Neurochem Res (2010) 35:955–966
DOI 10.1007/s11064-010-0144-0
OVERVIEW
Flavonoids and Astrocytes Crosstalking: Implications for Brain
Development and Pathology
Jader Nones • Joice Stipursky • Sı́lvia Lima Costa •
Flávia Carvalho Alcantara Gomes
Accepted: 18 February 2010 / Published online: 9 March 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Flavonoids are naturally occurring polypheno-
lic compounds that are present in a variety of fruits, veg-
etables, cereals, tea, and wine, and are the most abundant
antioxidants in the human diet. Evidence suggests that
these phytochemicals might have an impact on brain
pathology and aging; however, neither their mechanisms of
action nor their cell targets are completely known. In the
mature mammalian brain, astroglia constitute nearly half of
the total cells, providing structural, metabolic, and trophic
support for neurons. During the past few years, increasing
knowledge of these cells has indicated that astrocytes are
pivotal characters in neurodegenerative diseases and brain
injury. Most of the physiological benefits of flavonoids are
generally thought to be due to their antioxidant and free-
radical scavenging effects; however, emerging evidence
has supported the hypothesis that their mechanism of
action might go beyond these properties. In this review, we
focus on astrocytes as targets for flavonoids and their
implications in brain development, neuroprotection, and
glial tumor formation. Finally, we will briefly discuss the
emerging view of astrocytes as essential characters in
neurodegenerative diseases, and how a better understand-
ing of the action of flavonoids might open new avenues to
develop therapeutic approaches to these pathologies.
J. Nones  J. Stipursky  F. C. A. Gomes (&)
Laboratório de Neurobiologia Celular, Programa de Biologia
Celular e do Desenvolvimento, Instituto de Ciências Biomédicas,
Universidade Federal do Rio de Janeiro, Centro de Ciências da
Saúde, Bloco F, Sala F15. Ilha do Fundão,
Rio de Janeiro, RJ, Brazil
e-mail: fgomes@anato.ufrj.br
S. L. Costa
Instituto de Ciências da Saúde, Universidade Federal da Bahia,
Salvador, BA, Brazil
Keywords Flavonoids  Astrocytes 
Neurodegenerative diseases  Glioma
Introduction
Astroglia: Beyond the Classical Concept of Brain Glue
In the mid-nineteenth century, by analyzing postmortem
human tissues, the German pathologist Rudolf Virchow
described a connective tissue, acellular in nature, in the brain
and spinal cord. He called this tissue Nervenkitt (neuroglia),
which means nerve glue [1]. The Neuron Doctrine, created in
the late nineteenth century and which considered neurons as
the only cells with physiological relevance for NS function,
kept us in the dark concerning glial development and func-
tion. Since their description by Virchow and for at least the
following 100 years, glial cells were regarded as merely
supportive and passive elements with no role in brain func-
tion. The past decade, however, has been marked by a
thorough revisitation of the role of glial cells in the healthy
brain, and especially in brain disease.
Glial cells are classified into two main groups:
microglia, the macrophages of the central nervous system
(CNS) involved in programmed elimination of neural cells
during development and removal of toxic cellular debris;
and macroglia, constituted by a highly morphologically and
functionally heterogeneous class of neural cells that
includes ependymal cells, Schwann cells, oligodendroglia,
and astroglia. The last type is constituted by astrocytes,
marginal glia, radial glia in the developing brain and spinal
cord, Bergmann cells in the cerebellar cortex, Müller cells
in the retina, pituicytes in the neurohypophysis, and tany-
cytes in the hypothalamus [2].
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Evidence accumulating over the past decade has
revealed that neuron-astroglia interactions play key roles in
several events of brain development, such as the prolifer-
ation and differentiation of neuronal precursors [3–6],
neuronal migration [7], axonal guidance [8–11], synapse
formation [12, 13], and glial maturation [14–19]. The
identification of the astroglial origin of several progenitor
cells assigned a new attribute to these cells, as neural stem
cells in the developing and adult brain [20, 21].
Astroglial cells are emerging as key mediators of brain
development, function, and plasticity, which highlights the
critical need to better characterize the mechanisms under-
lying their development and interaction with neurons.
Although our understanding of these cells has expanded
dramatically during the past decade, much mystery still
surrounds the role of astrocytes in brain development and
injury.
