Ageing Research Reviews 11 (2012) 329–345

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Ageing Research Reviews

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Review

Natural polyphenols against neurodegenerative disorders: Potentials and pitfalls

Azadeh Ebrahimi ∗ , Hermann Schluesener
Division of Immunopathology of the Nervous System, Department of Neuropathology, Institute of Pathology and Neuropathology, University of Tuebingen, Calwer Str. 3, D-72076
Tuebingen, Germany

a r t i c l e i n f o a b s t r a c t

Article history: Within the last years, a rapidly growing number of polyphenolic compounds with neuroprotective effects
Received 1 November 2011 have been described. Many efforts have been made to explore the mechanisms behind the neuroprotec-
Received in revised form tive action of polyphenols. However, many pathways and mechanisms considered for mediating these
23 December 2011
effects are rather general than specific. Moreover, despite the beneficial effects of polyphenols in exper-
Accepted 31 January 2012
imental treatment of neurodegeneration, little has been achieved in bringing them into routine clinical
Available online 9 February 2012
applications. In this review, we have summarized the protective effects of polyphenols against neu-
rodegeneration, and we have also discussed some of the barricades in translating these biochemical
Keywords:
Polyphenol
compounds, into relevant therapeutics for neurodegenerative diseases.
Neurodegenerative disease © 2012 Elsevier B.V. All rights reserved.
Neuroprotection
Alzheimer’s disease
Parkinson’s disease

1. Why polyphenols?
Natural polyphenols are the most commonly found chemical
compounds in consumed herbal beverage and food worldwide
(Joseph et al., 2007; Ramos, 2007). They constitute a large group
of phytochemicals with more than 8000 identified compounds
(Table 1).
The primary function of these compounds is protection of plants
against reactive oxygen species (ROS), produced during photosyn-
thesis, and consumption by herbivores (Ramos, 2007). Within the
previous decades, most of the studies on polyphenols have been
focused on anti-oxidant properties of these chemical compounds as
their most prominent effect (Halliwell, 2001). Along with introduc-
ing resveratrol, as a potential anti-aging agent, much focus has been
placed on protective effects of various polyphenols against aging
and related neurodegenerative diseases (Kay, 2010). Increase in life
span by polyphenols can be associated with increased or improved
brain function. For instance, epigallocatechin gallate (EGCG) post-
poned the onset of neurological symptoms and prolonged life span
in a mice model of amyotrophic lateral sclerosis (ALS) (Koh et al.,
2006; Xu et al., 2006). Long term treatment with epigallocatechin
gallate increased the life span and enhanced movement abilities in
a transgenic Drosophila melanogaster model of PD (Ortega-Arellano
et al., 2011). Despite the prominent evidence of neuroprotective
effects of polyphenols from in vitro and preclinical models, overall
∗ Corresponding author. Fax: +49 7071 294846.
E-mail address: azadehebr@yahoo.com (A. Ebrahimi).
success in bringing these compounds into routine clinical applica-
tion has been limited.
Studies on neuroprotective effects of polyphenols can be divided
into the following categories: (1) neuroprotective action through
antioxidant pathways, (2) interaction with signaling pathways,
(3) neuroprotection through modulation of neural mediators and
enzymes like acetylcholine (Ach) and acetylcholinesterase (AChE),
(4) inhibition of NMDA neurotoxicity and (5) anti-amyloidogenic
effects.
In this review, we have focused on neuroprotective effects of
natural polyphenols and their interaction with specific molecular
targets and pathways of neurodegeneration. We have discussed
potentials and pitfalls of using these chemical compounds as neu-
roprotective agents in in vitro and in vivo experiments as well as
in clinical setting.
2. Polyphenols as antioxidants
The most prominently discussed effect of polyphenols is their
antioxidant activity. It is now established that oxidative/nitrosative
stress (OS/NS) has a pivotal role in pathophysiology of neurodegen-
erative diseases and many other types of human maladies (Aluise
et al., 2010; Bjelakovic et al., 2011; Gotz et al., 1994; Halliwell, 2001;
Tesch and Lim, 2011). Oxidative damage to neuronal molecules,
accumulation of iron ion species in the brain, and decreased cellular
reserve antioxidant pool are major pathological aspects of neu-
rodegenerative disorders, like Parkinson’s disease (PD), Alzheimer’s
disease (AD) or Amyotrophic lateral sclerosis (Gotz et al., 1990;
Halliwell, 1992; Mandel et al., 2004b, 2005; Riederer et al., 1989;

1568-1637/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.arr.2012.01.006
330 A. Ebrahimi, H. Schluesener / Ageing Research Reviews 11 (2012) 329–345
Table 1
A simplified classification of natural polyphenols.
Polyphenols Falvonoids Anthocyanins
Flavonols
Flavones
Flavanones
Isoflavonoids Isoflavones
Isoflavanes
Flavanols Monomers
Oligomers and polymers
Non-flavonoids Phenolic acids Derivatives of cinnamic acid
Derivatives of benzoic acid
Lignans
Stilbenes
Weinreb et al., 2004). It has been shown, that severe hypoxia or
ischemia episodes increase the susceptibility to development of AD
(Desmond et al., 2002). Hypoxia, in fact, can induce amyloid pre-
cursor protein (APP) up-regulation at both the mRNA and protein
level and subsequently leads to amyloid beta (A␤) accumulation
(Chen et al., 2003; Jendroska et al., 1997; Shi et al., 2000). NS can
damage bio-molecules through reactive species such as peroxyni-
trite and plays also a crucial role in PD by triggering mitochondrial
dysfunction (Lin and Beal, 2006; Mattson, 2004; Mythri et al., 2011;
Reddy, 2006).
Polyphenols exert their antioxidant effects through differ-
ent mechanisms like interaction with the HIF-1 alpha pathway,
inducing expression of protective genes against OS, regulation of
reactive oxygen species by interacting with oxidative pathways
and scavenging metal ions as pathogenic free radicals (Kelsey et al.,
2010). Table 2 summarizes recent studies on antioxidant effects of
polyphenols in neurodegenerative processes.
2.1. Hypoxia inducible factor 1 (HIF-1) alpha pathway
One strategy of neuroprotection is activation of hypoxia sig-
nal transduction pathways through which the hypoxic condition is
sensed and appropriate genes are activated and expressed in order
to mediate compensatory survival conditions for the cells. A high
percentage of hypoxic responses in cells, are controlled by hypoxia-
inducible transcription factor-1 (Ogunshola and Antoniou, 2009).
The HIF-1 complex is a heterodimer, consisting of two subunits:
The HIF-1␣ oxygen-regulated subunit and the HIF-1␤ subunit, also
known as aryl hydrocarbon receptor nuclear translocation (ARNT)
(Ratcliffe et al., 1998; Semenza, 1998; Soucek et al., 2003; Wang
and Semenza, 1993; Wenger and Gassmann, 1997). Alterations
in oxygen levels regulate HIF-1␣ activity. Under normoxic condi-
tions, HIF-1␣ is degraded by HIF prolyl-4-hydroxylases (Jaakkola
et al., 2001). These enzymes require iron as co-factor and oxy-
gen as co-substrate (Ivan et al., 2001; Jaakkola et al., 2001). In
contrast, under hypoxic conditions, HIF-1␣ is translocated to the
nucleus where it dimerises with ARNT and subsequently binds to
hypoxic binding sites of target genes involved in cell survival, gly-
colysis, angiogenesis, erythropoiesis, and iron metabolism (Hofer
et al., 2002). Consequently, stabilizing HIF-1␣ would be a strategy
to promote further cytoprotective events. Some natural polyphe-
nols induce HIF-1␣ protein and lead to a further increase in mRNA
levels of HIF-1␣ target genes (Hanson et al., 1999; Hanson and
E.g. aurantinidin, cyanidin, delphinidin, europinidin, luteolinidin,
pelargonidin, malvidin, peonidin, petunidin, rosinidin, etc.
E.g. 3-hydroxyflavone, azaleatin, fisetin, galangin, gossypetin,
kaempferide, kaempferol, isorhamnetin, morin, myricetin,
natsudaidain, pachypodol, quercetin, rhamnazin, rhamnetin, etc.
E.g. apigenin, luteolin, tangeritin, chrysin, 6-hydroxyflavone, baicalein,
scutellarein, wogonin, diosmin, flavoxate, etc.
E.g. butin, eriodictyol, hesperetin, hesperidin, homoeriodictyol,
isosakuranetin, naringenin, naringin, pinocembrin, poncirin,
sakuranetin, sakuranin, sterubin, etc.
E.g. genistein, daidzein, lonchocarpane, laxiflorane, etc.
E.g. equol, etc.
E.g. catechin, epicatechin (EC), epigallocatechin (EGC), epicatechin
gallate (ECG), epigallocatechin gallate (EGCG), epiafzelechin,
fisetinidol, guibourtinidol, mesquitol, robinetinidol, etc.
E.g. theaflavins, thearubigins, condensed tannins, proanthocyanidins
etc.
E.g. p-coumaric acid, caffeic acid, chlorogenic acid, ferulic acid, sinapic
acid, etc.
E.g. gallic acid, gentisic acid, protocatechuic acid, syringic acid, vanillic
acid, etc.
E.g. pinoresinol, podophyllotoxin, steganacin, etc.
E.g. resveratrol analogs, etc.
Leibold, 1999; Hofer et al., 2002; Thomas and Kim, 2005; Wang
and Pantopoulos, 2005; Zhou et al., 2004). Catechins, like EGCG, are
a group of polyphenols which exert their neuroprotective effects
through induction of the HIF-1␣ pathway (Weinreb et al., 2007;
Zhou et al., 2004). Resveratrol is another non-flavonoid polyphenol
with significant antioxidant activity, activating the HIF-1␣ pathway
(Harikumar and Aggarwal, 2008).
However, there is also evidence of definite links between
hypoxia, HIF-1 activation and APP/A␤ production (Wang et al.,
2006b; Zhang et al., 2007a,b). The precise role of HIF-1 alpha path-
way in neurodegeneration, albeit positive or negative, is in fact a
matter of debate (Ogunshola and Antoniou, 2009). HIF-1␣ acts like
a double-edged sword that can be both beneficial and detrimental
to neural cell survival (Ogunshola and Antoniou, 2009).
On the other hand, there are contradictory reports on effects
of the same polyphenol on HIF-1␣ expression and activity. For
example, in one study EGCG has been shown to exert antioxidant
effects through HIF-1 pathway activation, while in another study an
inhibitory effect on the same pathway has been reported (Domingo
et al., 2010; Weinreb et al., 2007; Zhou et al., 2004). Similarly,
other polyphenols have been reported to exert antioxidant effects
through inhibition rather than activation of the HIF-1 pathway (Lu
et al., 2009; Terzuoli et al., 2010).
Therefore, claiming neuroprotective effects for polyphenols
based on HIF-1 pathway modulation in vitro is still a matter of
debate.
2.2. ROS regulation
Free oxygen radicals can damage cellular micro-organelles
directly and in this regard mitochondrial damage is of great impor-
tance to neurodegenerative diseases (Higuchi et al., 2003; Lin and
Beal, 2006). Oxygen radicals can also reduce free metal ions to active
radicals, like super oxide anions, which are responsible for reduc-
tion of ferric (Fe3+ ) to ferrous (Fe2+ ) through the Fenton reaction
(Higuchi et al., 2003).
Polyphenols scavenge superoxide and hydroxyl radicals, as
well as the 1,1-diphenyl-3-picrylhydrazyl radical, peroxyl radicals,
nitric oxide, carbon-center free radicals, singlet oxygen and lipid
free radicals, and peroxynitrite (Guo et al., 1996; Lin et al., 2003;
Morel et al., 1993; Nanjo et al., 1996; Pannala et al., 1997; Salah
et al., 1995; Spencer et al., 2001b; Zhao et al., 2001).
 A. Ebrahimi, H. Schluesener / Ageing Research Reviews 11 (2012) 329–345 331

