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Current Drug Targets - CNS & Neurological Disorders, 2003, 2, 95-107 95
1568-007X/03 $41.00+.00 © 2003 Bentham Science Publishers Ltd.
Biochemical and Therapeutic Effects of Antioxidants in the Treatment of
Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral
Sclerosis
Vincenzo Di Matteo and Ennio Esposito
*
Istituto di Ricerche Farmacologiche “Mario Negri”, Consorzio Mario Negri Sud, 66030
Santa Maria Imbaro (Chieti), Italy
Abstract: Aging is a major risk factor for neurodegenerative diseases including
Alzheimer's disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis
(ALS). An unbalanced overproduction of reactive oxygen species (ROS) may give rise to
oxidative stress which can induce neuronal damage, ultimately leading to neuronal
death by apoptosis or necrosis. A large body of evidence indicates that oxidative stress
is involved in the pathogenesis of AD, PD, and ALS. Several studies have shown that
nutritional antioxidants (especially vitamin E and polyphenols) can block neuronal
death in vitro, and may have therapeutic properties in animal models of neurodegenerative
diseases including AD, PD, and ALS. Morever, clinical data suggest that nutritional antioxidants might exert
some protective effect against AD, PD, and ALS. In this paper, the biochemical mechanisms by which
nutritional antioxidants can reduce or block neuronal death occurring in neurodegenerative disorders are
reviewed. Particular emphasis will be given to the role played by the nuclear transcription factor -kB (NF-kB)
in apoptosis, and in the pathogenesis of neurodegenenerative disorders, such as AD, PD, and ALS. The effects
of ROS and antioxidants on NF-kB function and their relevance in the pathophysiology of neurodegenerative
diseases will also be examined.
Keyword: neurodegeneration, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, oxidative stress, nuclear
factor kB, antioxidants, polyphenols, neuroprotection, nutritional.
INTRODUCTION
Among the most common neurologic diseases are
neurodegenerative disorders, such as Alzheimer's disease
(AD), Parkinson's disease (PD), and amyotrophic lateral
sclerosis (ALS). As the elderly population increases, the
prevalence of these age-related diseases is likely to increase.
The cause of these diseases is not known and, with the
possible exception of PD, there is no treatment that alters
significantly the progression of any of these disorders. Of
the few risk factors that have been identified for these
diseases, increased age is the only one that is common to
AD, PD, and ALS. For AD, the incidence and prevalence of
the diseases increase dramatically after age 60; one study
showed a 47% prevalence for patients over age 85 [1]. In
addition to the possible involvement in aging,
mitochondrial dysfunction and oxidative damage may play
important roles in the slowly progressive neuronal death that
is characteristic of several neurodegenerative disorders
including AD, PD, and ALS [2-6].
There is substantial evidence that the brain, which
consumes large amounts of oxygen, is particularly
vulnerable to oxidative damage. Free radicals are normal
products of cellular metabolism [7]. The predominant
*Address correspondence to the author at the Istituto di Ricerche
Farmacologiche “Mario Negri”, Consorzio Mario Negri Sud, 66030 Santa
Maria Imbaro (Chieti), Italy; Tel: +39-0872-570274; Fax: +39-0872-
570416; E-mail: Esposito@negrisud.it
cellular free radicals are the superoxide (O
2
-
) and hydroxyl
(OH) species [5-8]. Other molecules, such as hydrogen
peroxide (H
2
O
2
) and peroxynitrite (ONOO
-
), although not
themselves free radicals, can lead to the generation of free
radicals through various chemical reactions. Thus H
2
O
2
, in
the presence of reduced metal, forms the highly reactive OH
via the Fenton Reaction [8]. Peroxynitrite (ONOO
-)
, formed
by the reaction of nitric oxide (NO) with O
2
-
, is a highly
reactive molecule that also breaks down to form OH
.
Together, these molecules are referred to as reactive oxygen
species (ROS) to signify their ability to lead to oxidative
changes within the cell [8]. Problems occur when the
production of ROS exceeds the ability of cells to defend
themselves against these substances. This imbalance between
cellular production of ROS and the ability of cells to defend
themselves against them is referred to as oxidative stress [8].