In the present review, we will focus on the role of
neuron-astrocyte interactions during brain development
and pathology. We will discuss the conceptual shift of
the role of astroglia in brain development. We argue that
astroglial cells should not be viewed primarily as support
cells, but rather as cells that actively control the structural
and functional organization of the developing and mature
brain. We begin by reviewing in vitro and in vivo evidence
of the role of astrocytes in the healthy brain; and the
enigmatic role of astroglia dysfunction for neurodegener-
ative diseases and brain tumor formation. In the second
part of the review, we address the role of astrocytes as
mediators of the action of polyphenols in brain develop-
ment; then we provide evidence of the effects of flavonoids
on brain tumor formation, with a special focus on glio-
blastoma biology. Finally, we will briefly discuss the
emerging view of astrocytes as essential characters in
neurodegenerative diseases, and how a better understand-
ing of flavonoids action might contribute to developing
therapeutic approaches to brain pathologies.
Role of Neuron-Astrocyte Interactions in the Healthy
Brain
Astroglial cells are emerging as key mediators of brain
development, function, and plasticity [22]. These cells
constitute nearly 50% of the total cells in the cerebral
cortex and comprise one-third of its volume, depending on
regions and species.
Astrocytes can be generally recognized by the expres-
sion of characteristic cytoskeletal proteins such as GFAP
(glial fibrillary acidic protein) and vimentin, by the pres-
ence of the S100b calcium-binding protein, and the glu-
tamine synthetase enzyme. More recently an astrocyte-
enriched protein was revealed, the aldehyde dehydrogenase
1 family member L1 (Aldh1L1) [2, 23].
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Astrocytes are considered the major energy-storage
support components of the mature mammalian brain. By
cell coupling through GAP junctions, astrocytes form syn-
cytium-like structures that fill the spaces between the neu-
ronal axons and synaptic terminals. This astrocyte network
is involved in modulating several brain processes, such as
ion buffering, modulation of CO2 concentration, clearance
of neurotransmitters, and extracellular pH control [24, 25].
In addition to homeostasis control, astrocytes also per-
form metabolic regulation as active components of the
blood–brain barrier (BBB), where, together with brain-ves-
sel endothelial cells, they maintain the cerebral parenchyma
isolated from the blood circulation [26, 27].Mutual interac-
tions among astrocytes, endothelial cells, and neurons are
absolutely required for the BBB function, providing an
interface structure, which regulates ion influx and nutrient
transport, and prevents the entrance of potentially nocive
molecules into the brain [27]. Disturbances of these inter-
actions are associated with the development of several neu-
ropathologies such as tumors and multiple sclerosis [26].
Astrocytes constitute the main source of trophic factors
in the CNS. These include members of the epidermal
growth factor (EGF) family, transforming growth factor
(TGF), and neuregulins (NRG); fibroblast growth factor
(FGF), nerve growth factor (NGF), and ciliary neurotrophic
factor (CNTF). By providing trophic support, astrocytes
might affect several events of brain development, such as
neuronal precursor proliferation, cell fate commitment, and
synaptogenesis [22].
In vitro and in vivo studies have demonstrated that
astrocyte-neuronal interactions are essential for the sur-
vival and function of neurons. The secretion of extracel-
lular matrix components such as fibronectin and laminin by
astrocytes is essential for neuronal polarity determination,
axonal growth [28], stem cell differentiation, and neuronal
migration and proliferation [11, 29].
Recently a novel attribute has been assigned to astro-
cytes, as neural stem cells of the adult brain [30]. Neuro-
genesis in the adult vertebrate brain occurs mainly through
the persistence of ‘‘niches’’ that harbor neural stem cells
(NSC) and constitute a microenvironment that constantly
supports and regulates neurogenic activity [21, 31]. Two
germinal regions within the adult mammalian brain have
been shown to contain active neurogenesis throughout life:
the subventricular zone (SVZ) of the lateral ventricles [21],
and the subgranular zone (SGZ) of the dentate gyrus in the
hippocampus [4]. Strikingly, in both the SVZ and SGZ, a
subset of astrocytes that is classically associated with
support functions in the brain was identified as the in vivo
primary precursors for adult neurogenesis [32, 33].
Accumulated data from the last 7 years suggest that
astrocytes are an integral part of synaptic connections, both
by promoting synapse formation and elimination and by
Neurochem Res (2010) 35:955–966
actively secreting neuromodulators or gliotransmitters. It
has been estimated that individual astrocytes in the adult
rodent brain ensheath and interact with as many as 140,000
synapses [34]. In the CNS, astrocytes envelop the pre- and
postsynaptic neuronal components. This cellular architec-
ture leads to the concept of the tripartite synapse, consti-
tuted by neurons and peri-synaptic glial cells, which are
regarded today as a third integral component of synapsesb
[35]. Neuron-astrocyte interactions in the synaptic cleft
play a pivotal role in synapse development.