Table 2
Antioxidant effects of polyphenols in in vivo and in vitro models of neurotoxicity and neurodegeneration.

Substance Studied cell line/animal model Effect References

Aloe-emodin N-methyl-d-aspartate • Elevates levels of RNA and protein Lin et al. (2007)
(NMDA)-induced toxicity in retinal expression of superoxide dismutase
ganglion cells (RGCs) (SOD)
• Attenuates NMDA-induced apoptosis
of RGCs
Curcumin N27 dopaminergic neurons • Protects against mitochondrial Mythri et al. (2011)
complex I inhibition (leading to
mitochondrial dysfunction) and NS
Curcumin Homocysteine-induced neurotoxicity • Reduces Malondialdehyde (MDA)a Ataie et al. (2010)
in rats and Superoxide anion levels
• Reduces lipid peroxidation
Improves learning and memory in rats
Curcumin N27 dopaminergic neuronal cell line • Increases glutathioneb (GSH) levels Harish et al. (2010)
Curcumin 3-Nitropropionic acid (3-NP)-induced • Improves the 3-NP-induced motor Kumar et al. (2007)
neurotoxicity in rats and cognitive impairment
• Attenuates 3-NP-induced OS
(including lipid peroxidation, reduced
GSH and nitrite activity)
• Restores the decreased succinate
dehydrogenasec activity
Epigallocatechingallat (EGCG) Glucose oxidase-induced neurotoxicity • Enhances cellular resistance to Romeo et al. (2009)
in H 19-7 (a rat neuronal cell line) glucose oxidase-mediated oxidative
damage
• Elevates heme oxygenase-1d (HO-1)
mRNA and protein expression
• Activates transcription factor Nrf2e
EGCG Glutamate-induced toxicity in HT22 • Reduces glutamate-induced Kang et al. (2010)
mouse hippocampus neuronal cells, oxidative cytotoxicity
Kainic acid-induced neurotoxicity in • Inactivates the NF-␬B signaling
rats pathwayf
• Reduces ROS accumulation and
NF-␬B transcriptional activity
EGCG Transient global cerebral ischemia • Reduces the development of delayed Park et al. (2009)
C57BL/6 in mice neuronal death after transient global
cerebral ischemia in mouse brain
EGCG Age-associated oxidative damage in rat • Amplifies the activities of enzymic Srividhya et al. (2008)
brain antioxidants like SOD, catalase,
glutathione peroxidase, glutathione
reductase and glucose-6-phosphate
dehydrogenase
• Improves the activity of non-enzymic
antioxidants like tocopherol, ascorbic
acid and glutathione
• Ameliorates the MDA and protein
carbonyl levels
EGCG Progressive neurotoxic model of • Decreases protein levels and mRNA Weinreb et al. (2007)
long-term serum deprivation in human expression of the beta subunit of the
SH-SY5Y neuroblastoma cells enzyme prolyl 4-hydroxylase
• Decreases protein levels of two
molecular chaperones that are
associated with HIF regulation, the
immunoglobulin-heavy-chain binding
protein and the heat shock protein 90
beta
EGCG SOD1-G93A transgenic mice (a model • Maintains the normal expression of Koh et al. (2006), Xu et al.
of ALS) p85a PI3-K, pAkt, and pGSK-3 (2006)
(molecular signals of survival)
• Reduces activation of NF-kB and the
cleaved form of caspase-3
• Reduces microglial activation
Prolongs the life span
• Delays the onset of symptoms
Mangiferin Glutamate-induced neurotoxicity in • Prevents neuronal death, oxidative Lemus-Molina et al. (2009)
rat cerebral cortex neurons stress and mitochondrial
depolarization
Mangiferin 1-Methyl-4-phenyl pyridinium • Restores the GSH content (to 60% of Amazzal et al. (2007)
(MPP(+))-induced oxidative stress in control levels), and down-regulates
the murine neuroblastoma cell line both SOD and catalase mRNA
N2A expression
• Quenches reactive oxygen
intermediates
Mangiferin Glutamate-induced neurotoxicity in • Reduces ROS formation Campos-Esparza et al.
Morin rat primary culture of neurons • Activates enzymatic antioxidant (2009)
system
• Restores mitochondrial membrane
potential
332 A. Ebrahimi, H. Schluesener / Ageing Research Reviews 11 (2012) 329–345

Table 2 (Continued )

