 19 (1999) 81148121.
[32] O. Shif, K. Gillette, C.M. Damkaoutis, C. Carrano, S.J. Robbins, J.R. Hoffman,
Pharmacol. Biochem. Behav. 84 (2006) 1725.
[33] R.E. Hartman, A. Shah, A.M. Fagan, K.E. Schwetye, M. Parsadanian, R.N.
Schulman, M.B. Finn, D.M. Holtzman, Neurobiol. Dis. 24 (2006) 506515.
[34] J.C. Winter, Physiol. Behav. 63 (1998) 425433.
[35] J.R. Hoffman, A. Donato, S.J. Robbins, Pharmacol. Biochem. Behav. 77 (2004)
533539.
[36] A. Walesiuk, E. Tromiuk, J.J. Braszko, Pharmacol. Res. 53 (2006) 123128.
[37] M.R. Ramirez, I. Izquierdo, R.M. Do Carmo Bassols, J.A. Zuanazzi, D. Barros, A.T.
Henriques, Pharmacol. Res. 52 (2005) 457462.
[38] F. Pu, K. Mishima, K. Irie, K. Motohashi, Y. Tanaka, K. Orito, T. Egawa, Y.
Kitamura, N. Egashira, K. Iwasaki, M. Fujiwara, J. Pharmacol. Sci. 104 (2007)
329334.
[39] C.M. Williams, M.A. El Mohsen, D. Vauzour, C. Rendeiro, L.T. Butler, J.A. Ellis,
M. Whiteman, J.P.E. Spencer, Free Radic. Biol. Med. 45 (2008) 295305.
[40] A.M. Haque, M. Hashimoto, M. Katakura, Y. Tanabe, Y. Hara, O. Shido, J. Nutr.
136 (2006) 10431047.
[41] G. Casadesus, B. Shukitt-Hale, H.M. Stellwagen, X. Zhu, H.G. Lee, M.A. Smith,
J.A. Joseph, Nutr. Neurosci. 7 (2004) 309316.
[42] H. van Praag, M.J. Lucero, G.W. Yeo, K. Stecker, N. Heivand, C. Zhao, E. Yip, M.
Afanador, H. Schroeter, J. Hammerstone, F.H. Gage, J. Neurosci. 27 (2007)
58695878.
[43] J.A. Joseph, B. Shukitt-Hale, N.A. Denisova, R.L. Prior, G. Cao, A. Martin, G.
Taglialatela, P.C. Bickford, J. Neurosci. 18 (1998) 80478055.
[44] C. Andres-Lacueva, B. Shukitt-Hale, R.L. Galli, O. Jauregui, R.M. LamuelaRaventos, J.A. Joseph, Nutr. Neurosci. 8 (2005) 111120.
[45] P. Goyarzu, D.H. Malin, F.C. Lau, G. Taglialatela, W.D. Moon, R. Jennings, E.
Moy, D. Moy, S. Lippold, B. Shukitt-Hale, J.A. Joseph, Nutr. Neurosci. 7 (2004)
7583.
[46] J.A. Joseph, N.A. Denisova, G. Arendash, M. Gordon, D. Diamond, B. ShukittHale, D. Morgan, Nutr. Neurosci. 6 (2003) 153162.
[47] D. Barros, O.B. Amaral, I. Izquierdo, L. Geracitano, R.M. do Carmo Bassols, A.T.
Henriques, M.R. Ramirez, Pharmacol. Biochem. Behav. 84 (2006) 229234.
[48] E.T. Rolls, R.P. Kesner, Prog. Neurobiol. 79 (2006) 148.
[49] I.A. Wilson, S. Ikonen, M. Gallagher, H. Eichenbaum, H. Tanila, J. Neurosci. 25
(2005) 68776886.
[50] S. Leutgeb, J.K. Leutgeb, A. Treves, M.B. Moser, E.I. Moser, Science 305 (2004)
12951298.
[51] M.E. Hasselmo, E. Schnell, E. Barkai, J. Neurosci. 15 (1995) 52495262.
[52] S.N. Burke, C.A. Barnes, Nat. Rev. Neurosci. 7 (2006) 3040.