Oxidative stress can cause cellular damage and ROS oxidize
critical cellular components such as membrane lipids,
proteins, and DNA, thereby inducing apoptosis or necrosis
[9-13]. Necrosis is characterized by a loss of plasma
membrane integrity, the formation of large vacuoles, and cell
swelling, whereas typical features of apoptotic cells are
nuclear changes that include chromatin margination and
condensation, DNA fragmentation, membrane blebbing, and
cell shrinkage [14]. There is a large scientific literature
regarding the relation between ROS production, the
induction of apoptosis (or necrosis) and the pathogenesis of
neurodegenerative disorders [14-22]. Although this subject is
still a matter of debate, increasing evidence supports the
hypothesis that neuronal death may occur primarily by
apoptotic mechanisms in AD, PD and ALS [23-27]. Thus,
96 Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 2 Di Matteo and Esposito
clinical evidence shows signs of apoptosis in patients with
AD, PD and ALS [26-29].
Cells normally have a number of mechanisms to resist
against damage induced by free radicals [7]. The major
antioxidant defenses consist of ROS scavengers such as
glutathione (GSH), vitamin C (ascorbic acid), vitamin E (α-
tocopherol), carotenoids, flavonoids, polyphenols, and
antioxidant enzymes. Severe depletion of GSH in mice by
administration of buthionine sulphoximine, which inhibits
GSH synthesis, causes neuronal damage and mitochondrial
degeneration [30]. There is a high concentration of ascorbic
acid in the gray and white matter of the central nervous
system in all species that have been examined [31]. Indeed,
the brain, spinal cord and adrenal glands have the highest
ascorbate concentrations of all the tissues in the body [31].
Ascorbate is a broad spectrum radical scavenger that is
effective against peroxyl and hydroxyl radicals, superoxide,
singlet oxygen, and peroxynitrite [31]. Also the lipid-
soluble chain breaking antioxidant vitamin E exerts a very
important protective function against oxidative stress in the
brain [9], and interacts with ascorbate enhancing its
antioxidant activity [32]. Little information is available on
the levels of carotenoids and flavonoids in the human brain.
The antioxidant enzymes in the brain include Cu/Zn
superoxide dismutase (SOD-1) and Mn superoxide
dismutase (SOD-2) which catalyze the conversion of O
2
-.
to
H
2
O
2
[33]. H
2
O
2
is then converted to H
2
O by either catalase
or glutathione peroxidase (GSH-Px). Antioxidant defense
mechanisms can be upregulated in response to increased
ROS or peroxyde production [34]. Although upregulating
antioxidant defense systems may confer protection against
ROS, they are not completely effective in preventing
oxidative damage. Moreover, the efficiency of gene
expression may decline with aging or become defective as
oxidative damage to the genome increases.
As already mentioned, the brain is especially vulnerable
to ROS damage because of its high oxygen consumption
rate, abundant lipid content, and relative paucity of
antioxidant enzymes compared with other organs [35]. If the
increased demand on the cell’s capacity to detoxify ROS is
not met, alterations, such as aldehydes or isoprostanes from
lipid peroxidation, protein carbonyls from protein oxidation,
and oxidized base adducts from DNA oxidation may occur
[9]. Oxidation of polyunsatured fatty acids (PUFA) results
in the production of multiple aldehydes with different carbon
chain lenghts including propanal, butanal, pentanal, hexanal
and 4-hydroxy-2-trans-nonenal (4-HNE). There is evidence
that 4-HNE is capable of inducing apoptosis in PC12 cells
and cultured rat hippocampal neurons suggesting that it is a
mediator of oxidative stress-induced apoptosis [36]. These
findings suggest that in addition to direct ROS damage to
phospholipid membranes, there is an indirect mechanism
involving 4-HNE, which may also be involved in neuronal
death. In this regard, it noteworthy that 4-HNE has been
suggested to be involved in the pathogenesis of PD [37,38].
Oxidative damage to proteins can be revealed by measuring
protein carbonyl content [39], which was found to be
elevated in AD and ALS patients [40]. Another indication of
protein oxidation is the formation of nitrotyrosine by
peroxynitrite. This might represent a useful clinical
parameter of the occurence of oxidative stress in
neurodegenerative diseases, since increased levels of
nitrotyrosine have been found in AD, PD and ALS [17,41-
46]. The most useful marker of DNA oxidation is 8-
hydroxy-2’-deoxyguanosine (8-OHdG) which is elevated in
patients with AD, PD and ALS [47-51].