Substance Studied cell line/animal model Effect References

Polyphenol-rich Hedeoma Biochemical assay on rat brain • Inhibits lipid peroxidation Dade et al. (2011)
multiflorum extract homogenates Scavenges
2,2 -diphenyl-1-picrylhydrazyl (DPPH)
radicals
Polyphenol-rich osmanthus Glutamate, arachidonic acid, and • Scavenges DPPH and hydroxyl anions Lee et al. (2007)
fragrans extract 6-hydroxydopamine-induced Inhibits lipid peroxidation
neurotoxicity in rat primary cortical
neurons
Red wine polyphenol Rat model of ischemic cerebral stroke • Prevent the burst of excitatory amino Ritz et al. (2008)
compounds acids in response to ischemia
• Reduce brain infarct volumes
• Enhance the residual cerebral blood
flow during occlusion and reperfusion
• Modulate expression of proteins
involved in the maintenance of
neuronal caliber and axon formation
Resveratrol Lipopolysaccaride (LPS)-induced • Reduces NADPHg oxidase-mediated Zhang et al. (2010)
dopaminergic neurodegeneration in rat generation of ROS
• Inhibits microglia activation
• Attenuates the activation of MAPK
and NF-␬B signaling pathways
• Implies neuroprotection against
LPS-induced dopaminergic
neurodegeneration
Resveratrol Glutamate-induced toxicity in mice • Induces heme oxygenase 1d (HO-1) in Sakata et al. (2010)
primary culture of neurons a dose- and time-dependent manner
Optimized ischemic-reperfusion stroke • Protects mouse neurons, subjected to
model in mice an optimized ischemic-reperfusion
stroke model
• Protects neurons against ecitotoxicity
Resveratrol 1-methyl-4-phenyl-1,2,3,6- • Protects from MPTP-induced motor Lu et al. (2008)
tetrahydropyridine (MPTP)- induced coordination impairment, hydroxyl
parkinson in mice radical overloading, and neuronal loss
• Scavenges free radicals
Resveratrol MPP(+)-induced neurotoxicity in • Prevents accumulation of ROS, Okawara et al. (2007)
dopaminergic neurons of midbrain depletion of cellular glutathione, and
slice culture cellular oxidative damage induced by
MPP(+)
• Activates sirtuin family of
NAD-dependent histone deacetylases
Resveratrol A-beta induced toxicity in neurons • Maintains normal expression of Manczak et al. (2010)
from a mouse model (Tg2576 line) and peroxiredoxins and mitochondrial
mouse neuroblastoma (N2a) cells structural genes
• Maintains normal mitochondrial
function
Tea polyphenol NMDA-induced neurotoxicity in mice • Attenuates the increased production Chen et al. (2008)
of synaptosomal ROS
• Reduces the deteriorative
ROS-sensitive Na(+), K(+)-ATPase and
Mg(2+)-ATPase activity
a
Malondialdehyde (MDA) is a highly reactive electrophile species that occurs naturally form degradation of polyunsaturated lipids and is a biomarker for measuring the
levels of OS.
b
Gluthation (GSH) is an antioxidant, preventing damage to important cellular components caused by ROS such as free radicals and peroxides.
c
Succinate dehydrogenase is a Complex II mitochondrial enzyme.
d
Heme oxygenase-1 (HO-1) is an enzyme that catalyzes the degradation of heme.
e
Transcription factor Nrf2 is a master regulator of the antioxidant response.
f
NF␬B signaling pathway is a pathway which is activated in response to cell stresses including OS.
g
NADPH is the reduced form of NADP+ , a coenzyme used in anabolic reactions, such as lipid and nucleic acid synthesis.

Amongst different polyphenols, EGCG has shown to be the most
efficient radical scavenger, even among its other counterparts like
ECG, EC and EGC (Guo et al., 1999; Nanjo et al., 1996, 1999). Strong
scavenging properties of EGCG are due to several hydroxyl groups
at the side rings of the chemical core (Guo et al., 1999; Nanjo et al.,
1996, 1999). Hydroxyl groups are especially important in biological
chemistry because of their tendency to form hydrogen bonds both
as donor and acceptor. In fact, polyphenols with hydroxyl groups
can act as strong reducing agents and vice versa.
Another important feature of some polyphenols is modulating
the activity of enzymes involved in OS. In this regard, previous stud-
ies have shown that EGCG can increase the activity of SOD and
catalase, two important antioxidant enzymes in the mouse stria-
tum (Levites et al., 2001). However, ROS generation is the final step
in many cell degeneration pathways and act as a non-specific rather
than specific neural damage mechanism. Although ROS regulation
can be mentioned as an additive mechanism of neuroprotection of
polyphenols, claiming a therapeutic effect for polyphenols via ROS
regulation as the only mechanism seems to be overdrawn.
2.3. Metal ion chelating
Polyphenols are also able to chelate metal ions, like copper (II)
and iron (III), to prevent free radical damage (Guo et al., 1999).
In this regard, some polyphenols have shown to be more efficient
than traditional antioxidants like Vitamin E and C (Nanjo et al.,
1996; Pannala et al., 1997). Studies have shown that some polyphe-
nols can inhibit lipid peroxidation in the brain (Guo et al., 1996;
 A. Ebrahimi, H. Schluesener / Ageing Research Reviews 11 (2012) 329–345 333

Table 3
Polyphenols with neuroprotective properties and their target cellular signaling pathways.

Substance Pathway References

Curcumin PI-3 K/MAPK signaling pathways Lin et al. (2011)

EGCG NF-␬B signaling pathway Kang et al. (2010), Kim et al. (2007)
EGCG Akt signaling pathways Chao et al. (2010)
EGCG HIF-1␣ pathway Weinreb et al. (2007)
EGCG Erk1/2 pathway Levites et al. (2002a), Weinreb et al. (2007)
EGCG PKC pathway Kalfon et al. (2007), Levites et al. (2003)
Fisetin ERK pathway Maher et al. (2011)
Fisetin NF-␬B signaling pathway Zheng et al. (2008)
GSE Erk1/2 pathway Kim et al. (2011), Min et al. (2010)
Huperzine A PKC pathway, MAPK pathway Peng et al. (2006), Peng et al. (2007)
Naringenin MAPK pathway Yang et al. (2011)
Resveratrol ERK pathway Maher et al. (2011)
Resveratrol NF-␬B signaling pathway Chen et al. (2005), Jang and Surh (2003), Zhang et al. (2010)
Resveratrol SIRT1- uncoupling protein 2 pathway Anekonda (2006), Anekonda and Reddy (2006), Della-Morte et al. (2009)
Resveratrol AMPK signaling pathway Dasgupta and Milbrandt (2007)
Resveratrol Nrf2/ARE antioxidant pathway Chen et al. (2005), Ghanim et al. (2011)
Resveratrol PKC pathway Han et al. (2004)
Resveratrol PI3K/AKT pathway Fukui et al. (2010)
Mangiferin, morin Erk1/2 pathway, Akt signaling pathway, NF-␬B signaling pathway Campos-Esparza et al. (2009)