By using glia-free cultures of purified retinal ganglion
cells (RGCs), Pfrieger and Barres [36] found that astrocytes
and oligodendrocytes strongly enhanced spontaneous syn-
aptic activity and the reliability of synaptic transmission [37,
38]. Later, the idea that glial cells induce synapse formation
was validated, in the central and peripheral nervous system,
by a number of studies using different neuronal cell lines
(murine and human) [38, 39], human embryonic stem cells
(hES) [40], and neuromuscular junction (NMJ) neurons [37].
In vitro or in vivo studies have revealed a variety of
putative synaptogenic secreted and contact glia-derived
factors. These include glutamate [41], cholesterol [42], the
extracellular matrix protein trombospondin [12], TGF-b1
[43], adenosine triphosphate [44], the neuromodulator
D-serine [45], and the glial protein S100b [46].
This evidence, together with the emerging character-
ization of gliotransmitters [47] and several neurotransmit-
ter receptors in astrocytes, supports the argument that
astrocytes are active partners of neurons, not only in syn-
apse development but in function as well. Further, the
growing evidence of astrocytes as intimate partners of
neurons also sheds light on the consequences of astrocyte
dysfunction to brain disorders.
Role of Astrocytes in Brain Pathology
A hallmark of brain reaction to physical and chemical
damage is characterized by an intense response of astro-
cytes known as reactive gliosis. Reactive astrocytes display
characteristic phenotypic changes characterized by hyper-
trophic nuclei and cell bodies, and development of thick
processes with an increased content of GFAP [48]. In
addition, they express a wide variety of markers such as
cytoskeleton proteins, cell surface and matrix molecules,
proteases, protease inhibitors, and several growth factors
and cytokines [49, 50]. Whereas the role of astrocytes in
reactive gliosis is well established and considered mainly a
consequence of neuronal death or dysfunction, astrocyte
dysfunction as a primary cause of nervous tissue damage
has only gained attention in recent years.
In the following section, we will briefly review the mech-
anisms of astrocytes in brain tumor formation and the evidence
for their involvement in neurodegenerative diseases (ND).
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Neurodegenerative Diseases
Several lines of evidence support the idea that astrocytes
might be involved in the pathogenesis of various neuro-
degenerative diseases, such as Parkinson’s disease (PD),
Alzheimer’s disease (AD), tumor, stroke, HIV-associated
neurotoxicity, and amyotrophic lateral sclerosis (ALS)
[51–59].
Astrocytes accumulate neuron-derived amyloid material
resulting from local neurodegeneration [60, 61], charac-
teristic of the AD brain. Once substantial accumulation of
this debris occurs, the astrocytes themselves might undergo
cell death, resulting in the formation of GFAP amyloid
plaques [62]. Whereas astrocyte dysfunction itself might
contribute to AD progression, or is merely a consequence
of neuronal degeneration is unknown.
PD, one of the most prevalent neurodegenerative diseases,
is caused by the disruption of dopaminergic neurotransmis-
sion in the basal ganglia. On pathological examination, the
numbers of dopaminergic neurons in the substantia nigra are
markedly reduced, and Lewy bodies (cytoplasmic inclu-
sions) are present in the residual dopaminergic neurons [63].
Disease-specific mechanisms include inflammation stimu-
lated by interaction of alpha-synuclein with microglia and
astrocytes [64], followed by an increase in GFAP expression
[65]. Astrocytes have also been shown to be critical in
modulating the neurotoxic effects of many toxins that induce
experimental parkinsonism; further, they produce sub-
stances in vitro that are able to modify the effects of L-DOPA
from neurotoxic to neurotrophic [66].
Implications of astroglial abnormalities and physiolog-
ical dysfunction as a primary cause of the disease have
been well described for ALS. The familial form of these
abnormality, resulting from the G85R mutation of the
superoxide dismutase (SOD-1) gene, includes reactive
astrocytosis, observed prior to motor-neuron degeneration
[67], and loss of glutamate transport and GLT1 protein
expression before the onset of clinical disease or overt
motor-neuron degeneration [68]. Other changes associated
with ALS include increased expression of several astro-
cytic proteins, including inducible nitric-oxide synthase
(iNOS), the copper chaperone CCS, and metallo-thioneins.
Pathologically, early cytosolic proteinaceous aggregates
have been found in spinal-cord astrocytes from all of the
mSOD1 mouse lines examined to date [69].
