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REVIEW
Flavonoids and brain health: multiple effects underpinned
by common mechanisms
Jeremy P. E. Spencer
Received: 21 July 2009 / Accepted: 21 July 2009 / Published online: 15 August 2009
Springer-Verlag 2009
Abstract The neuroprotective actions of dietary flavo-
noids involve a number of effects within the brain, includ-
ing a potential to protect neurons against injury induced by
neurotoxins, an ability to suppress neuroinflammation, and
the potential to promote memory, learning and cognitive
function. This multiplicity of effects appears to be under-
pinned by two processes. Firstly, they interact with impor-
tant neuronal signalling cascades leading to an inhibition of
apoptosis triggered by neurotoxic species and to a promo-
tion of neuronal survival and differentiation. These inter-
actions include selective actions on a number of protein
kinase and lipid kinase signalling cascades, most notably
the PI3K/Akt and MAP kinase pathways which regulate
pro-survival transcription factors and gene expression.
Secondly, they induce peripheral and cerebral vascular
blood flow in a manner which may lead to the induction of
angiogenesis, and new nerve cell growth in the hippocam-
pus. Therefore, the consumption of flavonoid-rich foods,
such as berries and cocoa, throughout life holds a potential
to limit the neurodegeneration associated with a variety of
neurological disorders and to prevent or reverse normal or
abnormal deteriorations in cognitive performance.
Keywords Flavonoid Brain Neurodegeneration
Neuroinflammation Memory Cognitive performance
Signalling
Introduction
Macronutrients, such as lipids are vital components of both
neurons and glial cells and their profile (saturated or un-
saturated) has been proposed to play a huge role in brain
function [3]. Furthermore, the brain has a very high energy
demand and as such utilises a large proportion of the
dietary intake of carbohydrates in order to function effec-
tively. However, it is less obvious how other dietary-
derived nutrients or non-nutrient components may impact
on the functioning of the brain. Despite this, a large number
of dietary intervention studies in humans and animals, in
particular those using foods and beverages derived from
Vitis vinifera (grape), Camellia sinensis (tea), Theobroma
cacao (cocoa) and Vaccinium spp. (blueberry) have dem-
onstrated beneficial effects on human vascular function and
on improving memory and learning [15,16,32,60,69,76,
80]. While such foods and beverages differ greatly in
chemical composition, macro- and micronutrient content
and caloric load per serving, they have in common that
they are amongst the major dietary sources of a group of
phytochemicals called flavonoids.
Historically, the biological actions of flavonoids,
including those on the brain, have been attributed to their
ability to exert antioxidant actions [51], through their
ability to scavenge reactive species, or through their pos-
sible influences on intracellular redox status [50]. However,
it has been speculated that this classical hydrogen-donating
antioxidant activity cannot account for the bioactivity of
flavonoids in vivo, particularly in the brain, where they are
found at only very low concentrations [59]. 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 [60]. Indeed, it has become
J. P. E. Spencer (&)
Molecular Nutrition Group, School of Chemistry,
Food and Pharmacy, University of Reading,
Reading RG2 6AP, UK
e-mail: j.p.e.spencer@reading.ac.uk
123
Genes Nutr (2009) 4:243–250
DOI 10.1007/s12263-009-0136-3
evident that flavonoids 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 [61,74,78]. This
review will examine the potential for flavonoids to influ-
ence brain function and will attempt to clarify the mech-
anisms which underpin such actions in the brain.
Inhibition of neuroinflammation
Neuroinflammatory processes in the brain are believed to
play a crucial role in the development of Alzheimer’s and
Parkinson’s disease [19,47] as well as injury associated
with stroke [81]. Activated microglia and/or astrocytes
release cytokines and other mediators which have been
linked to the apoptotic death of neurons. In particular,
increases in cytokine production (interleukin-1b, IL-1b;
tumour necrosis factor-alpha, TNF-a), inducible nitric
oxide synthase (iNOS) and nitric oxide (NO
•
), and
increased NADPH oxidase activation [31] all contribute to
glial-induced neuronal death (Fig. 1). The majority of these
events are controlled by upstream mitogen-activated pro-
tein kinase (MAPK) signalling which mediates both the
transcriptional and post-transcriptional regulation of iNOS
and cytokines in activated microglia and astrocytes [6,45].