Levites et al., 2002b). Polyphenols seem to exert this effect, through
chelating ferrous ions. For instance, EGCG attenuates paraquat-
induced microsomal lipid peroxidation and increases the survival
of paraquat-poisoned mice, a PD model, through this mechanism
(Higuchi et al., 2003; Ossowska et al., 2006).
The ability of polyphenols to chelate metal ions contributes to
their neuroprotective activity via inhibition of transition metal cat-
alyzed free radical formation. Two attachment sites for metal ions
have been suggested within the molecular structure of flavonols,
a subclass of polyphenols: The o-diphenolic groups in the 30, 40-
dihydroxy positions in the B ring, and the keto structure 4-keto,
3-hydroxy or 4-keto and 5-hydroxy in the C ring (Thompson et al.,
1976; van Acker et al., 1996). These functional groups bind tran-
sition metal ions, such as iron or copper (Rice-Evans et al., 1996).
With a closer look at the molecular structures, the same chemical
and molecular features can also be found in other polyphenol sub-
classes (Bors et al., 2001). Therefore, we can expect a broad range
of polyphenols with the ability to chelate metal ions.
2.4. Modulating cell signaling pathways
Several polyphenols have been shown to interact with cellu-
lar signaling pathways which are directly or indirectly involved
in neurodegeneration. Most of these pathways are, in fact, sig-
naling pathways involved in cell survival and programmed cell
death. In this respect, polyphenols have been reported to act at
phosphoinositide 3-kinase (PI 3K), Akt/protein kinase B (Akt/PKB),
tyrosine kinases, protein kinase C (PKC), and mitogen activated pro-
tein kinase (MAPK) signaling cascades (Table 3) (Williams et al.,
2004). They affect cellular function by altering the phosphoryla-
tion mode and expression level of targeted molecules within the
mentioned pathways.
The flavonoid superfamily of polyphenols has the potential to
bind to the ATP-binding sites of a large number of proteins of cel-
lular signaling pathways, including mitochondrial ATPase, calcium
plasma membrane ATPase, protein kinase A, protein kinase C and
topoisomerase (Barzilai and Rahamimoff, 1983; Boege et al., 1996;
Conseil et al., 1998; Di Pietro et al., 1975; Kantengwa and Polla,
1991; Revuelta et al., 1997; Rosenblat et al., 1999; Ursini et al.,
1994), as well as to benzodiazapine binding sites of GABA-A recep-
tors and adenosine receptors (Dekermendjian et al., 1999; Medina
et al., 1997). Resveratrol and the citrus flavanones, hesperetin and
naringenin inhibit the activity of a number of protein kinases (Pallas
et al., 2009; Sabarinathan et al., 2011; Vauzour et al., 2007).
PKC over-expression has been shown to reduce amyloid
plaque formation and A␤ levels in human APP transgenic mice
(Etcheberrigaray et al., 2004). There is strong evidence, that PKC
signaling pathways regulate important molecular events involved
in associative memory storage, and signaling deficits of PKC sig-
naling pathways play an important role in the pathophysiology of
neurodegenerative disorders like AD (Alkon et al., 2007; Mattson,
1991). EGCG, huperzine A and resveratrol have shown to interact
with PKC signaling pathway (Table 3).
The MAPK signaling pathway is a general target of flavonoids,
notably in the nervous system in the context of oxidative insults
(Williams et al., 2004). ERK1/2 and c-jun amino-terminal kinase
(JNK), two important components of MAPK signaling pathway, are
involved in various forms of cellular plasticity, such as differentia-
tion and apoptosis (Mielke and Herdegen, 2000; Yuan and Yankner,
2000).
The phosphatidylinositol 3 kinase (PI3K)-Akt/PKB pathway has
a pivotal role in neuronal survival (Rodgers and Theibert, 2002).
Activation of Akt/PKB in neurons leads to the inhibition of central
proteins of the cell death machinery, such as the proapoptotic Bcl-2
family member BAD and members of the caspase family (Bonni
et al., 1999; Datta et al., 1999; Zha et al., 1996). Akt1, an effec-
tor molecule of (PI3K)-Akt/PKB pathway, has also been shown to
attenuate the apoptotic effect of Abeta (25–35) (Martin et al., 2001).
Quercetin, has been shown to exert inhibitory activity on (PI3K)-
Akt/PKB pathway through inhibiting PI 3K (Spencer et al., 2003).
However, a large number of protein kinases, important medi-
ators of different cell signaling pathways, have been reported as
being potential targets of different polyphenols (Williams et al.,
2004). Therefore, we have an apparent lack of selectivity of action
for polyphenols in this respect. This might arise from the fact that
many studies reporting the interactions of polyphenols with cell
signaling pathways have not defined the primary cellular site of
action of the studied polyphenol.
3. Polyphenol’s anti-acetycholinesterase activity
The concept of cholinergic system deficit in neurodegeneration
and its important role in cognition was proposed nearly 30 years
ago (Perry et al., 1978). Loss of cholinergic activity, atrophy of the
nucleus basalis of Meynert as the major source of acetylcholine,
and loss of cortically projecting cholinergic neurons, along with
increasing cognitive deficits, are some of notable findings in differ-
ent neurodegenerative diseases, like Alzheimer’s and Parkinson’s
334 A. Ebrahimi, H. Schluesener / Ageing Research Reviews 11 (2012) 329–345
diseases (Bohnen et al., 2005; Davis et al., 1999; Hanyu et al., 2002;
Klein et al., 2010; Lahiri et al., 2004; Rosengarten et al., 2010;
Teipel et al., 2005; Whitehouse, 1998). Cholinergic dysfunction
in neurodegenerative diseases can be the result of reduction in
Ach synthesis due to reduced choline acetyltransferase (ChAT) or
choline uptake, cholinergic neuronal and axonal abnormalities, and
degeneration of cholinergic neurons (Fisher, 2008). Accordingly,
using acetylcholinesterase inhibitors, which exert their efficacy
through stimulation of both muscarinic and nicotinic acetylcholine
receptors (mAChR and nAChR), has been a proper therapeutic
approach to alleviate the cognitive symptoms of neurodegenerative
diseases (Lahiri et al., 2004; Larner, 2010; Rosengarten et al., 2010).
There are two distinct receptor subtypes in the brain for Ach: nico-
tinic and muscarinic. nAChRs are mainly ligand-gated ion channels,
while mAChRs are metabotropic receptors. Muscarinic receptors
include five distinct receptor subtypes (M1–M5). M1 mAChR is the
most abundant subtype in cerebral cortex and hippocampus, the
most sensitive brain areas to the development of amyloid plaques
and neurofibrilary tangles (Levey et al., 1991; Wei et al., 1994).
Several natural polyphenols have shown cholinesterase
inhibitory effect (Zhang et al., 2009). In most in vivo studies,
the anticholinergic activity of polyphenol was accompanied by
improvement of cognitive functions, like learning and memory
(Coma et al., 2010; Huang and Zhang, 2010; Kim et al., 2004;
Liu et al., 2010; Papandreou et al., 2009; Tota et al., 2010). How-
ever, the exact mechanism of interaction of polyphenols with
the cholinergic system is still not clear. EGCG has shown strong
anti-acetylcholinesterase activity (Zhang et al., 2009). In another
study, EGCG has been reported to modulate nAChR signaling
pathway through down regulation of ␣9-nAChR expression as
well as inhibition of (3H)-Nic/␣9-nAChR binding activity (Tu et al.,
2011). Resveratrol has shown in a study to block acetylcholine
release from adrenal chromaffin cells (Chang-Mu et al., 2010).
Some polyphenols such as huperzine A, quercetin, kuwanon U,
E, and C, kaempferol, tri- and tetrahydroxyflavone, etc. have
shown anti-butyrylcholinesterase effects in addition to their
anti-cholinesterase activity (Kim et al., 2011; Min et al., 2010; Tota
et al., 2010; Wang et al., 2011, 2010c, 2001; Zhang et al., 2009).
Huperzine A has shown the most promising effects in this
respect (Wang et al., 2011, 2010c, 2001; Zhang et al., 2009). Studies
have shown that huperzine A is highly specific for AChE (Zangara,
2003). The richest natural source of huperzine A is the plant
Huperzia serrata, a fascinating fungal reservoir of other AChEIs as
well (Wang et al., 2010d; Zhu et al., 2010). The drug is a potent,
reversible and selective inhibitor of acetylcholinesterase and its
potency is similar or superior to other AChEIs (Wang and Tang,
2005; Zangara, 2003). Huperzine A has shown a rival potency in
AChE inhibition over drugs, like tacrine, galanthamine, and rivastig-
mine, which are currently being used in the treatment of AD
patients (Liang and Tang, 2004; Ogura et al., 2000; Wang and
Tang, 1998a,b; Wang et al., 2006a, 1986; Zhao and Tang, 2002).
Huperzine A has the highest AChE inhibitory (AChEI) activity (IC50)
after donepezil, while tacrine, physostigmine, galantamine, and
rivastigmine were less potent (Ma et al., 2007). Compared to the
other AChE inhibitors, huperzine A has also shown better penetra-
tion through the blood–brain barrier, higher oral bioavailability,
and longer duration of AChEI activity (Wang et al., 2006a). The
mechanism of action of this drug has still not been clearly defined.
In silico studies have shown a direct binding of huperzine A to
acetylcholinesterase (Kitisripanya et al., 2011). Clinical trials with
huperzine A, for treatment of cognitive and functional impairments
of AD and schizophrenia and the increase in memory performance
of normal individuals, have been promising (Sun et al., 1999; Xu
et al., 1999, 1995; Zhang et al., 2002, 2007c). In China, huperzine A
has been studied in phase IV clinical trials and revealed a signifi-
cant improvement of memory of elderly people, patients with AD
and patients with vascular dementia (Xu et al., 1999, 1995; Zhang
et al., 2002). Several meta-analyses have shown that administra-
tion of huperzine A for at least 8 weeks might lead to a significant
improvement in cognitive function, mood, behavior and daily activ-
ity of patients with AD. Most of its side effects are cholinergic in
nature and are generally mild and of brief duration (Li et al., 2008;
Man et al., 2008; Wang et al., 2009a). Combinatorial regimens with
other selective AChE inhibitors have shown even more promising
results (Camps and Munoz-Torrero, 2001; Wang et al., 2003; Zhang
et al., 2007c). Huperzine A has also butyrylcholinesterase inhibitory
activity which is not as promising as the anti-AChE activity (Ogura
et al., 2000).
Not all polyphenols have an anti-cholinesterase activity. Some
of them have a reverse effect. For example, caffeic acid increases
AchE activity and expression (Rezg et al., 2008).
4. Polyphenols and protective effects against NMDA
neurotoxicity
The role of NMDA neurotoxicity and glutamate excitotoxicity
in neurodegenerative diseases like Huntington’s disease (HD), AD
and even in cognitive impairment associated with aging has been
confirmed many years ago (Choi et al., 1990; Fan and Raymond,
2007; Rosi et al., 2004; Waxman and Lynch, 2005). Excessive acti-
vation of NMDA receptors induces the production of damaging
free radicals (e.g., NO and ROS) and other enzymatic processes
that contribute to neuronal damage and cell death (Bonfoco et al.,
1995; Budd et al., 2000; Dawson et al., 1991; Lafon-Cazal et al.,
1993; Lipton et al., 1993; Lipton and Rosenberg, 1994). Therefore,
blocking the NMDA pathway has been a therapeutic strategy for
cognitive impairment not only in neurodegenerative diseases but
also in psychiatric disorders with cognitive dysfunction (Lipton,
2007; Shim et al., 2008). There is strong evidence of protective
effects of several natural polyphenols against NMDA neurotoxic-
ity (Table 4) (Chang-Mu et al., 2010; Davis et al., 1999; Shim et al.,
2008; Yazawa et al., 2006; Zhang et al., 2008). Polyphenols, act at
different locations within the NMDA pathway. (Fig. 1).
In most of these studies, a protective effect against NMDA exci-
totoxicity has been reported. However, the mechanism of such
protection has not been clearly addressed. A few in vitro studies
reported a reduction in frequency and amplitude of AMPA/NMDA
receptor mediated spontaneous excitatory postsynaptic currents
(sEPSCs) in pyramidal neurons. But it remains unclear, whether
this is the result of polyphenols’ antioxidant activity or their direct
NMDA receptor blocking effect (Gao et al., 2006; Yazawa et al.,
2006; Zhang et al., 2008).
5. Polyphenols and amyloidopathies
Tau hyperphosphorylation and beta amyloid accumulation are
believed to be the core pathologies of tauopathies and amy-
loidopathies (Iqbal et al., 2010; Kawahara and Kuroda, 2000;
Kawahara et al., 2000). Excessive A␤ accumulation can be the result
of either increased production or decreased clearance, which in
both situations is toxic to the cells (Selkoe, 2001). A␤ aggregation
leads to the formation of senile plaques (SP) and stimulates a series
of biological signaling pathways which leads to an impairment
of neuronal synapses and dendrites through oxidative stress and
inflammatory responses (Heneka and O‘Banion, 2007; Roberson
and Mucke, 2006). Beside SP and A␤ aggregation, neurofibrilary
tangles (NFTs), consisting of abnormally hyperphosphorylated tau
protein, are another pathologic hallmark of Alzheimer’s disease
(Iqbal et al., 2009; Wallin et al., 2006). For a long time, these two
pathological features have been the major therapeutic targets for
drug development in tau-amyloidopathies. Polyphenols exert their
 A. Ebrahimi, H. Schluesener / Ageing Research Reviews 11 (2012) 329–345 335