Another index of oxidative stress is the activation of the
transcriptional factor NF-κB (nuclear factor kappa B). A
large body of evidences thus indicate that ROS can act as
second messengers mediating intracellular responses,
including NF-κB activation [52-56]. In turn, activated NF-
κB can influence the expression of a large number of genes,
including SOD-2 [52,55,57]. Hence, NF-κB activation can
be considered as the executive branch of a feed-back
mechanism that operates to regulate the intracellular
concentration of ROS, trying to dampen an excessive
accumulation of ROS which can be dangerous for the cell.
Moreover, NF-κB induces the expression of the so-called
IAPs (inhibitor-of apoptosis proteins), Bcl-2, and calbindins
[57,58]. All these biochemical actions of NF-κB indicate
that this transcription factor can exert an antiapoptotic effect,
thereby protecting neurons against degeneration [55,57]. As
we will discuss below, these data are consistent with clinical
findings showing increased levels of NF-κB in vulnerable
regions of the central nervous system of AD, PD and ALS
[59-61].
Although the available data are still limited,
epidemiological studies indicate that dietary habits can
influence the incidence of neurodegenerative disorders such
as dementia (including AD) and PD [62-66]. For example,
incidence data from the so-called PAQUID (Personnes Agees
Quid) study showed that people drinking 3-4 glasses of wine
per day had an 80% decreased incidence of dementia and AD
3 years later, compared to those who drank less or did not
drink at all [64,65,67]. This protective effect was still highly
significant after adjusting the data for potential confounding
factors such as age, sex, education, occupation, and baseline
MMSE (Mini-Mental State Examination). However,
although in another study moderate wine consumption was
found to be associated with a four-fold reduction of the risk
for AD, this effect disappeared when institutionalization was
taken into account [68]. These protective effects are most
likely due to the presence of antioxidants in food and
beverages [62,65], in as much as it has been found that wine
drinking and the consumption of other foods and drinks
which are rich in polyphenols can increase the antioxidant
activity in serum [69-71]. Epidemiological studies have also
found an inverse association between high intake of dietary
vitamin E (but not flavonoids or vitamin C) and the
occurrence of PD [66,72]. However, these data were not
confirmed by other studies [63,73], although Hellenbrand et
al. [63] reported a significant statistical trend toward
protective effect by vitamin C in PD. The clinical findings
indicating a protective effect of dietary antioxidants against
neurodegenerative disease are supported by data obtained in
laboratory animals showing that diet supplementation
containing fruits and vegetables rich in antioxidants
(bluberries, strawberries and spinaches) can have beneficial
effects on age-related decline of neuronal and cognitive
function in old rats [74].
This review will focus on the actions of in vitro
application of natural nutritional antioxidants in
experimental models of neurodegenerative disorders. The
Biochemical and Therapeutic Effects of Antioxidants Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 2 97
capability of these compounds to counteract the damaging
effects of ROS, and the relevance of this biochemical effect
in their putative neuroprotective action will be examined.
Among the numerous biochemical effects of ROS and
antioxidants, particular emphasis will be given to their
interference with NF-κB function, whose role in the
pathophysiology of neurodegenerative disorders is gaining
increasing attention. Finally, the effects of the admistration
of “pharmacological” doses of nutritional antioxidants in
animal models and in patients with AD, PD, and ALS will
be reviewed.
DIETARY ANTIOXIDANTS AND NEURODE-
GENERATIVE DISORDERS
In recent years, there has been a increasing interest in
investigating the many positive pharmacological properties
of flavonoids. Much of this interest has been spurred by the
dietary anomaly referred to as the “French paradox”, the
apparent compatibility of a high saturated fat diet with a low
incidence of coronary atherosclerosis [75]. It was suggested
that the polyphenolic substances such as flavonoids in red
wine may provide protection against coronary heart disease.