Evidence suggests that the non-steroidal anti-inflammatory
drug, ibuprofen, may be effective in delaying the onset of
neurodegenerative disorders, particularly as Parkinson
disease, by reducing inflammatory injury in specific brain
regions [8]. As such, there is a desire to develop new drugs
capable of preventing progressive neuronal loss linked
to neuroinflammation. Recently, the flavanone naringenin
found at high concentrations in citrus fruits has been found
to be highly effective in reducing LPS/IFN-c-induced glial
NH2
HO
HO
S
COOHH2N
NH2
HO
S
HOOC
HN
5-S-Cys-DA DHBT-1
Caspase-3
Apoptosis
Modulation of Mitochondrial
Neuron
DA
ONOO-
ONOO-
Tyrosinase
ONOO -
DA-o-quinone
Oxidative stress
5-S-Cys -DA
Cys
cell signalling dysfunction
Caspase-8
Apoptosis
iNOS
NO
O2•-
O2•-
•
DHBT-1
NO •
NO •
p38
STAT-1
NADPH
oxidase
TNF-α
Microglia/Astrocyte
IFNγIL-1β
TNF-α
CD23
Fig. 1 Involvement of
neuroinflammation, endogenous
neurotoxins and oxidative stress
in neurodegeneration. The
structures of the 5-S-cysteinyl-
dopamine (5-S-Cys-DA) and
dihydrobenzothiazine-1
(DHBT-1) are shown
244 Genes Nutr (2009) 4:243–250
123
cell activation and resulting neuronal injury [70], via an
inhibition of p38 and STAT-1, and a reduction in iNOS
expression (Fig. 2). The structurally related flavanone
hesperetin and other flavonoids appeared incapable of
inhibiting pathways leading to NO
•
production, although
they were found to partially alleviate neuroinflammation
through the inhibition of TNF-aproduction [70].
Flavonoids present in blueberry have also been shown to
inhibit NO
•
, IL-1band TNF-aproduction in activated
microglia cells [33], while the flavonol quercetin [9], the
flavones wogonin and bacalein [35], the flavanols catechin
and epigallocatechin gallate (EGCG) [38] and the isoflavone
genistein [4] have all been shown to attenuate microglia and/
or astrocyte mediated neuroinflammation via mechanisms
that include inhibition of: (1) iNOS and cyclooxygenase
(COX-2) expression, (2) NO
•
production, (3) cytokine
release, and (4) NADPH oxidase activation and subsequent
reactive oxygen species (ROS) generation, in astrocytes and
microglia. All of these effects appear to rely via on an ability
to directly modulate the protein and lipid kinase signalling
pathways [58,61,78], for example, via the inhibition of
MAPK signalling cascades, such as p38 or ERK1/2 which
regulate both iNOS and TNF-aexpression in activated glial
cells [6] (Fig. 2). In this respect, fisetin inhibits p38 MAP
kinase phosphorylation in LPS-stimulated BV-2 microglial
cells [82] and the flavone luteolin inhibits IL-6 production in
activated microglia via the inhibition of the JNK signalling
pathway [21]. The effects of flavonoids on these kinases may
influence downstream pro-inflammatory transcription fac-
tors important in iNOS transcription. One of these, nuclear
factor-Kappa B (NF-jB), responds to p38 signalling and is
involved in iNOS induction [7], suggesting that there is
interplay between signalling pathways, transcription factors
and cytokine production in determining the neuroinflam-
matory response in the CNS. In support of this, some
flavonoids have been shown to prevent transcription factor
activation, with the flavonol quercetin and the flavanone
naringenin able to suppress NF-jB, signal transducer and
activator of transcription-1 (STAT-1) and activating pro-
tein-1 (AP-1) activation in LPS- and IFN-c-activated
microglial cells [9,70].