Table 4
Recent studies on protective effects of polyphenols against NMDA neurotoxicity.

Substance Cell line/animal model Effect References

Catechin, curcumin, tannic Rat NMDA neurotoxicity model, primary • Inhibits glutamate-induced excitotoxicity Yazawa et al.
acid culture of neurons • Inhibits PKC activity, and subsequent phosphorylation of NR1 of (2006)
the NMDA receptor
• Reduces glutamate-mediated Ca2+ influx
Inhibits glutamate-induced caspase-3 activation
• Reduces glutamate-induced ROS generation
EGCG Unilateral cerebral ischemia in gerbils • Reduces excitotoxin-induced MDA production and neuronal Lee et al. (2004)
damage
• Attenuates the increase in MDA level caused by cerebral ischemia
• Reduces the formation of postischemic brain edema and infarct
volume
Honokiol Mice NMDA toxicity model • Ameliorates behavioral and neurotoxic effects of NMDA Chang-Mu
• Reduces seizure occurrence, score, and latency et al. (2010)
• Decreases ROS production
Resveratrol Acute oxygen-glucose deprivation (OGD) • Reduces the frequency and amplitude of Zhang et al.
model in rat hippocampus slices 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid (2008)
(AMPA)-mediated sEPSCs in pyramidal neurons
• Attenuates OGD-induced neuronal impairment
• Reduces the OGD-enhanced AMPA/NMDA receptor mediated
neuronal EPSCs
Tea polyphenol Mice NMDA toxicity model • Ameliorates behavioral and neurotoxic effects of NMDA Chang-Mu
• Reduces seizure occurrence, score, and latency et al. (2010)
• Decreases ROS production
Trans-resveratrol CA1 region of rat hippocampus slices with • Suppresses glutamate-induced currents in postsynaptic CA1 Gao et al.
NMDA toxicity model pyramidal neurons (2006)
• Inhibits postsynaptic glutamate receptors
Morin, mangiferin Glutamate-induced neurotoxicity in rat • Protects cortical neurons from excitotoxic death Campos-
primary culture of neurons • Reduces ROS levels and maintains the homeostasis of the Esparza et al.
enzymatic antioxidant system after excitotoxic event (2009)
• Inhibits glutamate-induced calpain activity
• Regulates the release of pro-apoptotic proteins implicated in
caspase-dependent and -independent apoptotic neuronal death
• Modulates the activity of the Akt and Erk1/2 kinases after
excitotoxic events
• Prevents the activation of NF-␬B and its subsequent translocation
to the nucleus

effect through, modulation of ␣-, ␤- and ␥-secretases, inhibition of

Fig. 1. A schematic illustration of NMDA pathway and polyphenol targets within
pathway. Polyphenols interact with the NMDA pathway through inhibitory activ-
ity on various molecular targets. Catechin has shown to be an effective inhibitor
of caspase 3 (Yazawa et al., 2006). NMDA-induced intracellular Ca2+ accumulation
can activate caspase 3, contributing to ROS generation and neural damage (Zeng
et al., 2010). Polyphenols, such as morin, tannic acid, magniferin and resveratrol
affect glutamate-mediated Ca2+ influx (Yazawa et al., 2006). Catechin can eliminate
glutamate-induced toxicity by reducing ROS generation and further neural degen-
eration. Catechin is also able to inhibit PKC activity (Yazawa et al., 2006). Curcumin
and tannic acid are two polyphenols reducing glutamate induced excitotoxicity by
inhibiting PKC activity and subsequent phosphorylation of NR1 of the NMDA recep-
tor, thereby reducing glutamate induced Ca2+ influx (Yazawa et al., 2006). EGCG
has been shown to interact with the NMDA pathway in unilateral cerebral ischemic
gerbils by attenuating ischemia-induced MDA elevation (Lee et al., 2004). Morin
and magniferin are able to inhibit calpain activity and further cell degeneration
(Campos-Esparza et al., 2009).
A␤ oligomer formation, inhibition of A␤-induced neurotoxicity and
inhibition of A␤-induced neuroinflammation (Fig. 2).
Several natural polyphenols, have effectively reduced A␤ depo-
sition and A␤ protein concentrations in brain and serum, among
which EGCG has shown the most promising anti-amyloidogenic
effects (Table 5) (Ray et al., 2011; Vislocky and Fernandez, 2010).
Many studies have shown a direct binding of polyphenols to beta
sheet structures (Benaki et al., 2009; Bieschke et al., 2010; Hafner-
Bratkovic et al., 2008; Huang and Zhang, 2010). ECGC induces
␣-secretase cleavage activity and inhibit ␤- and ␥-secretases (Lee
et al., 2009; Obregon et al., 2006). Several other polyphenols reduce
A␤ levels through direct or indirect modulatory effects on ␣, ␤, and
␥-secretases (Table 5). Myricetin, quercetin, kaempherol, morin,
and apigenin directly inhibit ␤-secretase activity in a concentration
dependent manner (Shimmyo et al., 2008a). Some of these com-
pounds, like Dihydroguaiaretic acid (NDGA), GSE, tannic acid and
wine related polyphenols, affect beta aggregates and destabilize
preformed A␤, while some others affect A␤ (1–40) and A␤ (1–42)
and inhibit polymerization and fA␤ formation (Table 5) (Fig. 2).
6. Barrels and barricades in polyphenol research
The broad accessibility of polyphenols as a component of daily
dietary intake has always raised the question regarding the preva-
lence and incidence of neurodegenerative diseases in populations
with high polyphenol daily dietary intake, like Chinese populations
(Checkoway et al., 2002; Ng et al., 2008; Commenges et al., 2000;
Dai et al., 2006). Although some epidemiological studies suggest a
negative correlation of the amount of daily polyphenol consump-
tion and the incidence of neurodegenrative disorders, the number
336 A. Ebrahimi, H. Schluesener / Ageing Research Reviews 11 (2012) 329–345

