DOI 10.1007/s11064-008-9697-6
REVIEW ARTICLE
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polyphenols have been reported to undergo oxidation and demonstrated that many polyphenolic compounds are able
generate reactive oxygen species (ROS) [7], especially at to permeate brain barrier and to exert their antioxidant
high concentration and/or in the presence of transition action directly in the brain [1618].
metals and to be effective in arresting proliferation in a The beneficial effects of polyphenols on neurodegener-
number of tumor cells via redox-dependent pathways [8, ative disorders are likely to involve their ability to
9]. On the contrary, at lower concentration (nanomolar modulate the level of intracellular antioxidants and many
range) some polyphenols can function as direct or indirect biological processes including inflammation and cellular
antioxidants both in in vivo and in vitro [1012]. However, signal transduction [1921]. Moreover, they have direct
some polyphenols exhibit pro-oxidant activity and poten- antioxidant capacity both against ROS and RNS [10, 22].
tial carcinogenicity, therefore dietary supplementation with Their anti-inflammatory action, free radical scavenging
high concentration of a single antioxidant may be harmful activity and the ability to activate key antioxidant enzymes
to human health and must be tightly controlled [9]. in the brain allows breaking the vicious cycle of oxidative
The brain most often suffers from the long-term impact stress and tissue damage [23, 24].
of the increase of ROS and reactive nitrogen species Parkinsons disease (PD) is a neurological disorder
(RNS), which play a major role in eliciting neuronal cell characterized by degeneration of dopaminergic neurons in
death through irreversible oxidative/nitrosative injury to the substantia nigra zona compacta. The cause of sporadic
neuronal macromolecules [13]. The susceptibility of brain PD is still unknown although increasing evidence indicates
to oxidative stress derives from its scarce ability to coun- that it may represent the final outcome of a complex set of
teract the damaging effects of these reactive species. interactions, over decades of time, among factors that
Actually, brain is not endowed with an efficient antioxidant include genetic predisposition, innate characteristics of the
defense system, having low levels of glutathione and nigrostriatal dopaminergic system of the brain, and expo-
moderate activity of the antioxidant enzymes catalase, sure to environmental toxins [25, 26]. Oxidative stress is
superoxide dismutases (SODs) and glutathione peroxidase. related to potentially toxic reactions such as elevation of
On the contrary, brain possesses high concentration of iron, mitochondrial function impairment and alteration of
transition metals (iron, copper), high aerobic metabolism brain antioxidants pool [14, 27]. In recent years, an
and elevated levels of ascorbic acid, overall contributing to involvement of altered activity of NO synthases (NOSs)
production of ROS/RNS and oxidized products. Finally, (mainly the neuronal and inducible forms) has emerged. In
many neurotransmitters, including NO, are autooxidized to fact, high levels of neuronal NOS (nNOS) and inducible
generate ROS and RNS. A main cause of oxidative stress in NOS (iNOS) expression were observed in the nigrostriatal
neurodegenerative diseases is inflammation caused by region and basal ganglia in the post mortem PD brains. NO
microglia activation [14]. Particularly, beside the induction has been also proposed to have a role in the inflammatory
of immunocytes migration across the blood-brain barrier processes occurring in PD [28]. In dependence on their
and the engagement of astrocytes and endothelial cells, the biological activity, polyphenols may have cytotoxic or
observed activation of microglia affects neuronal viability therapeutical effects in PD. A number of groups have
through a persistent ROS and RNS generation. The rele- reported that administration of polyphenol herbicides such
vance of neuroinflammation in neurodegenerative disorders as rotenone and paraquat induces parkinsonism in rodents
derives from the evidence that it is detectable years before [2931]. On the contrary, molecules such as cathechines
significant loss of neurons occurs. and other polyphenols have been proposed as active factors
In vivo studies have demonstrated conjugation and in mitigating or preventing PD [5, 3235], as they have an
metabolism of dietary polyphenols in the small intestine anti-inflammatory and antioxidant activity. Here, we con-
and liver, generating circulating active forms that reach the sider the recent advances in the involvement of NO in PD.