The natural phytoalexin resveratrol and the flavonoids
quercetin and (+)-catechin have been invoked in order to
explain the beneficial effects of moderate red wine
consumption against coronary heart diseases [76,77]. In
addition, epidemiological studies have shown that moderate
wine consumption can be protective against neurological
disorders such as age-related macular degeneration [78] and
AD [65]. Moreover, in vitro and in vivo pre-clinical studies
have shown the neuroprotective effect of lyophilized red
wine [79], grape polyphenols [80], quercetin [81], trans-
resveratrol [82-84], and (+)-catechin [85]. Taken together,
these findings raise the possibility that red wine constituents
may be beneficial in the prevention of age-related
neurodegenerative disorders. There is also increasing interest
for the role of tea (Camellia sinensis) in maintaining health
and in treating disease. Although tea consists of several
components, research has focused on polyphenols, especially
those found in green tea. The green tea polyphenols include
(—)-epicatechin (EC), (—)-epigallocatechin (EGC), (—)-
epicatechin-3-gallate (ECG), (—)-epigallocatechin-3-gallate
(EGCG). Of these, EGCG generally accounts for greater than
40% of the total [86]. Green tea polyphenols are potent
antioxidants [87]. EGCG usually has the greatest antioxidant
activity, and is the most widely studied polyphenol for
disease prevention [88,89]. Many of the putative health
benefits of tea are presumed to be caused by its antioxidant
effects.
The epidemiological evidence indicating the putative role
of nutritional antioxidants in the prevention and attenuation
of neurodegenerative disorders is receiving experimental
confirmation in a number of laboratory studies. Thus, the
polyphenol epicatechin was shown to attenuate neurotoxicity
induced by oxidized low-density lipoprotein in mouse-
derived striatal neurons [90]. Tea extracts and EGCG
attenuated the neurotoxic action of 6-OHDA (6-
hydroxydopamine) in rat PC12 cells, human neuroblastoma
SH-SY5Y cells [88], and were shown to be neuroprotective
in a mouse model of PD [89]. Moreover, recent reports have
revealed that flavonoids may be neuroprotective in neuronal
primary cell cultures. For example, the Ginkgo biloba
extract, known to be enriched with flavonoids, has been
shown to protect hippocampal neurons from nitric oxide or
β-amyloid derived peptide-induced neurotoxicity [91,92]. In
addition, the extract of Ginkgo biloba referrred to as Egb
761 is one of the most popular plant extracts used in Europe
to alleviate symptoms associated with a range of cognitive
disorders [93,94]. The mechanism of action of Egb 761 in
the central nervous system is only partially understood, but
the main effects seem to be related to its antioxidant
properties, which require the synergistic action of the
flavonoids, the terpenoids (ginkgolides, bilobalide), and the
organic acids, principal constituents of Egb [95]. These
compounds to varying degrees act as scavengers of ROS,
which have been considered the mediators of the excessive
lipid peroxidation and cell damage observed in AD [96-98].
ROS, NF-κκ
κκ
B AND NEURODEGENERATIVE
DISORDERS
The transcription factor NF-κB, originally studied in
cells of the immune system wherein it regulates cell survival
[99-101], is widely expressed in the nervous system and
exists in neurons in both an inducible and a constitutively
active form [102-105]. NF-κB resides in the cytoplasm in an
inactive form consisting of three subunits: p65 and p50 and
an inhibitory subunit called IκB [99-101,105]. When IκB is
bound to p50/p65, it is inactive; signals that activate NF-κB
cause dissociation of IκB releasing p50/p65, which then
translocates to the nucleus and binds to specific κB DNA
consensus sequences in the enhancer region of a variety of
κB-responsive genes [55,57,99-101,106].
In neurons, NF-κB is activated by various intracellular
signals, including cytokines, neurotrophic factors, and
neurotransmitters [55,105,107]. Activation of glutamate
receptors, and membrane depolarization lead to activation of
NF-κB in hippocampal pyramidal neurons and cerebellar
granule neurons in culture [103,108]. The mechanism
whereby diverse stimulants lead to the activation of NF-κB
has been a subject of intense reasearch. Most work has
focused on the p50/p65 dimer, the predominant form of NF-
κB activated in many cells including neurons [55,57,108],
and its association with IκBα. Ιt is now known that upon
stimulation with many NF-κB inducers, IκBα is rapidly
phosphorylated on two serine residues (S32 and S36), which
targets the inhibitor protein for ubiquitination and
subsequent degradation by the 26 S proteasome [106].
Released NF-κB dimer can then translocate to the nucleus
and activate target genes by binding with high affinity to κB
elements in their promoters. The phosphorylation and
degradation of IκBα are tightly coupled events, so it is
always likely that agents that activate NF-κB do so by
stimulating a specific IκB kinase, or alternatively by
inactivating a particular phosphatase. Two IκB kinases
(IKKs) termed IKKα and IKKβ have been described [106].