Brain Tumors
Gliomas consist of poorly differentiated neoplastic astro-
cytes; their histopathological features [70] include cellular
polymorphism, nuclear atypia, mitotic activity, vascular
thrombosis, microvascular proliferation, and necrosis [71].
High-grade gliomas such as multiform glioblastoma (WHO
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grade IV) present glial character, as evidenced by expres-
sion of GFAP [72]. They are the most aggressive and the
most frequent primary tumors of the CNS [70, 73]. These
tumors are highly invasive, vascularized, rapidly prolifer-
ating tumors that develop in cerebral hemispheres and show
a poor prognosis and high recurrence [74]. Moreover, recent
advances in tumor biology, especially those conduced in
genetically engineered mouse models (GEMMs) revealed
potential targets for therapeutic intervention. As revised by
Jason and Holland [75], the disruption of a set of tumor
suppressor pathways with direct effects on cell cycle control
appears be crucial in the evolution of glioma. The p53 gene,
for example, is frequently either mutated or deleted in
astrocytic gliomas, particularly those that progress from
low-grade astrocytoma to multiform glioblastoma.
Surgical removal of the tumor constitutes the first-line
therapy. Unfortunately, glioblastoma cells are extremely
mobile and infiltrate the surrounding tissues. Therefore,
surgery must be followed by radiation therapy, and in most
cases by chemotherapy to further lower the number of
remaining tumor cells. Standard chemotherapy consists of
alkylating drugs including carboplatine, carmustine, and
fotemustine [76]. Agents such as tamoxifen, selenium,
retinoids, and cytokines have also been proposed, but their
effects are still under discussion [77, 78].
Despite recent advances in the therapy of glioblastomas
with the introduction of the methylating agent temozolo-
mide [79], and antibody antiangiogenic therapy against the
vascular endothelial growth factor [80], the median sur-
vival time for glioblastoma patients is still around
14 months [81]. Therefore, compounds that show antitu-
mor activity may be key allies to improve the conventional
treatment applied to tumors of the CNS.
The search for alternative drugs for therapeutic inter-
ventions against brain tumors or neurodegenerative dis-
eases has shed light on phytochemical drugs. Although
several lines of evidence, especially their use in popular
medicine in several countries, show that they might have
an impact on brain pathology (see Sect. 3), both their
mechanisms of action and cell targets are incompletely
known. Here, we review the role of flavonoids, a phyto-
chemical compound, in astrocyte biology and its implica-
tion for brain development and pathology.
Polyphenols Function in the Brain
Classification, Structure and Actions of Flavonoids
in the Central Nervous System
Flavonoids are naturally occurring polyphenolic com-
pounds that are present in a variety of fruits, vegetables,
cereals, tea, wine, and fruit juices [82, 83]. They are
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Neurochem Res (2010) 35:955–966
secondary metabolites formed in plants from the aromatic
amino acids phenylalanine and tyrosine, and from malonate
[84].
The main groups of flavonoids are (1) flavonols (e.g.,
kaempferol, quercetin), which are found in onions, leeks,
and broccoli; (2) flavones (e.g., apigenin, luteolin), which
are found in parsley and celery, (3) isoflavones (e.g.,
daidzein, genistein), which are mainly found in soy and soy
products; (4) flavanones (e.g., hesperetin, naringenin),
which are mainly found in citrus fruit and tomatoes; (5)
flavanols (e.g., catechin, epicatechin, epigallocatechin,
epigallocatechin gallate (EGCG), which are abundant in
green tea, red wine, and chocolate; and (6) anthocyanidins
(e.g., pelargonidin, cyanidin, malvidin), whose sources
include red wine and berry fruits [85] (Fig. 1).
The basic flavonoid structure is the flavan nucleus,
which consists of 15 carbon atoms arranged in three rings
(C6-C3-C6), labeled A, B, and C. These compounds con-
sist of two aromatic carbon rings, benzopyran (A and C
rings) and benzene (B ring), and can be divided into six
subgroups as previously described, 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 [86].
Most of the known actions of flavonoids are related to
their antioxidant properties [87, 88]. According to Halli-
well [89], mechanisms of antioxidant action can include (1)
suppression of reactive oxygen species formation (2)
scavenging of reactive oxygen species; and (3) upregula-
tion or protection of antioxidant defenses.
However, it has been speculated that their classical
hydrogen-donating antioxidant activity cannot explain the
bioactivity of flavonoids in vivo. Indeed, it has become
evident that neuroprotective actions of flavonoids are likely
to be due to (1) modulation of intracellular signaling cas-
cades which control neuronal survival, death, and differ-
entiation; (2) effect on gene expression; and (3)
interactions with mitochondria [90, 91].