tissues in glucuronidated, methylated or sulfated forms at a Moreover, we also delineate the antioxidant and anti-
nanomolar range after oral administration [15]. However, inflammatory action of some polyphenolic compounds and
the notion of polyphenols bioavailability in tissues inte- the beneficial impact that these natural molecules may have
grates several variables such as intestinal absorption and in the prevention and treatment of PD.
excretion as well as cellular and tissue uptake, which are
specific for the polyphenol considered [15]. The uptake of
polyphenols and its metabolites is quite more complicated Nitric Oxide and Nitric Oxide Synthase in PD
in the brain in which an additional variable has to be
considered that is the blood-brain barrier, a regulatory PD is the most common age-related neurodegenerative
interface selectively limiting passage of most small polar disease after Alzheimers disease and is grouped among
molecules and macromolecules from the cerebrovascular motor system disorders. PD is a slow and progressive
circulation to the brain. Nevertheless, it has been disease, mainly characterized by resting tremor, slowness
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2418 Neurochem Res (2008) 33:24162426
of movement (bradykinesia), stiffness (rigidity), and poor from the induction of iNOS as consequence of the
balance (postural instability). Beside mitochondrial dys- inflammatory processes due to microglia activation [28].
functions, inflammation, apoptosis, oxidative and In this complex scenario, where the interaction of sev-
nitrosative stress, mutated genes were also found in eral pathogenic pathways concurs to PD, NO seems to
familial PD. These include genes encoding for mitochon- represent an important downstream mediator and enhancer
drial proteins such as Parkin, PTEN-induced putative of molecular events leading to dopaminergic neurons
kinase 1 (PINK1), DJ-1, mitochondrial polymerase gamma death. As below reviewed, NO overproduction appears to
1 (POLG1), and non-mitochondrial proteins such as be an event that significantly contributes to death of
a-synuclein, leucine-rich repeat kinase 2 (LRRK2). A dopaminergic neurons via oxidative damage on cellular
significant number of researchers found an association lipids, proteins and DNA. This hypothesis is supported by
between the expression of such mutated proteins and the studies reporting that NOSs inhibitors or NOSs gene
occurrence of redox status and/or mitochondrial homeo- knock-out significantly mitigate nigral cell loss in animal
stasis alteration in PD models, thus reinforcing the experimental models [5355].
relevance of oxidative stress and mitochondrial dysfunc-
tion in the pathogenesis of familial and sporadic forms of Neuronal Nitric Oxide Synthase in PD
the disease [3638].
The role of NO in the pathogenesis of PD is still con- When the production of NO is abundant and uncontrolled,
troversial. Some research groups reported data showing no it results in damaging effects mainly mediated by its
correlation between PD and NO [39, 40]. On the contrary, a reactive species. In PD, NO increase is caused either by
large number of groups suggest that NO could be regarded overexpression of NOSs or by other mechanisms including
as one of the factors contributing to oxidative stress and glutamate excitotoxicity. The latter event causes the raise
oxidative damage evidenced in post mortem studies, of intracellular calcium levels, which in turn increases
in vitro and animal experimental models [41, 42]. NO is a nNOS dephosphorylation and its enzymatic activity. NO
free radical playing an important messenger role in a wide reacts with superoxide anion formed during dopamine
range of physiologic processes including vasodilatation, metabolism thus generating peroxynitrite that is considered
immune response, neurotransmission [43]. This molecule is one of the main damaging molecule in dopaminergic
synthesized from L-arginine by cytosolic NO synthases neuronal cells [56].