[53] S.A. Small, W.Y. Tsai, R. DeLaPaz, R. Mayeux, Y. Stern, Ann. Neurol. 51 (2002)
290295.
[54] S.A. Small, M.K. Chawla, M. Buonocore, P.R. Rapp, C.A. Barnes, Proc. Natl. Acad.
Sci. USA 101 (2004) 71817186.
[55] G.F. Xavier, F.J. Oliveira-Filho, A.M. Santos, Hippocampus 9 (1999) 668681.
[56] H.G. Kuhn, H. Dickinson-Anson, F.H. Gage, J. Neurosci. 16 (1996) 20272033.
[57] G. Kempermann, H.G. Kuhn, F.H. Gage, J. Neurosci. 18 (1998) 32063212.
[58] E. Drapeau, W. Mayo, C. Aurousseau, M.M. Le, P.V. Piazza, D.N. Abrous, Proc.
Natl. Acad. Sci. USA 100 (2003) 1438514390.
[59] T.J. Shors, D.A. Townsend, M. Zhao, Y. Kozorovitskiy, E. Gould, Hippocampus
12 (2002) 578584.
[60] J.P.E. Spencer, Chem. Soc. Rev. 38 (2009) 11521161.
[61] G. Agullo, L. Gamet-Payrastre, S. Manenti, C. Viala, C. Remesy, H. Chap, B.
Payrastre, Biochem. Pharmacol. 53 (1997) 16491657.
[62] E.H. Walker, M.E. Pacold, O. Perisic, L. Stephens, P.T. Hawkins, M.P. Wymann,
R.L. Williams, Mol. Cell 6 (2000) 909919.
[63] K.A. Jacobson, S. Moro, J.A. Manthey, P.L. West, X.D. Ji, Adv. Exp. Med. Biol. 505
(2002) 163171.
[64] G.A. Johnston, Curr. Pharm. Des. 11 (2005) 18671885.

[65] N. Adachi, S. Tomonaga, T. Tachibana, D.M. Denbow, M. Furuse, Eur. J.

Pharmacol. 531 (2006) 171175.
[66] A.P. Nii, A. Bosson-Kouame, N. Papadopoulou, C. Kogia, M. Kampa, C.
Castagnino, C. Stournaras, J. Vercauteren, E. Castanas, Exp. Cell Res. 309
(2005) 329339.
[67] Y.S. Han, S. Bastianetto, Y. Dumont, R. Quirion, J. Pharmacol. Exp. Ther. 318
(2006) 238245.
[68] G. Neves, S.F. Cooke, T.V. Bliss, Nat. Rev. Neurosci. 9 (2008) 6575.
[69] E. Bruel-Jungerman, S. Davis, S. Laroche, Neuroscientist 13 (2007) 492505.
[70] S.R. Williams, C. Wozny, S.J. Mitchell, Neuron 56 (2007) 947953.
[71] J.G. Howland, Y.T. Wang, Prog. Brain Res. 169 (2008) 145158.
[72] E.J. Weeber, J.D. Sweatt, Neuron 33 (2002) 845848.
[73] P.K. Dash, A.N. Moore, N. Kobori, J.D. Runyan, Learn. Mem. 14 (2007) 554563.
[74] T. Tully, Nat. Neurosci. 1 (1998) 543545.
[75] T.J. Carew, Neuron 16 (1996) 58.
[76] E.R. Kandel, Science 294 (2001) 10301038.
[77] W.S. Sossin, Prog. Brain Res. 169 (2008) 325.
[78] C.R. Bramham, D.G. Wells, Nat. Rev. Neurosci. 8 (2007) 776789.
[79] K.C. Martin, M. Barad, E.R. Kandel, Curr. Opin. Neurobiol. 10 (2000) 587592.
[80] R.J. Kelleher III, A. Govindarajan, S. Tonegawa, Neuron 44 (2004) 5973.
[81] A.F. Arnsten, B.P. Ramos, S.G. Birnbaum, J.R. Taylor, Trends Mol. Med. 11
(2005) 121128.
[82] M.S. Perkinton, T.S. Sihra, R.J. Williams, J. Neurosci. 19 (1999) 58615874.