IKKα and β have been shown to be activated by important
inducers of NF-κB such as IL-1 and TNF, to specifically
phosphorylate S32 and S36 of IκBα and to be crucial for
NF-κB activation by these cytokines [106]. The IKKs are
part of a larger multiprotein complex called the IKK
signalsome. It appears that multiple pathways can regulate
NF-κB, most of which lead to IκB phosphorylation via the
98 Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 2 Di Matteo and Esposito
IKK-containing signalsome [106]. A model has been
proposed whereby diverse agents all activate NF-κB by
causing oxidative stress [54,100,109]. This hypothesis is
based on four main lines of evidence: a) direct application of
H
2
O
2
to culture medium activates NF-κB in some cell lines
[110-113]; b) in some cell types ROS have been shown to
be increased in response to agents that also activate NF-κB
[100,110-114]; c) virtually all stimuli known to activate NF-
κB can be blocked by antioxidants, including L-cysteine (a
precursor of glutathione), N-acetyl-L-cysteine (NAC), caffeic
acid phenethyl ester (CAPE), (—)-epigallocatechin-3-gallate,
resveratrol, thiols, dithiocarbamates, vitamin E and its
derivatives, and thioredoxin (an important cellular protein
oxidoreductase with antioxidant activity)
[52,53,77,100,110,115-118]; d) inhibition or overexpression
of enzymes that affect the level of intracellular ROS has been
shown to modulate the activation of NF-κB by some agents
[114,119]. Ultimately, this theory led to the proposal of
H
2
O
2
as the central second messenger to NF-κB activation
[114].
A large body of evidence indicates that NF-κB is
involved in the control of cell survival. The great majority
of the available data show that NF-κB exerts an anti-
apoptotic action. Thus, activation of NF-κB can prevent cell
death in various culture paradigms [55,120]. Moreover,
increasing data suggest that NF-κB activation may transduce
anti-cell death signals in neurons [55]. For example, TNFα
protected cultured hippocampal neurons against death
induced by metabolic, excitotoxic, and oxidative insults
[55,121]. The involvement of NF-κB in such neuronal cell
death paradigms is suggested by data showing that TNFα
induces activation of NF-κB in cultured hippocampal
neurons against excitotoxic and oxidative insults [121-123].
Moreover, in the PC12 neuronal cell line [124] and in
primary sympathetic neurons [125], activated NF-κB has
been found to mediate the anti-apoptotic effect of NGF
(nerve growth factor). It has also been shown that the
resistence of selected clones of PC12 cells to oxidative cell
death induced by Aβ and H
2
O
2
is mediated by NF-κB
[126]. An inhibition of NF-κB potentiated Aβ peptide-
mediated apoptotic damage in primary cultures of cerebellar
granule cells [127], and increased the apoptotic death of
PC12 cells induced by auto-oxidation of dopamine [128].
Similarly, a lack of p50 subunit increased the vulnerability
of hippocampal neurons to excitotoxic injury [129]. Recent
studies have shown that NF-κB is activated, and may play a
protective role in neurodegenerative disorders such as AD
[130], PD [59] and ALS [61] and severe epileptic seizures
[129]. There is also evidence that NF-κB plays a pivotal role
in the cell survival-promoting action of ADNF9, a nine
amino acid ADNF (activity-dependent neurotrophic factor)
peptide [131]. In addition, it has recently been reported that
NF-κB is involved in the neuroprotective effect exerted by
subtoxic concentration of NMDA (N-methyl-D-aspartate),
and can counteract low potassium-induced apoptosis in
cultured cerebellar granule neurons [132,133]. Also
preconditioning-induced neuroprotection in cultured
hippocampal neurons seems to be mediated by activation of
NF-κB [134]. The mechanism by which NF-κB can exert its
anti-apoptotic effect is still unclear. One possible
mechamism would be the trascription of genes encoding
trophic factors, antioxidant enzymes, and calcium-regulating
proteins. One of the first genes shown to be responsive to
NF-κB was SOD-2, a mitochondrial antioxidant enzyme
that protects cells against apoptosis [130]. Other genes
induced by NF-κB include the cell adhesion molecules such
as ICAM-1 [135], the inducible form of nitric oxide
synthase [136], Bcl-2, Bcl-x, and the Bcl-2 homologue Bfl-
1/A1 [58,137,138].