Inhibition of neurodegeneration
The underlying neurodegeneration observed in Parkin-
son’s, Alzheimer’s, and other neurodegenerative diseases is
believed to be triggered by multi-factorial processes,
including neuroinflammation, glutamatergic excitotoxicity,
increases in iron and/or depletion of endogenous antioxi-
dants [5,22,67]. There is a growing body of evidence
to suggest that flavonoids and other polyphenols may be
able to counteract this neuronal injury, thereby delaying the
progression of these brain pathology [41,58,59]. For
example, a Ginkgo biloba extract has been shown to pro-
tect hippocampal neurons against nitric oxide- and beta-
amyloid-induced neurotoxicity [39]; and studies have
demonstrated that the consumption of green tea may have
beneficial effect in reducing the risk of Parkinson’s disease
[28,42–44]. In agreement with the latter study, tea extracts
and pure (-)-epigallocatechin-3-gallate (EGCG) have been
shown to attenuate 6-hydroxydopamine-induced toxicity
ROS/RNS DHBT-1
Scavenging by
Flavonoids
Activation
Inhibition CysDA
NO •
Microglia/Astrocyte
ASK1
JNK1/2
BAD
Akt
/
PI3K
Activation by Flavonoids
STAT-1
TNF-αCaspase-8
Caspase-9
Caspase-3
Bcl-xL
MEK1/2
CREB
Inhibition by
Flavonoids
IFNγ
IL-1β
TNF-α
CD23
Neuronal
Apoptosis
Neuron
p38
iNOS ERK1/2
Fig. 2 The cellular
mechanisms by which
flavonoids and their metabolites
protect against
neuroinflammation and
neuronal injury induced by 5-S-
Cys-DA, DHBT-1 and related
ROS. Flavonoids inhibit the p38
pathway glia cells leading to a
reduction in iNOS expression
and NO
•
release. In neurons,
they scavenge neurotoxic
species and induce pro-survival
signalling pathways, such as
ERK1/2 and PI3-kinase/Akt,
leading to an inhibition of
neuronal apoptosis
Genes Nutr (2009) 4:243–250 245
123
[37], to protect against hippocampal injury during transient
global ischemia [34] and to prevent nigral damage induced
by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
[36].
The death of nigral neurons in Parkinson’s disease is
thought to involve the formation of the endogenous neu-
rotoxin, 5-S-cysteinyl-dopamine (5-S-cys-DA) and its oxi-
dation product, dihydrobenzothiazine (DHBT-1) [18,65]
(Fig. 1). 5-S-cysteinyl-catecholamine conjugates possess
strong neurotoxicity and initiate a sustained increase in
intracellular ROS in neurons leading to DNA oxidation,
caspase-3 activation and delayed neuronal death [65]
(Fig. 1). Such adducts may be generated by reactive spe-
cies [73] and have been observed to be elevated in the
human substantia nigra of patients who died of Parkinson’s
disease [62], suggesting that such species may be potential
endogenous nigral toxins. However, 5-S-cysteinyl-dopa-
mine-induced neuronal injury is effectively counteracted
by nanomolar concentrations of various flavonoids,
including pelargonidin, quercetin, hesperetin, caffeic acid,
the 40-O-Me derivatives of catechin and epicatechin [73]
(Fig. 2). Furthermore, in the presence of the flavanol, (?)-
catechin, tyrosinase-induced formation of 5-S-cysteinyl-
dopamine was inhibited by a mechanism linked to the
capacity of catechin to undergo tyrosinase-induced oxida-
tion to yield cysteinyl-catechin adducts [72]. In contrast,
the inhibition afforded by flavanones, such as hesperetin,
was not accompanied with the formation of cysteinyl-
hesperetin adducts, indicating that it may inhibit via direct
interaction with tyrosinase [72].
Reactive oxygen and nitrogen species have also been
proposed to play a role in the pathology of many neuro-
degenerative diseases [22] (Fig. 1). There is abundant
evidence that flavonoids are effective in blocking this oxidant-
induced neuronal injury, although their potential to do so is
thought not to rely on direct radical or oxidant scavenging
activity [63,64]. Instead, they are believed to act by mod-
ulating a number of protein kinase and lipid kinase signal-
ling cascades, such as the PI3 kinase (PI3K)/Akt, tyrosine
kinase, protein kinase C (PKC) and MAPK signalling
pathways [58,78]. 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 [78]. For example, flavonoids have been
observed to block oxidative-induced neuronal damage by
preventing the activation of caspase-3, providing evidence
in support of their potent anti-apoptotic action [63,64]. The
flavanols 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 [53]. Flavanones, such as hes-
peretin 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
[71]. Similarly, the flavone, bacalein, has been shown to
significantly inhibit 6-hydroxydopamine-induced JNK
activation and neuronal cell death and quercetin may sup-
press JNK activity and apoptosis induced by hydrogen
peroxide [20,75], 4-hydroxy-2-nonenal [68] and tumour
necrosis factor-alpha (TNF-alpha) [30].