[83] M.S. Perkinton, J.K. Ip, G.L. Wood, A.J. Crossthwaite, R.J. Williams, J.
Neurochem. 80 (2002) 239254.
[84] D.L. Alkon, M.K. Sun, T.J. Nelson, Trends Pharmacol. Sci. 28 (2007) 5160.
[85] F. Wei, C.S. Qiu, J. Liauw, D.A. Robinson, N. Ho, T. Chatila, M. Zhuo, Nat.
Neurosci. 5 (2002) 573579.
[86] J.D. Sweatt, J. Neurochem. 76 (2001) 110.
[87] J.D. Sweatt, Curr. Opin. Neurobiol. 14 (2004) 311317.
[88] S. Impey, S.R. McCorkle, H. Cha-Molstad, J.M. Dwyer, G.S. Yochum, J.M. Boss, S.
McWeeney, J.J. Dunn, G. Mandel, R.H. Goodman, Cell 119 (2004) 10411054.
[89] A. Barco, C.H. Bailey, E.R. Kandel, J. Neurochem. 97 (2006) 15201533.
[90] K.M. Harris, S.B. Kater, Annu. Rev. Neurosci. 17 (1994) 341371.
[91] V.A. Alvarez, B.L. Sabatini, Annu. Rev. Neurosci. 30 (2007) 7997.
[92] H. Schroeter, J.P.E. Spencer, C. Rice-Evans, R.J. Williams, Biochem. J. 358
(2001) 547557.
[93] D. Vauzour, K. Vafeiadou, C. Rice-Evans, R.J. Williams, J.P.E. Spencer, J.
Neurochem. 103 (2007) 13551367.
[94] F. Llorens, L. Garcia, E. Itarte, N. Gomez, FEBS Lett. 510 (2002) 149153.
[95] H. Schroeter, C. Boyd, J.P.E. Spencer, R.J. Williams, E. Cadenas, C. Rice-Evans,
Neurobiol. Aging 23 (2002) 861880.
[96] A.N. Kong, R. Yu, C. Chen, S. Mandlekar, T. Primiano, Arch. Pharm. Res. 23
(2000) 116.
[97] P. Maher, T. Akaishi, K. Abe, Proc. Natl. Acad. Sci. USA 103 (2006) 16568
16573.
[98] H. Schroeter, P. Bahia, J.P.E. Spencer, O. Sheppard, M. Rattray, C. Rice-Evans,
R.J. Williams, J. Neurochem. 101 (2007) 15961606.
[99] J.P.E. Spencer, C. Rice-Evans, R.J. Williams, J. Biol. Chem. 278 (2003) 34783
34793.
[100] Y. Levites, T. Amit, M.B. Youdim, S. Mandel, J. Biol. Chem. 277 (2002) 30574
30580.
[101] L. Reznichenko, T. Amit, M.B. Youdim, S. Mandel, J. Neurochem. 93 (2005)
11571167.
[102] S.E. Pollard, M. Whiteman, J.P.E. Spencer, Biochem. Biophys. Res. Commun.
347 (2006) 916923.
[103] T.A. Pham, S. Impey, D.R. Storm, M.P. Stryker, Neuron 22 (1999) 6372.
[104] S. Impey, D.M. Smith, K. Obrietan, R. Donahue, C. Wade, D.R. Storm, Nat.
Neurosci. 1 (1998) 595601.
[105] S. Impey, M. Mark, E.C. Villacres, S. Poser, C. Chavkin, D.R. Storm, Neuron 16
(1996) 973982.
[106] R. Bourtchuladze, B. Frenguelli, J. Blendy, D. Ciof, G. Schutz, A.J. Silva, Cell 79
(1994) 5968.
[107] T. Tully, R. Bourtchouladze, R. Scott, J. Tallman, Nat. Rev. Drug Discov. 2
(2003) 267277.
[108] M.D. Conkright, E. Guzman, L. Flechner, A.I. Su, J.B. Hogenesch, M. Montminy,
Mol. Cell 11 (2003) 11011108.
[109] S. Finkbeiner, Neuron 25 (2000) 1114.
[110] S. Finkbeiner, S.F. Tavazoie, A. Maloratsky, K.M. Jacobs, K.M. Harris, M.E.