(NOSs) using NADPH and molecular oxygen. To date, Multiple lines of evidence indicate that NO increase is
three isoforms of NOS have been identified: nNOS, associated with DNA damage, protein modifications and
endothelial NOS (eNOS) and iNOS [43]. While nNOS and citotoxicity, which are common pathogenic mechanisms
eNOS are constitutively expressed with their activity involved in PD and other neurodegenerative diseases.
depending on intracellular calcium levels, the activity of Unpublished data from our laboratory support the idea that
iNOS is induced during cell inflammatory response. nNOS NO plays a negative role in PD progression. In fact,
is the predominant isoform in neurons, however, in central dopaminergic SH-SY5Y neuroblastoma cells overexpress-
nervous system, also eNOS and iNOS are expressed. In ing nNOS are more sensitive to apoptosis elicited by the
particular, eNOS is present in cerebral vascular endothelial PD-inducing drug rotenone (Fig. 1). The DNA damage is
cells and in motor neurons [44]; iNOS is expressed in mediated by direct reaction of RNS with DNA, through
astrocytes and microglia when these cells respond to inhibition of repair processes and by increasing the pro-
inflammatory stimuli [45]. Recently, an additional isoform duction of genotoxic species such as lipid peroxidation
of NOS has been identified in mitochondria (mtNOS), products (mainly 4-hydroxynonenal) and hydrogen perox-
whose nature and function is still a debated matter of ide. RNS also inhibit ribonucleotide reductase resulting in
research [46]. In fact, it has been proposed that it may blockage of DNA synthesis and induces over-single-strand
represent a portion of iNOS, eNOS or nNOS translocating DNA breaks [57]. Overall, these DNA damages trigger
into mitochondria where it likely participates in the regu- secondary effects including up-regulation of the tumor
lation of electron transfer chain [47, 48]. suppressor p53 and increase of nuclear enzyme poly ADP-
The implication of NO in PD has been firstly proposed ribose polymerase (PARP-1), which might promote apop-
when high levels of nNOS and iNOS were found in the tosis in PD animal models [58].
nigrostriatal region and basal ganglia of the post mortem In addition to DNA damage, NO may also cause protein
PD brains [49, 50]. Immunoreactivity for nNOS and down- modifications such as nitrosylation and nitration. Protein
stream effector guanylate cyclase were also found consis- nitration, generally, adds a nitro (NO2) group onto one of
tently increased in the substantia nigra after treatment with the two carbons in position 3 of the aromatic ring of
PD-inducing drugs [51, 52]. It has been suggested that a tyrosine residues to form nitrotyrosine. Increased nitroty-
significant portion of the increased NO production derives rosine were detected in substantia nigra in in vivo models
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Neurochem Res (2008) 33:24162426 2419
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2420 Neurochem Res (2008) 33:24162426
and to the expression of adhesion molecules and chemo- signaling pathway, which involves phosphorylation of the
attractant factors from endothelial and immune cells. I-jB inhibitory subunit and its detachment from NF-jB,
Importantly, inflammation is not per se healthy or unheal- allowing NF-jB translocation into the nucleus where acti-
thy, because it helps the immune system to counteract vates transcription of these genes [43]. iNOS displays a
pathological states such as infection, but it can also lead to relative slow turnover and produce NO at very high levels
progressive tissue damaging if unbalanced or prolonged. for long periods. During inflammation, the concomitant
This sort of paradox is particularly evident in the aetiology activation of iNOS, NADPH oxidase and COX-2 produce
of PD. Here the physiological inflammatory functions of high levels of ROS and RNS. Given that microglia is
immune system in terms of cytokines and ROS/RNS pro- particularly abundant in the substantia nigra and that
duction by activated immune cells and complement cascade dopaminergic neurons are highly susceptible to oxidative/
launch are protracted and uncontrolled, leading to the fea- nitrosative stress, the resulting ROS/RNS overproduction
tures of neurodegeneration [28]. The main cell type severely damage their cellular structures and macromole-
involved in inflammation and consequent neurodegenera- cules mainly as consequence of peroxynitrite formation. The
tion within PD is represented by microglia, which are iNOS-derived NO is also implicated in the release of iron
phagocytic cells participating in the physiological immune from transferrin, thus enhancing Fenton reaction leading to
control of the central nervous system [65]. Activation of production of highly reactive hydroxyl radicals [83].