Dietary intervention studies in several mammalian spe-
cies, including humans, using flavonoid-rich plant or food
extracts have indicated an ability of these dietary compo-
nents to improve memory and learning [92–96], by pro-
tecting vulnerable cells, enhancing existing neuronal
function, or by stimulating neuronal regeneration.
Whereas many reports have supported the in vitro
antioxidant activity of flavonoids, their in vivo efficacy is
still controversial, possibly due to the limited knowledge of
their pharmacokinetics [97, 98].
Although flavonoids can access the brain, it is clear that
these substances and their metabolite forms reach lower
concentrations in vivo than those recorded for small-
molecule antioxidant nutrients such as ascorbic acid and
a-tocopherol [99, 100]. Consequently, the beneficial effects
of flavonoid metabolites in vivo are unlikely to result from
Neurochem Res (2010) 35:955–966
Fig. 1 Main groups of flavonoids. The naturally occurring polyphe-
nolic compounds can be classified in at least 6 distinct groups based
on their structural intramolecular differences. The basic structure of
their ability to out-compete antioxidants such as ascorbate,
which are present in higher concentrations.
Considerable variation in BBB permeability for differ-
ent flavonoids has been reported. Naringenin, a member of
the flavanone family, exhibits high permeability as mea-
sured by in vitro and in situ BBB models, suggesting that
this family of flavonoids should afford good neuroprotec-
tion within the CNS. Nevertheless, some restriction of
entry caused by efflux transporters may affect certain
flavonoids, such as quercetin [101].
Although evidence suggests that flavonoids have an
impact on brain pathology and aging, neither their mech-
anisms of action nor their cell targets are completely
known. In the next section, we will discuss the emerging
view of astrocytes as targets for flavonoids, and its impli-
cation for brain development and pathology.
Role of Astrocytes as Mediators of Flavonoid Effects
In the past decade, emerging evidence points to astrocytes
as potential targets for mediating the actions of flavonoids.
This is supported by the broad spectrum of responses that
flavonoids elicit in astrocytes in culture. Recently, it was
demonstrated that the flavonoid rutin has a direct effect on
glial cells in vitro, inducing activation of astrocytes and
microglia, release of tumor necrosis factor alpha (TNF-a),
and induction of iNOS [102]. Moreover, it has been shown
that the dietary flavonoid (-)epicatechin stimulates the
activity of the anti-oxidant response element in primary
cortical astrocytes [103].
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flavonoids is composed of the known flavan nucleus, formed of 15
carbon atoms arranged in three aromatic rings
Quercetin was shown to inhibit synthesis of the heat
shock protein (HSP70) and GFAP [104], and generation of
reactive oxygen species (ROS) in rat glioma cells
line[105].
Several actions of flavonoids on astrocytes are associ-
ated with their ability to modulate astrocyte response to
oxidative stress, such as decreasing the ROS release from
astrocytes stimulated with the proinflammatory cytokine
IL-1[106]. This event is followed by an increase in the
expression of SOD-1and thioredoxin (TRX1), both medi-
ators of protection against cell death from oxidative stress.
Further, flavonoids might modulate GFAP and glutamine
synthetase expression by IL-1-activated astrocytes, result-
ing in reduction of reactive gliosis and improvement of
astrocytes’ ability to handle inflammatory conditions, thus
avoiding neuronal cell death.
Although most physiological benefits of flavonoids are
generally thought to be due to their antioxidant and free-
radical scavenging effects, emerging evidence supports the
hypothesis that their mechanism of action might extend
beyond these properties. The high responsiveness of
astrocytes to several flavonoids supports the hypothesis that
these cells might be mediators of flavonoid actions in the
mature brain. Recently, it has been shown that resveratrol
counteracts oxidative damage caused by H2O2, not only by
its antioxidant properties, but also through the modulation
of important glial functions, particularly improving gluta-
mate uptake activity, increasing glutathione content and
stimulating S100b secretion, thus contributing to functional
recovery after brain injury [106, 107].
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Recently, our group investigated the neuroprotective
properties of the flavonoid casticin, extracted from Croton
betulaster, a common plant of the state of Bahia in Brazil,
on rat cerebral cortex neurons in vitro. By employing a cell
culture system, we observed that casticin increased the cell
population labeled for the neuronal markers bTubulinIII
and Tbr2, derived from neuronal progenitors isolated from
the mouse embryonic cerebral cortex. This event was due
to inhibition of neuronal cell death. Moreover, we observed
that astrocytes were active mediators of the effects of
casticin, since culture of neuronal progenitors over astro-
cyte monolayers previously treated with casticin yielded a
40% increase in neuronal population as well. This event
was mediated by secretion of neuroprotective soluble fac-
tors by astrocytes that protected neuronal progenitors from
apoptotic cell death.