Greenberg, Neuron 19 (1997) 10311047.
[111] C.R. Bramham, E. Messaoudi, Prog. Neurobiol. 76 (2005) 99125.
[112] S. Peng, J. Wuu, E.J. Mufson, M. Fahnestock, J. Neurochem. 93 (2005) 1412
1421.
[113] B. Michalski, M. Fahnestock, Brain Res. Mol. Brain Res. 111 (2003) 148154.
[114] M.F. Egan, M. Kojima, J.H. Callicott, T.E. Goldberg, B.S. Kolachana, A. Bertolino,
E. Zaitsev, B. Gold, D. Goldman, M. Dean, B. Lu, D.R. Weinberger, Cell 112
(2003) 257269.
[115] L. Gamet-Payrastre, S. Manenti, M.P. Gratacap, J. Tulliez, H. Chap, B. Payrastre,
Gen. Pharmacol. 32 (1999) 279286.
[116] P.C. Ferriola, V. Cody, E. Middleton Jr., Biochem. Pharmacol. 38 (1989) 1617
1624.
[117] W.F. Matter, R.F. Brown, C.J. Vlahos, Biochem. Biophys. Res. Commun. 186
(1992) 624631.
[118] C.J. Vlahos, W.F. Matter, K.Y. Hui, R.F. Brown, J. Biol. Chem. 269 (1994) 5241
5248.

J.P.E. Spencer et al. / Archives of Biochemistry and Biophysics 492 (2009) 19

[119] G.M. Schratt, E.A. Nigh, W.G. Chen, L. Hu, M.E. Greenberg, J. Neurosci. 24
(2004) 73667377.
[120] Y. Yin, G.M. Edelman, P.W. Vanderklish, Proc. Natl. Acad. Sci. USA 99 (2002)
23682373.
[121] R. Waltereit, B. Dammermann, P. Wulff, J. Scadi, U. Staubli, G. Kauselmann,
M. Bundman, D. Kuhl, J. Neurosci. 21 (2001) 54845493.
[122] G.L. Lyford, K. Yamagata, W.E. Kaufmann, C.A. Barnes, L.K. Sanders, N.G.
Copeland, D.J. Gilbert, N.A. Jenkins, A.A. Lanahan, P.F. Worley, Neuron 14
(1995) 433445.
[123] H. Schroeter, C. Heiss, J. Balzer, P. Kleinbongard, C.L. Keen, N.K. Hollenberg, H.
Sies, C. Kwik-Uribe, H.H. Schmitz, M. Kelm, Proc. Natl. Acad. Sci. USA 103
(2006) 10241029.
[124] D. Grassi, T.P. Mulder, R. Draijer, G. Desideri, H.O. Molhuizen, C. Ferri, J.
Hypertens. 27 (2009) 774781.
[125] W.L. Hall, N.L. Formanuik, D. Harnpanich, M. Cheung, D. Talbot, P.J.
Chowienczyk, T.A. Sanders, J. Nutr. 138 (2008) 12881292.
[126] D. Grassi, G. Desideri, S. Necozione, C. Lippi, R. Casale, G. Properzi, J.B.
Blumberg, C. Ferri, J. Nutr. 138 (2008) 16711676.
[127] M.L. McCullough, K. Chevaux, L. Jackson, M. Preston, G. Martinez, H.H.
Schmitz, C. Coletti, H. Campos, N.K. Hollenberg, J. Cardiovasc. Pharmacol. 47
(Suppl. 2) (2006) S103S109.
[128] N.K. Hollenberg, G. Martinez, M. McCullough, T. Meinking, D. Passan, M.
Preston, A. Rivera, D. Taplin, M. Vicaria-Clement, Hypertension 29 (1997)
171176.
[129] J. Balzer, T. Rassaf, C. Heiss, P. Kleinbongard, T. Lauer, M. Merx, N. Heussen,
H.B. Gross, C.L. Keen, H. Schroeter, M. Kelm, J. Am. Coll. Cardiol. 51 (2008)
21412149.
[130] C. Heiss, H. Schroeter, J. Balzer, P. Kleinbongard, S. Matern, H. Sies, M. Kelm, J.