microglia can be triggered by different molecules such as
lipopolysaccharide from Gram-negative bacteria and by
PD-inducing agents both in humans and experimental Polyphenols in PD Treatment
models of PD. In particular, microglia activation is trig-
gered using rotenone from pesticides and herbicides [75], Overall these findings suggest that a therapeutical approach
neurotoxins such as 6-hydroxydopamine (6-OHDA) [76] to PD could be the employ of nNOS or iNOS inhibitors. In
or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) fact, the toxic role of NO in PD was also demonstrated by
[77]. Such activation implies microglia to up-regulate the the use of NOS inhibitors, which protect mice and monkey
expression of molecules involved in antigen presentation models from PD [55, 84]. Apart NOS isoforms, mtNOS is
(e.g. CD1, MHCII), as well as cell adhesion molecules. emerging as a new target for therapeutics in the diseases
Subsequently, microglial cells adhere to neurons, driven by associated with mitochondrial dysfunction and neurode-
the recognition of chemoattractant proteins expressed by generative disorders. Moreover, another way to ameliorate
neurons themselves and by ligation of activated comple- the effects of excessive NO production such as abnormal
ment. If the activating stimulus does not decrease, microglia S-nitrosylations and nitrotyrosine formation, could be to
definitively assumes phagocytic functionality, leading to inhibit NMDAR, whose altered activity is able to elicit
neuronal cell death and consequent chemoattractants NO-mediated excitotoxicity. In fact, moderate blockade of
release, which in turn induce a greater microglia infiltration NMDAR activity by memantine can protect neurons from
and enhanced neuroinflammation. this type of injury and death [67]. However, among the
The inflammation developed within neuronal tissue has novel therapeutic strategies proposed for achieving neuro-
been observed in several studies involving PD patients, protection in PD are included ROS/RNS scavengers, metal
which primarily show increased number of activated chelators and anti-inflammatory molecules. Due to their
microglial cells [28]. However, the most reasonable evi- antioxidant and anti-inflammatory actions, polyphenols
dence of neuroinflammation in PD patients is the elevated represent novel promising tools for PD treatment (Fig. 2).
level of inflammatory cytokines, such as tumour necrosis
factor a (TNFa) and IL-6 [78]. Importantly, the up-regula- Antioxidant Function
tion of the inflammatory genes encoding for cyclooxygenase
2 (COX-2) and iNOS was observed in a population of Numerous studies have demonstrated that specific poly-
amoeboid microglial cells from PD patients [45, 79]. COX-2 phenols are effective direct scavengers of physiologically
can provoke neuronal cell death by producing prostaglan- relevant ROS and RNS in vitro, including superoxide,
dins such as PGE2, which can exert a direct effect upon peroxyl radicals, singlet oxygen, peroxynitrite, and hypo-
dopamine-containing neurons inducing intraneuronal tox- chlorous acid [12, 8589]. Oxidative damage-induced
icity [80]. iNOS up-regulation in microglia seems to play an apoptosis in neuronal cells could be protected by naturally
important role in the onset of inflammatory processes in PD occurring polyphenols [90]. The green tea flavonoid cate-
and acts synergistically with other inflammatory mediators. chins have been found to be the most efficient antioxidants;
PD-inducing drugs such as rotenone and MPTP or dopamine however, other polyphenols such as oxyresveratrol, resve-
overexposure provoke activation of iNOS expression [39, ratrol and quercetin are able to protect against NO
81, 82]. iNOS and COX-2 expression is induced by NF-jB cytotoxicity as well [22, 89, 91]. Direct free radical
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Neurochem Res (2008) 33:24162426 2421
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2422 Neurochem Res (2008) 33:24162426
and peroxidases [18]. The enhancement of SOD activity inflammation pathways [21], most of which are typical
by resveratrol could be effective against NO toxicity as, features of chronic diseases such as PD.