However, in some cases NF-κB can promote neuronal
death [139-141]. Thus, the neuroprotective effect of
acetylsalicylic acid is apparently mediated by inhibition of
NF-κB [140]. More recently, it was found that NF-κB is
essential for dopamine-induced apoptosis in PC12 cells
[142]. Whether NF-κB inhibits or promotes apoptosis might
depend on the cell type and the nature of the apoptosis-
inducing stimulus [141]. However, the explanation for the
conflicting results concerning an anti-apoptotic versus pro-
apoptotic role of NF-κB activation is still not clear and has
been described as “janus faces” of NF-κB [141].
ALZHEIMER’S DISEASE
The estimated prevalence of senile dementia in Europe
increases with age from 1% in men and women of 60 years
of age to 44.7% in the population 90-95 years of age [143].
Alzheimer’s disease is the commonest form of dementia,
with a prevalence of 0.4% in women and 0.3% in man aged
60-69 years [144]. A community based study has suggested
that approximately 4 million persons in the United States
have AD [66]. AD is a progressive dementing disorder
characterized by selective neuronal loss in several areas of the
central nervous system. In AD, the progressive memory
deficits, cognitive impairments and personality changes are
due to progressive dysfunction and death of the neocortex,
limbic system, hippocampus and several of the subcortical
regions of the brain. The majority of cases of AD are age-
related and, indeed, age is the only reliable risk factor for the
non-genetic sporadic forms (85% of all cases) and, therefore,
for the majority of cases of this disorder [145]. The
characteristic histopathologic alterations in AD are neuritic
or senile plaques (SPs) composed largely of amyloid β-
peptides (Aβ) and neuronal aggregates of abnormally
phophorylated cytoskeletal proteins [neurobifrillary tangles
(NFTs)]. A number of data indicate that Aβ is responsible
for the neuronal death in AD. Thus, aggregates of Aβ
peptides are toxic to neurons in cultures [145-148] and can
cause cell death by apoptosis [14,26,27,148,149], however,
the exact mechanisms of Aβ-induced neurotoxicity are still
unknown. Several lines of evidence suggest that the
overproduction of ROS is implicated in Aβ neurotoxicity: a)
exposure of cultured neurons or neuronal cell lines to Aβ
increases the intracellular levels of ROS [11,150-155]
leading to the activation of NF-κB [60]; b) markers of
oxidative stress are found increased in a transgenic mouse
model of AD [98,156]; c) the neurotoxicity of Aβ is
attenuated by antioxidants such as vitamin E, the spin-trap
compound PBN (α-phenyl-tert-butyl nitrone), and lazaroids
[11,145-147,157-159], and/or free radical scavengers [160].
Thus, in 1992 the protective effect of vitamin E was first
described on neurons in culture against Aβ–induced cell
death [147]. Following these initial findings, a number of
subsequent studies confirmed the role of oxidative stress in
the neurotoxic effect of Aβ peptide. For example, Behl et al.
Biochemical and Therapeutic Effects of Antioxidants Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 2 99
[161] found that Aβ can induce the formation of H
2
O
2
in
hippocampal neurons which causes peroxidation of cell
membranes and ultimately leads to neuronal death.
Consistent with these findings, exposure of cultured
hippocampal neurons to Aβ induced a significant increase in
4-HNE [162]. Moreover, it has recently been found that the
phenolic antioxidant curcumin, which is largely used as a
food preservative and herbal medicine in India, reduces
oxidative damage and amyloid pathology in a transgenic
mouse model of AD [163]. However, in another study, Aβ-
induced neurotoxicity in rat hippocampal neurons in culture
was not affected by several antioxidants [164]; nevertheless,
pretreatment of cultures with Aβ significantly increased the
sensitivity of neurons to H
2
O
2
, suggesting that Aβ can
render neurons more susceptible to ROS damage [164].
In agreement with data obtained in experimental models,
clinical findings indicate that oxidative stress occurs in AD,
as indicated by the finding that higher than normal levels of
lipid, protein, and DNA oxidation are found in the brains of
AD patients [43,45,96,97,165]. Thus lipid peroxidation,
measured as thiobarbituric acid reactive substances (TBARS)
were found to be increased in various brain regions of AD
patients [166-168]. Moreover, Mecocci et al. [50] found a
significant three-fold increase in mitochondrial DNA
oxidation in the parietal cortex of AD patients. In addition,
immunohistochemical analysis of brain sections from AD
patients using an antibody with selectivity for the activated
nuclear form of p65 revealed that NF-κB was activated in
neurons and astrocytes [60]. Cells with activated NF-κB
were restricted to the close proximity of early plaque stages
[60]. Thus, it is possible that Aβ-induced NF-κB activation
contributes to the pathological changes observed in AD via
the induction of proinflammatory and cytotoxic genes or,
more likely, that Aβ-induced NF-κB activation is part of a
cellular defense program.