Fig. 2. A schematic illustration of amyloidogenic and non-amyloidogenic pathways. Polyphenols exert their effect at different sites within the amyloidogenic pathway.
Basically, there are two pathways through which APP can be cleaved. Depending on the enzyme which cleaves the APP, the final product can be amyloidogenic or non-
amyloidogenic (Nunan and Small, 2000). In the non-amyloidogenic pathway, APP is cleaved by the membrane-bound enzyme ␣-secretase within its A␤ domain, resulting
in secretion of extracellular soluble sAPP␣ fragments and a short membrane-bound COOH-terminal fragment, ␣-CTF or C83, which is cleaved by ␥-secretase to p3, a 3-kDa
peptide, whereas APP intracellular domain (AICD) is secreted into the cytoplasm (Cao and Sudhof, 2004; Esch et al., 1990). Within the amyloidogenic pathway, APP cleavage
by beta-site APP-cleaving enzyme1 (BACE-1, ␤-secretase) and ␥-secretase leads to extracellular sAPP␤ fragments and the membrane bound ␤-C-Terminal Fragment (␤-CTF)
or C99 fragment, which is subsequently cleaved by ␥-secretase at the C-terminal part of the A␤ domain. This leads to the release of APP into the intracellular domain (AICD)
and secretion of A␤ into the extracellular spaces (Selkoe, 1998, 2001; Tanzi and Bertram, 2005). Excessive production of A␤ or decreased A␤ clearance in the later pathway
leads to the accumulation and aggregation of A␤, which is toxic to cells. Therefore, inhibition of either ␤ or ␥-secretases or stimulation of ␣-secretase has been a therapeutic
target in amyloidopathies (Nunan and Small, 2000). The polyphenol targets within pathway are indicated by * and a representative compound has been mentioned for each
target. For more polyphenols that can affect the pathway, please refer to Table 5. N: nucleus, G: Golgi apparatus, ER: endoplasmic reticulum.

of such studies are still too small and other confounding variables
need to be considered to make a realistic conclusion (Weinreb et al.,
2009). The accurate and exact polyphenol intake has also never
been investigated or reported in these epidemiological studies. In
fact, it is extremely difficult to quantify the health effects of nat-
ural polyphenols as part of dietary intake, regarding their great
diversity in foods, the limited information about their quantity and
metabolism, the interacting effect of foods’ chemicals on each other
and the presence of too many potential other bioactive compounds
(Spencer et al., 2008).
However, there are also many of in vivo and in vitro studies on
neuroprotective effects of polyphenols. Within the last decade, sig-
nificant short course human interventions have been performed
in order to confirm the bio-efficacy of different polyphenol sub-
classes (Kennedy et al., 2010; Krikorian et al., 2010). However, they
mostly failed to show a validated neuroprotective effect for the
studied polyphenols. The poor outcome of these studied might be
due to several factors including the lack of standardized biomark-
ers of intake, using non-purified compounds, lack of long term
efficacy investigations, lack of standards for an effective dose and
blood level, and lack of knowledge of pharmacokinetics (Kay, 2010).
Moreover, there is still a lack of a complete understanding of intake,
absorption, metabolism and excretion of polyphenols. Therefore
the validity of many in vivo and in vitro experiments performed
on neuroprotective effects of polyphenolic compounds are still a
matter of debate.
The discussed health effects of natural polyphenols depend on
their bioavailability.
Not all natural polyphenols are absorbable through ingestion.
Glycon forms of polyphenols can be absorbed from the small intes-
tine. Most of the natural polyphenols are in the form of ester, glyco-
sides or polymers which are poorly absorbed via the gastrointesti-
nal tract (GI), highly metabolized, and rapidly eliminated from the
body (Scalbert and Williamson, 2000; Singh et al., 2008; Thompson
et al., 1976). Proanthocyanidins are virtually not absorbed in the gut
because of their high molecular weight and hydrosolubility (Deprez
et al., 2001; Donovan et al., 2002; Holt et al., 2002; Manach et al.,
2005). Except catechins and proanthocyanidins, polyphenols are
mostly glycosylated in food, and glycosylation influences absorp-
tion of some of these polyphenols through the gut barrier (Hollman
et al., 1995; Morand et al., 2000; Scalbert and Williamson, 2000).
For catechins, intestinal absorption can be influenced by esterifica-
tion with gallic acid. The recovery of galloylated catechins in human
urine after black tea consumption has been reported 10-fold lower
than that of non-galloylated catechins (Warden et al., 2001).
In addition, polyphenols that are absorbed via GI are extensively
metabolized through the first-pass effect (Scalbert et al., 2002).
Most dietary polyphenols are quickly eliminated in both urine and
bile after ingestion and they undergo phase I and II liver metabolism
(Lin et al., 2003; Possemiers et al., 2011). In human subjects, a
post-prandial peak 1–2 h after ingestion of various flavonols and
flavanols has been reported but this plasma concentration peak
is achieved after a longer time course for isoflavones and other
polyphenols (Scalbert and Williamson, 2000). For some polyphe-
nols, the plasma concentrations decline rapidly within 1–2 h, which
shows a rapid metabolism and elimination. To maintain a high con-
centration of these polyphenols in plasma, a repeated ingestion of
them is required (Scalbert and Williamson, 2000; van het Hof et al.,
1999).
In the context of anti-oxidant activity, some polyphenols, like
EGCG and grape seed polyphenol extract (GSE), exert their effect
locally in the intestine by blocking iron transport across the basolat-
eral membrane of the enterocyte (Kim et al., 2008; Ma et al., 2010),
but polyphenols mainly exert their anti-oxidant effect in the body
through their metabolites. Metabolic modifications of polyphenols
have been reported in many studies to alter their antioxidant nature
 A. Ebrahimi, H. Schluesener / Ageing Research Reviews 11 (2012) 329–345
Table 5
Polyphenols with protective effect against beta amyloidopathy and protein aggregation.
Substance Studied cell line/animal model
Alvidin Biochemical assay (UV–visible
measurements)
Blueberry polyphenolic Primary hippocampal neurons, LPS,
fractions dopamine (DA) or A␤ (42)-induced
deficits in Ca2+ recovery (CAR)
Curcumin Brain sections of variant
Creutzfeldt–Jakob disease cases
Curcumin APP/PS1 transgenic mice model of
AD)
Dihydroguaiaretic acid Biochemical assay (fluorescence
(NDGA) spectroscopic analysis)
EGCG Yeast prion protein Sup35
Biochemical assay
EGCG Biochemical assay
EGCG Biochemical assay (a generic model
of fibril formation by protein,
reduced and carboxymethylated
kappa-casein (RCM kappa-CN))
EGCG Biochemical assay
EGCG Inflammatory response induced by
interleukin (IL)-1␤ and A␤ (25–35)
in human astrocytoma, U373MG
cells
EGCG Wild type N2 (Bristol), transgenic
mutant strain daf-16 (mgDf50),
and transgenic A␤ muscle
expressing strain of C. elegans
(behavioral and biochemical
analysis)
EGCG N2a cells stably transfected with
“Swedish” mutant human APP
(SweAPP N2a cells)
EGCG Human SH-SY5Y neuroblastoma
cells, Chinese hamster ovary cells
(CHO) overexpressing “Swedish”
mutant human APP
EGCG Human SH-SY5Y neuroblastoma,
rat pheochromocytoma PC12 cells,
C57/BL mice
EGCG Cultured hippocampal neurons
exposed to A␤
EGCG MPTP- and DA-induced
neurodegeneration in mice and
rats
337
Effect References
• Implies anti-amyloidogenic effects against whole A␤ Riviere et al. (2008)
peptides (1–40 and 1–42)
• Antagonizes LPS, DA- or A␤ (42)-induced deficits in CAR Joseph et al. (2010)
in primary hippocampus neuronal cells
• Inhibits in vitro conversion of prion protein (PrP)a and Hafner-Bratkovic
formation of protease resistant PrP et al. (2008)
• Binds to the alpha-helical intermediate of PrP
• Binds to the native form of PrP
• Reduces A␤ levels in the brain and serum of mice Wang et al. (2009b)
• Reduces amyloid plaques and microgliosis in the brain of
transgenic mice
• Reduces brain A␤ burden and microglia activation
• Inhibits A␤ fibril (fA␤)b formation and extension from A␤ Ono et al. (2004)
(1–40) and A␤ (1–42)
• Destabilizes preformed fA␤ (1–40) and fA␤ (1–42)
• Inhibits the formation of aggregating amyloid forms Duennwald and
(prions) of Sup35 Shorter (2010)
• Remodels preassembled prions
• Binds directly to beta-sheet-rich aggregates and Bieschke et al.
mediates the conformational change without their (2010)
disassembly into monomers or small diffusible oligomers
• Converts large, mature alpha-synuclein and A␤ fibrils
into smaller, amorphous protein aggregates that are
nontoxic to mammalian cells
• Inhibits in vitro fibril formation by RCM kappa-CN Hudson et al.
• Inhibits amyloid-fibril formation (2009)
• Inhibits the fibrillogenesis of both alpha-synuclein and Ehrnhoefer et al.
A␤ (2008)
• Binds directly to unfolded polypeptides and preventing
their conversion into toxic aggregation intermediates
• Promotes the formation of unstructured, nontoxic
alpha-synuclein and A␤ oligomers of a new type
• Inhibits IL-6, IL-8, VEGF and PGE2 Kim et al. (2007)
• Attenuates cyclooxygenase-2 expression and activation
of NF-␬B induced by IL-1␤ and A␤ (25–35)
• Suppresses IL-1␤ and A␤ (25–35)-induced
phosphorylation of the mitogen-activated protein kinase
p38 and the c-Jun N-terminal kinase, two protein
mediators of MAPK signaling pathway
• Induces mitogen-activated protein kinase phosphatase-1
expression
• Attenuates hydrogen peroxide levels Brown et al. (2006)
• Attenuates age-related behavioral decline
• Alleviates an A␤-induced pathological behavior
• Elevates active ADAM10 protein Obregon et al.
• Increases APP␣ cleavage (2006)
• Increases ␣-secretase cleavage activity
• Produces no significant alteration in ␤-or ␥-secretase
activities
• Elevates soluble sAPP␣
• Shows potent iron-chelating activity Reznichenko et al.
• Increases transferrin receptor TfR protein and mRNA (2006)
levels
• Reduces immature and full-length cellular holo-APP
• Reduces toxic A␤ peptide generation in Chinese hamster
ovary cells overexpressing the “Swedish” mutant human
APP
• Increases PKC␣ and PKC in the membrane and the Levites et al. (2003)
cytosolic fractions of mice hippocampus
• Enhances the release of non-amyloidogenic sAPP␣
• Decreases membrane-bound holo-APP levels, with a
concomitant increase in sAPP␣ levels in the hippocampus
• Increases cell survival Choi et al. (2001)
• Decreases caspase activity
• Employs neuroprotection through scavenging ROS
• Prevents the accumulation of iron and ␣-synuclein in the Mandel et al.
substantia nigra (2004a)
338 A. Ebrahimi, H. Schluesener / Ageing Research Reviews 11 (2012) 329–345