Modulation of memory and learning
There is now much evidence to suggest that fruit and
vegetable derived phytochemicals, in particular flavonoids,
are capable of promoting beneficial effects on memory and
learning [23–27,56,57,79]. It appears that these low
molecular weight, non-nutrient components are able to
impact upon memory through their ability to exert effects
directly on the brains innate architecture for memory [60].
This innate cellular and anatomical architecture of the
brain, and its role in the acquisition, storage and retrieval of
memories, was originally postulated by Immanuel Kant in
1781 in his revolutionary ‘‘Critique of pure reason’’ [29].
Kant suggested that there must be such ‘architecture’ in the
brain, in order that we may interpret sensory information
(Kant’s so called ‘a priori’ or ‘innate knowledge’). This
may now be interpreted not only psychologically but also
physiologically [40,46], in that one does not come to
sensory data as a ‘blank tablet’, but rather brings a sort of
relational structure within the nervous system to interpret
sense data [1,2,46]. Consequently, the nature of our
sensory impressions is determined a priori by the physio-
logical apparatus of our senses or by the sensory nerve
centres and the memory acquisition, storage and recall
centres of the brain [2]. It is now understood that this
underlying structure has a molecular basis and thus inter-
action with this physiological apparatus may yield changes
in the way we acquire, store and retrieve memory. Fur-
thermore, this innate cellular architecture is well known
to deteriorate with aging, with neuronal populations or
synaptic connections lost over time, leaving the system
less efficient in the processing and storage of sensory
information.
The ability of flavonoids to impact upon this memory
system appears to be, in part, underpinned by an ability to
interact with this molecular and physiological apparatus.
The concentrations of flavonoids and their metabolites
which reach the brain are thought to be sufficiently high to
exert pharmacological activity at receptors, kinases and
transcription factors. Although the precise site of their
interaction with signalling pathways remains unresolved,
evidence indicates that they are capable of acting in a
246 Genes Nutr (2009) 4:243–250
123
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 Ca
2?
homeo-
stasis, thereby preventing Ca
2?
-dependent activation of
kinases in neurons, and (5) by modulating signalling cas-
cades lying downstream of kinases, i.e. transcription factor
activation and binding to promoter sequences. By affecting
such pathways they have the potential to induce new pro-
tein synthesis in neurons and thus an ability to induce
morphological changes which have a direct influence on
memory acquisition, consolidation and storage.
Various individual cascades have been linked with this
control of de novo protein synthesis in the context of LTP,
synaptic plasticity and memory (Fig. 3): (i) cAMP-depen-
dent protein kinase (protein kinase A), (ii) protein kinase B
(PKB/Akt) 78, (iii) protein kinase C (PKC), (iv) calcium-
calmodulin kinase (CaMK) 80 and (v) extracellular signal-
regulated kinase (ERK) [61]. All five 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-model-
ling, synaptic plasticity and memory (Fig. 3). Flavonoids
are now well known to modulate neuronal signalling
pathways crucial in inducing synaptic plasticity [61], and
although each of these pathways are known to be involved
in increasing the number of, and strength of, connections
between neurons, flavonoids appear to interact primarily
with the ERK and PKB/Akt pathways [55,58,66]. The
activation of these pathways by blueberry flavonoids, along
with the activation of the transcription factor CREB and
production of neurotrophins such as brain-derived neuro-
trophic factor brain-derived neurotrophic factor (BDNF) is
known to be required during memory acquisition and
consolidation and agents capable of inducing pathways
leading to CREB activation will have the potential to
enhance both short-term and long-term memory [79], by
providing a more efficient structure for interpreting afferent
nerve or sensory information. One mechanism by which
this may come about is through flavonoid-induced increa-
ses in neuronal spine density and morphology, two factors
considered vital for learning and memory [17]. 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 syn-
aptic connectivity and strength between neuronal partners,
affecting the efficacy of synaptic communication (Fig. 3).
In support of this, high flavanol and anthocyanin supple-
mentation has been shown to cause activation of mTOR
and an increased expression of hippocampal Arc/Arg3.1
[79], events which are likely to facilitate changes in syn-
aptic strength through the stimulation of the growth of
small dendritic spines into large mushroom-shaped spines.