by scavenging superoxide, it counteracts the formation of The most evident effect of flavonoids is the inhibition of
peroxynitrite [99]. Among the antioxidant genes modu- inflammatory cytokines production, previously described
lated by resveratrol, there is heme oxygenase (HO), which as principal actors in the development of neuronal injury
is responsible for degradation of heme into biliverdin/ within PD tissues. On this ground, genistein has been
bilirubin, iron and carbon monoxide. Being heme a pro- reported to inhibit IL-1b, TNFa and IL-6 production by
oxidant molecule, while biliverdin and bilirubin are anti- LPS-activated human monocytes [104]. In addition to
oxidants, induction of high HO level by resveratrol is direct cytokine inhibition, flavonoids interfere with their
antiapoptotic and cytoprotective against ROS/RNS dam- synthesis by blocking various components of the signal
age [33]. transduction that leads to inflammatory genes activation.
Mangiferin, a polyphenol extracted from mango, is For instance, flavonols inhibit protein kinase C (PKC)
another recently proposed antioxidant for PD treatment [105] and mitogen activated protein kinases (MAPK). In
[100]. It is able to cross the blood-barrier [101], displays particular, quercetin reduces the activity of p38 MAPK and
direct antioxidant capacity and is a good iron chelator, Jun N-terminal kinase/stress-activated protein kinase, thus
thus preventing ROS production through the Fenton and inhibiting the binding of activator protein 1 (AP1) to the
HaberWeiss reactions [102]. Mangiferin has been dem- DNA [106]. Quercetin and wogonin interfere with the
onstrated to protect against cytotoxicity mediated by the activation of extracellular signal-related kinase 1/2 leading
PD-inducing toxin MPTP and its active metabolite to NF-jB inhibition [22]. NF-jB is also inhibited by sev-
MPP + in murine N2A neuroblastoma cells [100]. Par- eral other flavonoid compounds, such as genistein,
ticularly, mangiferin is able to revert the oxidative stress kaempferol, amentoflavone [21]. These evidences show
most probably through its scavenging activity against that flavonoids, by counteracting the activation of several
ROS. factors including NF-jB and AP-1, can inhibit the syn-
Although mainly suggested as promising therapeutic thesis and the activity of several inflammation-involved
agent in Alzheimers disease [5], the polyphenol curcumin cytokines, which are important events during the patho-
has a protective role also against MPTP toxicity [103]. genesis of PD.
Indeed, in murine dopaminergic neuroblastoma cells, cur- Another important target of flavonoids for their anti-
cumin induces overexpression of the anti-apoptotic Bcl-2, inflammatory effect is COX. Particularly, COX-2 is the
reduces the loss of mitochondrial membrane potential and most represented in inflammation-related immune cells,
the increase of ROS. such as macrophages, and it is typically induced through
LPS stimulation. Some flavonoids, i.e. luteolin or galangin
Anti-inflammatory Activity were firstly noted as COX inhibitors [107]. Following this
observation, a huge amount of papers have been published
Referring to the above reported observations, it appears on this topic showing other flavonoids to inhibit COX. In
that inhibition of any step in the inflammation pathway particular, flavone, kaempferol and quercetin were
can be useful for the attenuation of its harmful conse- observed to be efficient COX inhibitors [21]. Additionally,
quences in the progression of PD. Therefore, anti- flavonoids can exert an inhibitory effect upon NF-jB
inflammatory agents that suppress microglial activation or activation [22]. Since COX-2 is synthesized through an
interfere with the production of neurotoxic factors by NF-jB-mediated pathway, the effect of flavonoids upon
activated microglia are candidates for therapeutic inter- COX-2 activity is exerted also at expression level. In
vention in PD. The usually employed drugs, such as particular, genistein, apigenin and kaempferol counteract
steroidal and non-steroidal anti-inflammatory molecules, the activity of inhibitor-jB (I-jB) kinase, thus preventing
produce their effect in the treatment of acute inflammatory NF-jB to address the DNA [108, 109]. The evidences of
diseases, whereas they are not resolutive when adminis- flavonoids as COX inhibitors enforce the idea of their
tered in course of chronic disorders, such as rheumatoid employ in the treatment of inflammatory pathologies,
arthritis, atopic dermatitis or PD itself. Additionally, the including PD.