Table 5 (Continued )

Substance Studied cell line/animal model Effect References

EGCG Yeast model of HD, Transgenic HD • Inhibits mutant htt exon 1 protein aggregation Ehrnhoefer et al.
flies overexpressing a pathogenic • Modulates misfolding and oligomerization of mutant htt (2006)
Huntingtin gene (htt) exon 1 exon 1 protein
protein • Reduces polyQ-mediated htt-protein aggregation and
cytotoxicity in yeast model of HD
• Ameliorates photoreceptor degeneration and motor
function in flies
EGCG Biochemical assay • Binds to beta-sheet-rich aggregates and mediates the Bieschke et al.
conformational change without their disassembly into (2010)
monomers or small diffusible oligomers
• Converts large, mature alpha-synuclein and A␤ fibrils into
smaller, nontoxic amorphous aggregates
EGCG Human SH-SY5Y neuroblastoma • Reduces the levels of cellular holo- APP in SH-SY5Y cells Avramovich-Tirosh
cells (serum deprivation model), • Reduces levels of toxic A␤ peptides in CHO cells et al. (2007)
CHO cells overexpressing over-expressing the APP “Swedish” mutation
“Swedish” mutant human APP • Reduces the pro-apoptotic proteins, Bad and Bax
• Inhibits the cleavage and activation of caspase-3
• Improves neuronal differentiation
EGCG N2a cells stably transfected with • Promotes non-amyloidogenic processing of APP Smith et al. (2010)
“Swedish” mutant human APP • Upregulates ␣-secretase
(SweAPP N2a cells)
EGCG PS2 transgenic mice model of AD • Enhances memory function Lee et al. (2009)
• Induces brain alpha-secretase activity
• Reduces brain beta- and gamma-secretase activities
Ellagic acid Biochemical assay • Inhibits beta-secretase (BACE1) activity Kwak et al. (2005)
Exifone Biochemical assay • Inhibits heparin-induced tau filament formation Taniguchi et al.
• Inhibits the formation of A␤ fibrils (2005)
GSE Tg2576 transgenic mice model of • Inhibits A␤ protein aggregation Guo et al. (2010)
AD • Attenuates AD-type cognitive deterioration along with
reducing HMW soluble oligomeric A␤ in the brain
GSE Transgenic HD PC-12 cells, • Inhibits polyQ aggregation Wang et al. (2010a)
transgenic HD model drosophila, • Improves life span
R6/2 rodent model of HD • Attenuates motor skill decay
GSE TMHT transgenic mice model of • Induces unfolding of tau and diminishes structural stability Ksiezak-Reding
tauopathy • Neutralizes phospho-epitopes and disrupts fibrillary et al. (2010), Wang
conformation leading to disintegration of paired helical et al. (2010b)
filaments (PHFs)c
• Attenuates AD type tau neuropathology development in
brain
• Attenuates extracellular signal-receptor kinase 1/2
signaling in the brain.
GSE APP/PS1 transgenic mice model of • Reduces A␤ levels in the brain and serum of the mice Wang et al. (2009b)
AD • Reduces amyloid plaques and microgliosis in the brain of
transgenic mice
• Reduces brain A␤ burden and microglia activation
Green tea polyphenol Mice model of AD induced by • Ameliorates deleterious effects of d-galactose and A␤ Lu et al. (2006)
d-galactose and A␤ (25–35) (25–35)
(behavioral study) • Improves animal’s learning and memory
• Reduces prolonged latency time and the error numbers
• Increases the autonomic activities
Myricetin Biochemical assay • Inhibits fA␤ formation from A␤ Ono et al. (2003)
Destabilizes preformed fA␤
Myricetin A␤-induced neurotoxicity in rat • Reduces apoptotic changes and caspase-3 activation Shimmyo et al.
primary neuronal cells • Decreases A beta 1–40 and A beta 1–42 levels in culture (2008b)
media
• Activates and up-regulates alpha-secretase (ADAM10)
protein levels
• Directly binds and inhibits beta-secretase (BACE-1)
Myricetin In silico study • Directly binds and inhibits beta-secretase (BACE-1) Chakraborty et al.
(2011)
Oligonol A␤-induced oxidative cell death on • Attenuates A␤-induced cytotoxicity, apoptotic features, Li et al. (2004)
rat pheochromocytoma cells intracellular ROS accumulation, and lipid peroxidation
(PC12) • Increases cellular glutathione pool
• Suppresses A␤-induced activation of NF-␬B
Piceid Biochemical assay • Destabilizes A␤ fibrils and oligomers back to monomers Riviere et al.
• Inhibits A␤ polymerization (2009), Riviere
et al. (2007)
Phenolsulfon-phthalein Biochemical assay • Inhibits amyloid fibril formation by islet amyloid Levy et al. (2008)
polypeptide (IAPP)
Resveratrol HEK293 and N2a cells stably • Increases cytosolic calcium levels and promotes AMPK Vingtdeux et al.
transfected with human APP695, activation by the calcium/calmodulin-dependent protein (2010)
APP/PS1 transgenic mice model of kinase kinase-beta
AD • Loweres extracellular A␤ accumulation
• Inhibits AMPK target, mTOR, to trigger autophagy and
lysosomal degradation of A␤
• Activates AMPK and reduces cerebral A␤ levels and
deposition in cortex
 A. Ebrahimi, H. Schluesener / Ageing Research Reviews 11 (2012) 329–345
Table 5 (Continued )
Substance Studied cell line/animal model
Resveratrol Tg19959 transgenic mice model of
AD
Resveratrol Biochemical assay
Resveratrol HEK293 cells stably transfected
with human APP695 (a cell model
of AD)
Resveratrol A␤-induced neurotoxicity in
SH-SY5Y neuroblastoma cells,
biochemical assay
Resveratrol Biochemical assay
Salvianolic acid B A␤ (25–35) mediated injury of
PC-12 cells
Tannic acid Biochemical assay
Wine-related polyphenols Biochemical assay
a
Prion protein (PrP), in misfolded form, produces transmissible spongiform encephalopathies including bovine spongiform encephalopathy (BSE, also known as “mad cow
disease”) in cattle and Creutzfeldt–Jakob disease (CJD) in humans.
b
Poly Q or polyglutamine is a polypeptide induced by trinucleotide repeat expansion important in trinucleotide repeat disorders like HD.
c
PHFs or paired helical filaments are aggregations of hyperphosphorylated tau protein.
so that their metabolites are less effective scavengers and antioxi-
dants than the original substances (Miyake et al., 2000; Shirai et al.,
2001; Terao et al., 2001; Yamamoto et al., 1999). Glucuronides and
O-methylated forms and intracellular metabolites of flavonoids for
example, have shown a reduced ability to donate hydrogen and less
effective scavenging capacity (Spencer et al., 2001a). Moreover, the
capacity of polyphenol molecules for metal ion scavenging is lim-
ited and usually high concentrations of a polyphenol are needed to
produce an effective metal ion scavenging effect (Halliwell et al.,
2000; Ma et al., 2010). Considering the very low bioavailability of
these natural compounds, notably in the brain, it is unlikely that
metal ion scavenging property of polyphenols produces a signifi-
cant therapeutic effect.
It should be also noted that polyphenols are extensively metabo-