There is also evidence to suggest that flavonoids may be
capable of preventing many forms of cerebrovascular dis-
ease, including those associated with stroke and dementia
[10,11]. Flavonoids may exert effects on endothelial func-
tion and peripheral blood flow [54], and these vascular
effects are potentially significant as increased cerebrovas-
cular function is known to facilitate adult neurogenesis in the
hippocampus [14] (Fig. 3). Indeed, new hippocampal cells
are clustered near blood vessels, proliferate in response to
vascular growth factors and may influence memory [49].
Efficient cerebral blood flow (CBF) is vital for optimal brain
function, with several studies indicating that there is a
decrease in CBF in patients with dementia [48,52]. Brain
imaging techniques, such as ‘functional magnetic resonance
imaging’ (fMRI) and ‘trans-cranial Doppler ultrasound’
(TCD) has shown that there is a correlation between CBF
and cognitive function in humans [52]. For example, CBF
velocity is significantly lower in patients with Alzheimer
disease and low CBF is also associated with incipient
markers of dementia. In contrast, non-demented subjects
with higher CBF were less likely to develop dementia. In this
context, flavonoids have been shown to cause significantly
increased CBF in humans, 1–2 h post intervention [12,13].
After consumption of a flavanol-rich cocoa drink, the ‘flow
oxygenation level dependent’ (BOLD)-fMRI showed an
increase in blood flow in certain regions of the brain, along
Plant Bioactives
Cell Signalling and Gene Expression
PKA, PKB/Akt, PKC, CaMK, ERK
CREB
BDNF, NRF, Arc mTOR, VEGF-B,TGF-β
NMDA-R
Increased Blood Flow
Angiogenesis
New nerve cell growth
Dendritic spine growth
Neuronal communication
Synaptic plasticity
Vascular Effects
Neuronal Morphology
Enhanced Memory, Learning and Cognition
Fig. 3 Flavonoid-induced activation of neuronal signalling and gene
expression in the brain. Such processes may lead to changes in
synaptic plasticity and neurogenesis in the brain which ultimately
influence memory, learning and cognition
Genes Nutr (2009) 4:243–250 247
123
with a modification of the BOLD response to task switching.
Furthermore, ‘arterial spin-labelling sequence magnetic
resonance imaging’ (ASL-MRI) [77] also indicated that
cocoa flavanols increase CBF up to a maximum of 2 h after
ingestion of the flavanol-rich drink. In support of these
findings, an increase in CBF through the middle cerebral
artery has been reported after the consumption of flavanol-
rich cocoa using TCD [12].
Summary
The neuroprotective actions of dietary flavonoids involve a
number of effects within the brain, including a potential to
protect neurons against injury induced by neurotoxins, an
ability to suppress neuroinflammation, and the potential to
promote memory, learning and cognitive function. This
multiplicity of effects appears to be underpinned by two
processes. Firstly, they interact with important neuronal
signalling cascades in the brain leading to an inhibition of
apoptosis triggered by neurotoxic species and to a pro-
motion of neuronal survival and differentiation. These
include selective actions on a number of protein kinase and
lipid kinase signalling cascades, most notably the PI3K/Akt
and MAP kinase pathways which regulate pro-survival
transcription factors and gene expression. It appears that
the concentrations of flavonoids encountered in the brain
may be sufficiently high to exert such pharmacological
activity on receptors, kinases and transcription factors.
Second, they are known to induce beneficial effects on the
peripheral and cerebral vascular system, which lead to
changes in cerebrovascular blood flow. Such changes are
likely to induce angiogenesis, new nerve cell growth in the
hippocampus and changes in neuronal morphology, all
processes known to important in maintaining optimal
neuronal function and neuro-cognitive performance.
The consumption of flavonoid-rich foods, such as ber-
ries and cocoa, throughout life holds a potential to limit
neurodegeneration and prevent or reverse age-dependent
deteriorations cognitive performance. However, at present,
the precise temporal nature of the effects of flavonoids on
these events is unclear. For example, it is presently unclear
as to when one needs to begin consuming flavonoids in
order to obtain maximum benefits. It is also unclear which
flavonoids are most effective in inducing these changes.
However, due to the intense interest in the development of
drugs capable of enhancing brain function, flavonoids may
represent important precursor molecules in the quest to
develop of a new generation of brain enhancing drugs.
Acknowledgment Dr. Spencer is funded by the Biotechnology and
Biological Sciences Research Council (BB/F008953/1; BB/E023185/1;
BB/G005702/1).
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