raising of unpleasing side effects during the prolonged As above mentioned, the inflammatory process and the
treatment with such drugs evidences the need for new safe consequent PD-related dopaminergic neuronal damage
and effective anti-inflammatory molecules, which often found in PD is due to the production of NO from L-arginine
are recruited among natural compounds. Flavonoids have by iNOS. The isolation of some compounds that selectively
been proposed as anti-inflammatory agents and their inhibit NO synthesis by iNOS without affecting eNOS or
activity is exerted by intervening in a wide range of nNOS is attractive. Nevertheless, none of the studies
molecular and cellular mechanisms ascribable to reported so far showed a significant effect of flavonoids
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Neurochem Res (2008) 33:24162426 2423
ROS/RNS scavenging
RNS Induction of cellular antioxidants
Polyphenols Inhibition of iNOS expression
upon iNOS activity perhaps due to the high level of NO employed in neurodegenerative diseases associated with
produced by this NOS isoforms. To our knowledge, the oxidative/nitrosative stress.
only flavonoid compound which showed a relevant activity The potential therapeutic function of polyphenols is
in iNOS inhibition was echinoisosophoranone, being strictly related to their capacity to cross blood-brain barrier
effective at a reasonable concentration [110]. On the other and exert their beneficial activity directly [112, 113]. The
hand, several flavonoids have been reported to inhibit antioxidant function likely depends on the scavenging
iNOS expression. Liang and colleagues firstly found that activity of free radicals among which is included NO-derived
apigenin, genistein and kaempferol inhibited NO produc- reactive species. Moreover, many polyphenols display the
tion by down-regulating iNOS synthesis [108]. Following ability to induce the expression of intracellular antioxidants
these findings, many other flavonoids were discovered to enzymes. The anti-inflammatory activity of polyphenols
be potent inhibitors of iNOS expression, including oroxylin depends on the inhibition of the expression of inflammatory
A, quercetin, resveratrol, bilobetin and ginkgetin via inhi- genes such as eicosanoid generating enzymes and iNOS,
bition of NF-jB signaling pathway [21, 111]. Altogether, mainly through interfering with the activation of the
these data demonstrate that some flavonoids are inhibitors upstream NF-jB transcription factor. Moreover, some
of iNOS expression but not of its activity. Anyway, since polyphenols may inhibit the release of pro-inflammatory
there is the possibility of a non-selective NOS inhibition, molecules (IL-1b, TNFa and IL-6). Being PD a multifactor
the role of these compounds in counteracting inflamma- disease in which NO, inflammation and oxidative stress
tory-related NO production is still far from being play important roles, the employ of compounds such as
elucidated. polyphenols, having poly-pharmacological activities, is
attractive. The schematic model reported in Fig. 4 summa-
Conclusions rizes the mechanisms by which polyphenolic compounds can
modulate NO toxicity in PD.
In recent years, NO and its reactive metabolites have been Overall the findings reported in literature strongly sug-
proposed as important actors in the processes leading to gest that anti-oxidant and anti-inflammatory agents based
neuronal cell death in PD both in terms of pro-oxidants and on polyphenols molecule could be proposed for treatment
mediators of inflammatory responses. Therefore, the of PD.
blockage of NO synthesis or the scavenging of RNS could
Acknowledgements This work was partially supported by Minis-
represent an efficient tool against PD progression. In this tero della Salute, MIUR and FIRB Idee Progettuali. We thank Dr.
context, polyphenols are promising natural antioxidant and Giovanni Auricchio for his advice in the matter of PD inflammatory
anti-inflammatory molecules that are proposed to be processes and helpful critical reading of the manuscript.
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