lized by gut microflora (Gardana et al., 2009; Possemiers et al., 2011;
Rastmanesh, 2011). Acid hydrolysis of polyphenol conjugates by
microflora in the gut is actually required for producing bioavailable
bioactive polyphenolic compounds from primary phenolic struc-
tures. While oxidative and conjugative metabolism of polyphenols
in liver generates hydrophilic high molecular weight biotransfor-
mation products, their mainly anaerobic, reductive and hydrolytic
metabolism in the gut microbial community generates non-polar
low molecular weight products (Sousa et al., 2008).
Another important question to answer is whether the inves-
tigated poylphenols reach the brain in sufficient concentrations
and in biologically active forms. Generally there is little infor-
mation regarding the interaction of polyphenols with the BBB.
There are two main obstacles for polyphenols to cross the BBB:
(1) endothelium of the brain microvessles (BBB) and (2) multidrug
resistance-associated proteins (MRPs) (Singh et al., 2008). Cur-
cumin is highly lipophilic and can cross the BBB (Wang et al., 2005).
However, the drug is metabolized very rapidly before reaching the
BBB by conjugation, and as a result, the bioavailability for brain is
very low (Kelloff et al., 1996). Increasing levels of EGCG in brain
tissue after direct gastric lavage of EGCG has also been shown
(Suganuma et al., 1998). However even after continuous admin-
istration of EGCG until 24 h, levels of the compound in brain tissue
reaches 5–10% of its blood levels. This suggests that a very high
339
Effect References
• Diminishes plaque formation in a region specific manner Karuppagounder
• Reduces brain glutathione et al. (2009)
• Increases brain cysteine
• Inhibits A␤ polymerization Riviere et al. (2007)
• Shows no inhibition of A␤ production Marambaud et al.
Shows no effect on ␤- and -secretases (2005)
• Promotes intracellular degradation of A␤ via proteasome
system
• Reduces secreted and intracellular A␤ levels in different
cell lines
• Restores GSH content Savaskan et al.
• Employs neuroprotective effects through antioxidant (2003)
activity
• Inhibits A␤ (42) fibril formation
• Employs no effect on A␤ (42) oligomerization
• Inhibits BACE1 (beta-secretase) activity Choi et al. (2011),
Jeon et al. (2007)
• Antagonizes A␤ (25–35)-induced cytotoxicity Zhou et al. (2009)
• Inhibits fA␤ formation and extension from A␤ (1–40) and Ono et al. (2004)
A␤ (1–42)
• Destabilizes preformed fA␤ (1–40) and fA␤ (1–42)
• Inhibits fA␤formation and extension from A␤ (1–40) and Ono et al. (2004)
A␤ (1–42)
• Destabilizes preformed fA␤ (1–40) and fA␤ (1–42)
plasma concentration is needed for EGCG to reach a reasonable
therapeutic level in brain, and in this case, such a high concentration
will raise questions regarding the safety and adverse effects of the
drug (Suganuma et al., 1998). Catechins are able to cross BBB after
oral administration, but they have been found in glucuronide and
30-O-methyl glucuronide forms in the brain tissue (Abd El Mohsen
et al., 2002; Mandel et al., 2006). Production of conjugates has
been a good experimental strategy to promote polyphenol absorp-
tion and activity. For example, the glutamoyl diester of curcumin
is a better neuroprotective agent than curcumin alone (Mythri
et al., 2011). For increasing the bioavailability of EGCG in vivo,
using fully acetylated EGCG has been suggested, which functions
as a pro-drug. The acetyl group can be hydrolyzed intracellular by
esterases to release EGCG inside the cell. This strategy minimizes
auto-oxidation and allows better cellular uptake (Chao et al., 2010;
Huo et al., 2008; Lambert et al., 2006). Free radical grafting of gallic
acid on multi-walled carbon nanotubes has been shown to improve
biological properties of gallic acid (Cirillo et al., 2011). However, the
application of such conjugates is still not common and the outcome
of using them has not been sufficiently addressed.
More importantly, hazards, risks, and safety of consuming
polyphenols as life-long therapeutics should always be considered.
There are few reports about adverse effects of polyphenols (Cordier
and Steenkamp, 2011; Mennen et al., 2005). Feeding rats with high
doses of quercetin (2% or 4%) caused chronic nephropathy in one
study (Dunnick and Hailey, 1992). Adding quercetin (0.1%) to the
diet of mice in a study significantly reduced mice life expectancy
(Jones and Hughes, 1982). High-dose green tea polyphenols in
the diet (1%) disrupted kidney function through the reduction of
antioxidant enzymes and heat-shock protein expressions in mice
(Inoue et al., 2011). Even carcinogenic effects have been reported
for some polyphenols. For example, caffeic acid induced gastroin-
testinal (GI) and kidney tumors in rats and mice when presented in
2% and more in their diet (Hagiwara et al., 1991). Similarly, green
tea catechins (1% of the diet) enhanced tumor development in the
colon of male rats (Hirose et al., 2001). Some polyphenols, such as
naringenin, have interaction with liver cytochrome P450 system,
which is a main enzymatic system involved in drug metabolism and
340 A. Ebrahimi, H. Schluesener / Ageing Research Reviews 11 (2012) 329–345
bioactivation (Lilja et al., 2000; Veronese et al., 2003). Such interac-
tions might be problematic when the polyphenol is used with drugs
of narrow therapeutic range like phenytoin. Other reported hazards
related to polyphenol consumption include thyroid toxicity (Chang
and Doerge, 2000; Doerge and Chang, 2002; Doerge and Sheehan,
2002; Ferreira et al., 2002), malnutrition (Arts and Hollman, 2005;
Temme and Van Hoydonck, 2002; Zijp et al., 2000), estrogenic activ-
ity and infertilization (Delclos et al., 2001; Hughes, 1988; Mendez
et al., 2002; Sharpe and Franks, 2002; Wisniewski et al., 2003). Stud-
ies on safety assessment of polyphenols are needed before human
intervention trials are designed. Guidelines for such assessments
in natural products have been previously presented and can be
adapted to polyphenol research (Schilter et al., 2003).
The way to bring natural polyphenols into routine clinical appli-
cation against neurodegeneration seems to be long. Comprehensive
investigation models have been previously proposed to cover all
aspects of polyphenol studies (Kay, 2010). Such models require a
multidisciplinary approach, including epidemiological, clinical and
cellular-molecular studies. Structurally modified bioactive com-
pound might be used and systemic metabolism, pharmacokinetics,
brain bioavailability, local metabolism and modification in CNS and
bioactive by-products need to be considered.
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