Therefore, in this study we identified two different
mechanisms by which the flavonoid casticin modulates
neuronal population: direct, by decreasing neuronal cell
death; and indirect, via astrocytes, by reducing the death of
neuronal precursors (Fig. 2). Our group provided, for the
first time, evidence that astrocytes are mediators of the
effects of casticin, and through secretion of neuroprotective
molecules protect neurons against cell death [108].
All these results, together with the recent findings that
flavonoids can rescue astrocyte dysfunction in in vitro
models, might open new perspectives for the use of these
substances as novel compounds for neurodegenerative
disease therapy, and contribute to elucidating the role of
glial cells in the development and pathology of the nervous
system.
Flavonoids in Brain Pathologies: Implications
of Astroglial Cells
In popular medicine, the actions of flavonoids have been
associated with the prevention of certain chronic diseases
such as cancers and cardiovascular diseases, mostly due to
their anti-oxidant and anti-inflammatory effects [109].
More recently, the search for alternative drugs to treat
neurodegenerative diseases and brain tumors has shed light
on these natural compounds [91, 110]. In the next section
we will describe recent advances in elucidating the role of
natural compounds and their mechanisms of action on
glioblastoma and neurodegenerative diseases.
Flavonoids and Glial Tumors
Several studies have indicated that flavonoids are active
principles responsible for various biological effects,
including anticancer activity [109]. However, little is
known about the antitumor properties of naturally occur-
ring and synthetic flavonoids against gliomas. As demon-
strated by Scheck and collaborators [111], an extract from
Scutellaria baicalensis (Baikal skullcap) containing flavo-
noids inhibited the viability of human glioblastoma cells,
and also inhibited growth and induced apoptosis. Ferguson

Fig. 2 Mechanism of action of

casticin in neuroprotection.
Casticin acts by two distinct
mechanisms to modulate
neuronal population: (1)
directly, casticin acts as an
extracellular signal protecting
neurons from various insults
and death, which leads to an
increase in the neuronal
population (4); (2) indirectly, by
acting through astrocytes,
casticin induces the secretion of
a soluble factor, which might
protect neural progenitors from
death (3) and induces neuronal
differentiation, resulting in the
increase of the neuronal
population (4). Thus, the
flavonoid casticin contributes to
enhance the neuronal population
by increasing either the
precursor pool or the neuronal
number

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and collaborators [112] also showed that flavonoids present

in Vaccinia macrocarpa (blackberry) induced inhibition of
cell proliferation, growth arrest, and apoptosis in the
human glioblastoma cell line U87. Moreover, the flavonoid
quercetin has been shown to inhibit cell proliferation of the
glioblastoma multiforme cell line U138MG, decreasing
cell viability and inducing apoptosis [113]. Sharma and
collaborators [114], observed that kaempferol induced
apoptosis in glioblastoma cell lines LN229, U87MG and
T98G, and potentiated the toxic effect of the chemothera-
peutic agent doxorubicin by elevating intracellular oxida-
tive stress and decreasing the efflux of doxorubicin. Son
and collaborators [115] observed that treatment with sub-
toxic doses of silibinin, a flavonoid isolated from Silybum
marianum (milk thistle) can, in combination with tumor
necrosis factor-related apoptosis-inducing ligand (TRAIL),
induce rapid apoptosis in TRAIL-resistant glioma cells, but
not in human astrocytes, suggesting that this combined
treatment may offer an attractive strategy for safely treating
gliomas.
Recently, isoquercitrin isolated from Hyptis fasciculata
was shown to dramatically inhibit glioblastoma (Gbm) cell
growth, mainly by reducing cyclin D1 levels and increasing
p27 levels. Moreover, this event was associated with the
reorganization of beta-catenin, suggesting that beta-cate-
nin-mediated signaling may mediate the antiproliferative
activity of isoquercitrin [116].