Based on the preclinical and clinical data indicating the
presence of oxidative stress in AD, clinical trials were carried
out to test the effect of antioxidants in this pathological
condition. Thus, a controlled clinical trial with dl-α-
tocopherol (synthetic form: 2,000 IU/d) in patients with
moderately severe impairment from AD showed some
beneficial effects with respect to rate of deterioration of
cognitive function [169]. In the same dl-α-tocopherol
clinical trial, selegiline (10 mg/d), a monoamine oxidase
inhibitor, produced beneficial effects similar to that produced
by dl-α-tocopherol [169]. It is interesting to note that there
was no significant difference in effect between the groups
receiving a combination of dl-α-tocopherol and selegiline
and those receiving treatment with the individual agent
[97,169]. Several possibilities were proposed to explain the
lack of additive effect. One of them was that selegiline and
vitamin E may act by the same mechanism. Indeed, both
reduce the levels of free radicals, although by different
mechanisms. Vitamin E protects neurons by destroying
formed ROS (“quenching”), whereas selegiline protects
neurons by preventing the formation of ROS and by
inhibiting oxidative metabolism of catecholamines.
Therefore, clinical studies involving vitamin E and
selegiline support the concept that ROS are one of the
intermediary risk factors for the progression of
neurodegeneration in AD [145].
PARKINSON’S DISEASE
Parkinson’s disease is a neurological syndrome
manifested by any combination of tremor at rest, rigidity,
bradykinesia, and loss of postural reflexes. The
neuropathological hallmark of PD is the selective
degeneration of dopamine (DA) neurons in the nigrostriatal
system [170,171]. These neurons synthesize and release DA,
and the loss of dopaminergic influence on other structures in
the basal ganglia leads to the classic parkinsionian
symptoms. Moreover, PD is characterized by degeneration of
monoamine-containing neurons in the brain stem nuclei
(predominantly the locus coeruleus) and is variably
associated with pathology in non-nigral systems causing
multiple neurotransmitter dysfunctions [172].
Although idiopathic PD is usually sporadic, it is now
well established that there is a genetic component to the
disease [174,174]. Approximately 5-10% of PD patients
have a familial form of parkinsonism with an autosomal-
dominant pattern of inheritance [174]. Case control studies
have typically indicated a 2-14-fold increase in incidence in
close relatives of PD patients [175] and although
concordance rates between identical twins are low for overt
expression of the disease, they are much higher when
subclinical decline in striatal dopaminergic function is
measured by positron emission tomography (PET) imaging
(53% in monozygotic twins of PD patients, compared with
13% in dizygotic cases) [176]. Nevertheless, in sporadic PD,
environmental factors have been emphasized [177]. Thus,
epidemiological studies indicate that a number of factors
may increase the risk of developing PD [178]. These include
exposure to well water, herbicides, industrial chemicals,
wood pulp mills, farming, and living in a rural
environment. A number of exogenous toxins have been
associated with the development of parkinsonism, including
trace metals, cyanide, lacquer thinner, organic solvents,
carbon monoxide, and carbon disulfide [174]. There has also
been interest in the possible role of endogenous toxins such
as tetrahydroisoquinolines and β-carbolines. However, no
specific toxins has been found in the brain of PD patients.
The most compelling evidence for an environmental factor in
PD relates to the toxin 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP). MPTP is a byproduct of the
illicit manufacture of a synthetic meperidine derivative.
Some of the drug addicts who took MPTP developed a
syndrome that strikingly resembled PD, both clinically and
pathologically [179,180]. MPTP induces toxicity through
its conversion in astrocytes to the pyridinium ion (MPP
+
) in
a reaction catalyzed by by monoamine oxidase B (MAO-B)
[8]. MPP
+
is then taken up by DA neurons and causes
mitochondrial complex I defect similar to that found in PD
[181]. This observation supports the possibility that an
environmental factor might cause PD; however, no MPTP-
like factor has been identified in PD patients to date.