Cardiovasc. Pharmacol. 47 (Suppl. 2) (2006) S128S135.
[131] S.T. Francis, K. Head, P.G. Morris, I.A. Macdonald, J. Cardiovasc. Pharmacol. 47
(Suppl. 2) (2006) S215S220.
[132] N.D. Fisher, F.A. Sorond, N.K. Hollenberg, J. Cardiovasc. Pharmacol. 47 (Suppl.
2) (2006) S210S214.
[133] D.F. Dinges, J. Cardiovasc. Pharmacol. 47 (Suppl. 2) (2006) S221S223.
[134] J.J. Ohab, S. Fleming, A. Blesch, S.T. Carmichael, J. Neurosci. 26 (2006) 1300713016.
[135] T.D. Palmer, A.R. Willhoite, F.H. Gage, J. Comp. Neurol. 425 (2000) 479494.
[136] C. Zhao, W. Deng, F.H. Gage, Cell 132 (2008) 645660.
[137] L. Hooper, P.A. Kroon, E.B. Rimm, J.S. Cohn, I. Harvey, K.A. Le Cornu, J.J. Ryder,
W.L. Hall, A. Cassidy, Am. J. Clin. Nutr. 88 (2008) 3850.
[138] M. Ziche, L. Morbidelli, J. Neurooncol. 50 (2000) 139148.
[139] J.P. Cooke, Atheroscler. Suppl. 4 (2003) 5360.
[140] P.W. Shaul, Annu. Rev. Physiol. 64 (2002) 749774.
[141] J.A. Kim, G. Formoso, Y. Li, M.A. Potenza, F.L. Marasciulo, M. Montagnani, M.J.
Quon, J. Biol. Chem. 282 (2007) 1373613745.
[142] M. Ndiaye, M. Chataigneau, I. Lobysheva, T. Chataigneau, V.B. Schini-Kerth,
FASEB J. 19 (2005) 455457.
[143] E. Anter, S.R. Thomas, E. Schulz, O.M. Shapira, J.A. Vita, J.F. Keaney Jr., J. Biol.
Chem. 279 (2004) 4663746643.
[144] C. Lange-Asschenfeldt, G. Kojda, Exp. Gerontol. 43 (2008) 499504.
[145] E.T. Ang, F. Gomez-Pinilla, Curr. Med. Chem. 14 (2007) 25642571.
[146] C.W. Cotman, N.C. Berchtold, Trends Neurosci. 25 (2002) 295301.
[147] E.C. Hirsch, S. Hunot, A. Hartmann, Parkinsonism Relat. Disord. 11 (Suppl. 1)
(2005) S9S15.
[148] E.G. McGeer, P.L. McGeer, Prog. Neuropsychopharmacol. Biol. Psychiatry 27
(2003) 741749.
[149] A. Barzilai, E. Melamed, Trends Mol. Med. 9 (2003) 126132.

[150]
[151]
[152]
[153]
[154]

[155]
[156]
[157]
[158]
[159]
[160]
[161]
[162]
[163]
[164]
[165]
[166]
[167]
[168]
[169]
[170]
[171]
[172]
[173]
[174]
[175]
[176]
[177]
[178]
[179]
[180]
[181]
[182]

K.A. Jellinger, J. Cell Mol. Med. 5 (2001) 117.

T.L. Spires, A.J. Hannan, FEBS J. 272 (2005) 23472361.
S. Mandel, M.B. Youdim, Free Radic. Biol. Med. 37 (2004) 304317.
D. Vauzour, K. Vafeiadou, A. Rodriguez-Mateos, C. Rendeiro, J.P. Spencer,
Genes Nutr. 3 (2008) 115126.
Y. Luo, J.V. Smith, V. Paramasivam, A. Burdick, K.J. Curry, J.P. Buford, I. Khan,
W.J. Netzer, H. Xu, P. Butko, Proc. Natl. Acad. Sci. USA 99 (2002) 12197
12202.
S.A. Mandel, T. Amit, O. Weinreb, L. Reznichenko, M.B. Youdim, CNS Neurosci.
Ther. 14 (2008) 352365.
S.A. Mandel, T. Amit, L. Kalfon, L. Reznichenko, O. Weinreb, M.B. Youdim, J.