The magnitude of anti-tumoral effect of flavonoids tes- Fig. 3 Effects of flavonoids on glioblastoma cells. a Effect of
ted against glioblastoma has been related to flavonoids flavonoids 5-hydroxy-7, 4’-dimethoxyflavone (HDOF), casticin
(CAS), apigenin (API), penduletina (PEN), and rutin on secretion
structure, especially to the degree of hydroxylation and of TGF-b1 and VEGF by human G-15 glioblastoma cells. b Nestin
methylation. We previously isolated flavonoids presenting and GFAP immunocytochemistry in GL-15 cell cultures in control
different degrees of methylation from a species of Croton conditions (vehicle 0.5% DMSO) or exposed to 50 lM penduletin.
betulaster Müll. Arg., a shrub adopted in popular medicine Scale bar = 10 lm
and found in Chapada Diamantina, Bahia, Brazil [117].
Hence, we conducted a study to investigate the effects penduletina can induce morphological changes on GL-15
on glioblastoma cells of the flavonoids 5-hydroxy-7, human glioblastoma cells towards a glial phenotype. It
4’-dimethoxyflavone, 5,7,40 trihidroxyflavone (apigenin), induced overexpression of GFAP, and downregulation of
50 ,40 -dihidroxy-3,6,7-trimethoxyflavone (penduletin), and the neural precursor marker, nestin (Fig. 3b). These find-
5,30 -dihidroxy-3,6,7,40 tetramethoxyflavone (casticin) iso- ings suggest that the amount of hydroxyl and methyl
lated from C. betulaster, and also rutin, a glucoside flavo- groups is essential to antitumor activity in GL-15 glio-
noid isolated from Dimorphandra mollis Bent (data not blastoma cells and support the idea of flavonoids as
published). We observed that besides inhibition of prolif- promising supplementary and alternative molecules in the
eration and induction of apoptosis, the flavonoids rutin, treatment of malignant gliomas.
apigenin, casticin and penduletin, but not 5-hydroxy-7,
40 -dimethoxyflavone, down regulated the secretion of pro- Flavonoids and Neurodegenerative Diseases
angiogenic cytokine TGF-b1 by the high proliferative
human glioblastoma cell line GL-15. On the other hand Despite the wide distribution of flavonoids, research on
rutin, but not the other flavonoids tested, down regulated their human health benefits began only in the mid-1990s.
the secretion of other pro-angiogenic cytokine, VEGF These substances have attracted increasing interest because
(Fig. 3a). From the flavonoids used in our experiments numerous epidemiological studies have suggested associ-
5-hydroxy-7,4-dimetoxiflavon was apparently the less effec- ations between the consumption of polyphenol-rich foods
tive, and the flavonoids casticin and penduletin, were the or beverages and the prevention of certain chronic diseases
most effective. Moreover, we also observed that flavonoid such as cancers and cardiovascular pathologies [118–120].

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In neuropathology, studies have also reported the beneficial
effects of these substances, such as in AD, PD, Hunting-
ton’s disease, and ALS [103, 121–124].
In vitro and in vivo studies support the neuroprotective
activity of polyphenols against diverse neuronal insults such
as ischemia, oxidative-induced damage, and dopamine-
induced neurotoxicity [121–127]. The best-known effect of
flavonoids on the nervous system is related to the ability of
these substances to protect neurons from oxidative stress. In
normal conditions, the brain is more vulnerable to oxidative
stress than other organs, as concomitant low activity and
the capacity of antioxidative protection systems allow for
increased exposure of target molecules to ROS. Since
neurons are postmitotic cells, they are likely to exist with
cellular damage accumulated over many decades. Increased
levels of ROS, produced by normal mitochondrial activity,
inflammation, and excess glutamate levels, are proposed to
accelerate neurodegenerative disorders. Accumulating evi-
dence supports the hypothesis that brain iron misregulation
and oxidative stress (OS), resulting in ROS generation from
H2O2 and inflammatory processes, trigger a cascade of
events leading to apoptotic/necrotic cell death in neurode-
generative disorders [128].
Overproduction of ROS during ischemia/reperfusion
causes an imbalance between oxidative and antioxidative
processes [129]. Polyphenols attenuate ischemia–reperfu-
sion injury by interfering with inducible nitric oxide syn-
thase activity, inhibiting lipid peroxidation, decreasing the
number of immobilized leukocytes during reperfusion, and
reducing complement activation, which results in a
diminished inflammatory response [130]. Most impor-
tantly, in addition to their antioxidant actions, they also
influence neuroprotective and neurorestorative signal
transduction mechanisms [90]. Epidemiological studies
show an inverse relationship between stroke and polyphe-
nol consumption [109].