Alzheimers Dis. 15 (2008) 211222.
L. Kalfon, M.B. Youdim, S.A. Mandel, J. Neurochem. 100 (2007) 9921002.
S.A. Mandel, Y. Avramovich-Tirosh, L. Reznichenko, H. Zheng, O. Weinreb, T.
Amit, M.B. Youdim, Neurosignals 14 (2005) 4660.
Y. Levites, M.B. Youdim, G. Maor, S. Mandel, Biochem. Pharmacol. 63 (2002)
2129.
S. Lee, S. Suh, S. Kim, Neurosci. Lett. 287 (2000) 191194.
Y. Levites, O. Weinreb, G. Maor, M.B. Youdim, S. Mandel, J. Neurochem. 78
(2001) 10731082.
J.P.E. Spencer, M. Whiteman, P. Jenner, B. Halliwell, J. Neurochem. 81 (2002)
122129.
T.G. Hastings, J. Neurochem. 64 (1995) 919924.
D. Vauzour, G. Ravaioli, K. Vafeiadou, A. Rodriguez-Mateos, C. Angeloni, J.P.
Spencer, Arch. Biochem. Biophys. 476 (2008) 145151.
J.P.E. Spencer, P. Jenner, S.E. Daniel, A.J. Lees, D.C. Marsden, B. Halliwell, J.
Neurochem. 71 (1998) 21122122.
M. Masuda, M. Suzui, J.T. Lim, A. Deguchi, J.W. Soh, I.B. Weinstein, J. Exp. Ther.
Oncol. 2 (2002) 350359.
J.P.E. Spencer, H. Schroeter, G. Kuhnle, S.K. Srai, R.M. Tyrrell, U. Hahn, C. RiceEvans, Biochem. J. 354 (2001) 493500.
J.P.E. Spencer, H. Schroeter, A.J. Crossthwaithe, G. Kuhnle, R.J. Williams, C.
Rice-Evans, Free Radic. Biol. Med. 31 (2001) 11391146.
L. Wang, K. Matsushita, I. Araki, M. Takeda, Nephron 91 (2002) 142147.
Y. Ishikawa, M. Kitamura, Kidney Int. 58 (2000) 10781087.
K. Uchida, M. Shiraishi, Y. Naito, Y. Torii, Y. Nakamura, T. Osawa, J. Biol. Chem.
274 (1999) 22342242.
H. Kobuchi, S. Roy, C.K. Sen, H.G. Nguyen, L. Packer, Am. J. Physiol. 277 (1999)
C403C411.
D. Casper, U. Yaparpalvi, N. Rempel, P. Werner, Neurosci. Lett. 289 (2000)
201204.
K. Vafeiadou, D. Vauzour, H.Y. Lee, A. Rodriguez-Mateos, R.J. Williams, J.P.
Spencer, Arch. Biochem. Biophys. 484 (2009) 100109.
F.C. Lau, D.F. Bielinski, J.A. Joseph, J. Neurosci. Res. 85 (2007) 10101017.
J.C. Chen, F.M. Ho, L.C. Pei-Dawn, C.P. Chen, K.C. Jeng, H.B. Hsu, S.T. Lee, T.W.
Wen, W.W. Lin, Eur. J. Pharmacol. 521 (2005) 920.
H. Lee, Y.O. Kim, H. Kim, S.Y. Kim, H.S. Noh, S.S. Kang, G.J. Cho, W.S. Choi, K.
Suk, FASEB J. 17 (2003) 19431944.
R. Li, Y.G. Huang, D. Fang, W.D. Le, J. Neurosci. Res 78 (2004) 723731.
N.R. Bhat, P. Zhang, J.C. Lee, E.L. Hogan, J. Neurosci. 18 (1998) 16331641.
R.J. Williams, J.P. Spencer, C. Rice-Evans, Free Radic. Biol. Med. 36 (2004) 838
849.
L.T. Zheng, J. Ock, B.M. Kwon, K. Suk, Int. Immunopharmacol. 8 (2008) 484
494.
S. Jang, K.W. Kelley, R.W. Johnson, Proc. Natl. Acad. Sci. USA 105 (2008) 7534
7539.