Oxidative stress and increased lipid peroxidation, low
glutathione levels, DNA damage, and iron exposure have
been reported as the main causes of PD [131]. Nutritional
studies have demonstrated that consumption of green tea
could have a beneficial role in reducing the risk of this
pathology. Administration of the polyphenol EGCG sig-
nificantly delayed the onset of symptoms and prevented the
loss of substantia nigra dopaminergic neurons in experi-
mental animal models of Parkinson’s disease [128, 132].
Previous evidence demonstrated that flavonoids have
anti-amyloidogenic properties in addition to their anti-
inflammatory activity [133, 134]. Although there is no
significant outcome relative to tea consumption in AD,
several in vitro studies have shown that green tea extract
could protect neurons from amyloid b-induced damage
[135, 136]. Moreover, treatment with other sources of
flavonoids than those from tea or wine, such as those from
123
Neurochem Res (2010) 35:955–966
the Ginkgo biloba extract EGb 761, can also improve the
cognitive performance of Alzheimer’s patients [137].
Further, long-term administration of a preparation of green-
tea catechins has been demonstrated to improve special
cognition and learning ability in rodents and to reduce
amyloidosis in a transgenic model of AD [138, 139].
Although experimental data are consistent in demon-
strating the neuroprotective effects of antioxidants in vitro
and in animal models, the clinical evidence that antioxidant
agents may prevent or slow the course of these diseases is
still relatively unsatisfactory, and is insufficient to strongly
modify clinical practice [140]. It is not at all clear whether
these compounds reach the brain in sufficient concentra-
tions and in a biologically active form to exert beneficial
effects. Therefore, a deeper understanding of their intra-
cellular and molecular targets as well as the special path-
ways underlying distinct polyphenol-induced neuroprotec-
tion is still necessary.
Concluding Remarks
Consumption of dietary flavonoids has been associated
with reduced risk of neurodegenerative diseases in humans,
neuroprotection against disease-producing insults in
rodents, and improvements in cognition and learning in
animal models [123, 139]. The capacity of several flavo-
noids including naringenin, quercetin, hispidulin, hespere-
tin, naringenin and EGCG to cross BBB, either due to their
lipophilic nature or to their interactions with specific efflux
transporters expressed in the BBB, supports the hypothesis
that these natural polyphenol compounds might be regar-
ded as potential neuroprotective agents in vivo. Neverthe-
less, it is evident that flavonoids are potent bioactive
molecules, and a clear understanding of their mechanism of
action is crucial to the evaluation of their therapeutic
potential.
Since glial cells were described more than a 100 years
ago, Virchow’s concept of an inert substance has changed
profoundly. Today, astrocytes are widely recognized as
active partners of neurons in many brain functions. The
generation of animal models in which astrocyte-specific
proteins and pathways have been manipulated has greatly
contributed to understanding the role of these cells in brain
pathology.
This role is supported by growing evidence of the
involvement of astrocytes in the current view of the non-
cell-autonomous mechanism by which neurodegenerative
diseases are triggered (or at least influenced) by both
neuronal and non-neuronal cells [141]. This is best exem-
plified by ALS, where mutation of SOD1 in astrocytes
has proven to be a key event in the development and
Neurochem Res (2010) 35:955–966
progression of motor deficiency in ALS experimental
models [142].
The recent finding that astrocytes are targets for flavo-
noids may lead to the development of new therapy proto-
cols based on astrocyte-specific cell replacement and
function. Recently, Marchetto and collaborators [143]
suggested that human astrocytes overexpressing mutated
SOD1G37R can activate NOX2 to produce superoxide.
Addition of antioxidants, including flavonoids, completely
reversed this process, preventing the loss of motor neurons
caused by coculture with SOD1-mutated astrocytes.
Indeed, another group demonstrated that oral administra-
tion of EGCG significantly delayed the onset of ALS
symptoms, and extended the life span [143].
In summary, it is evident that flavonoids are potent
bioactive molecules, and a clear understanding of their
mechanisms of action as modulators of cell signaling will
be crucial in the evaluation of their potential to act as
inhibitors of neurodegeneration or as modulators of brain
function. We argue that advances in the understanding of
the mechanisms underlying neuron-astrocyte interactions
during brain development may represent a promising goal
for developing novel neuroprotective strategies for neuro-
degenerative diseases, based especially on target therapies
for specific astrocytic pathways.
Acknowledgments We thank Dr. Janet W. Reid, JWR Associates,
Biological Consulting and Editing Services for revising the English
text. This study was supported by grants from the Fundação Carlos
Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
(FAPERJ), Conselho Nacional de Desenvolvimento Cientı́fico e
Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pes-
soal de Nı́vel Superior (CAPES).
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