The principal cytoskeletal pathology of PD is the Lewy
body, which, in 85-100% of cases occurs in many
monoaminergic and other subcortical nuclei, spinal cord,
sympathetic ganglia, and less frequently in cerebral cortex,
myenteric plexuses, and adrenal medulla [170,182-185]. In
the majority of cases, the mechanisms involved in nigral
degeneration in PD are unknown, but evidence from studies
of post-mortem brain tissue suggests the involvement of
100 Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 2 Di Matteo and Esposito
ROS and oxidative stress [8,162,186]. Oxidative stress may
arise from the metabolism of DA with the production of
potentially harmful free radical species [186,187]. This may
be important as surviving neurons increase DA turnover to
compensate for diminishing synaptic transmission.
Circumstantial evidence exists that defects in
mitochondrial energy metabolism may cause nigral neuronal
denegeration in PD. As already mentioned, MPTP produces
dopaminergic neuronal degeneration and parkinsonian
symptoms in humans and nonhuman primates [188]. 1-
methyl-4-phenylpyridinium (MPP
+
), produced by the
catabolism of MPTP by MAO-B in glia, is selectively taken
up into dopaminergic neurons by the DA transporter. Within
dopaminergic neurons, MPP
+
is concentrated by the
electrochemical gradient into mitochondria. MPP
+
selectively inhibits NADH CoQ reductase (complex I) of the
mitochondrial electron transport chain and induces neuronal
degeneration. Evidence exists that similar mitochondrial
dysfunction may occur in idiopathic PD. Thus, a defect in
complex I has been reported in the striatum of patients with
PD [189-192]. Similar defects have been found in the
platelets [193] but not muscles [194] of patients with PD.
Reductions have been found in the substantia nigra but not
in other regions of the brain, such as the globus pallidus or
cerebral cortex [195]. Therefore, the specificity of
mitochondrial impairment may play a role in the
degeneration of nigrostriatal dopaminergic neurons.
Interestingly, recent evidence indicates that exposure to
complex I inhibitor rotenone can cause nigrostriatal
dopaminergic degeneration associated with parkinsonian-like
symptoms and accumulation of protein aggregates
containing ubiquitin and α-synuclein [196].
Alterations in pro- and antioxidant molecules have been
reported in post-mortem tissue from individuals with PD.
Increased total iron has been found in the substantia nigra in
PD [187,197-199]. Iron could increase oxidative stress by
promoting the formation of OH
.
from H
2
O
2
via the Fenton
reaction. Reductions in GSH levels in the substantia nigra
have also been reported [199-204]. These reductions were not
detected in other neurodegenerative diseases in which nigral
cell loss occurs, suggesting they are specific to PD and not
secondary to cell loss alone. Decreases in GSH have also
been found in the substantia nigra in individuals with
incidental Lewy bodies at postmortem, a potential marker of
preclinical PD, suggesting that alterations in GSH are an
early event [205]. Reductions in GSH levels could promote
or be a consequence of oxidative stress, or both. Because
GSH is involved in the detoxification of H
2
O
2
, reductions
in GSH could result from increased concentrations of H
2
O
2
and in the presence of metals, the highly reactive OH
.
. The
presence of lipid peroxidation and oxidative DNA damage
further supports the existence of oxidative stress in PD
[186,206-208].
As already mentioned, the hallmark of PD is a severe
reduction of DA in all components of the basal ganglia. DA
and its metabolites are depleted in the caudate nucleus,
putamen, globus pallidus, nucleus accumbens, the ventral
tegmental area, and the substantia nigra pars compacta and
reticulata. Moderate losses of DA are found in the lateral
hypothalamus, medial olfactory region and amygdaloid
nucleus [209]. In early parkinsonism, there appears to be a
compensatory increase in DA receptors to accomodate the
initial loss of DA neurons [210,211]. As the disease
progresses, the number of DA receptors decreases, apparently
due to the concomitant degeneration of DA target sites on
striatal neurons. In the remaining neurons in patients with
PD, DA turnover seems greatly increased, judging from the
concentrations of homovanillic acid (HVA) in the nerve
terminals in the striatum and the cell bodies and dendrites in
the substantia nigra [212], and the ROS production may
very well increase in consequence. This hypothesis is
strengthened by a study showing that the concentrations of
GSH decrease when DA turnover increases after reserpine
treatment in rats, indicating increased activity of the
peroxide scavenging enzyme GSH-Px [213]. If the increase
in ROS production due to increased DA turnover is not
buffered by the scavenging enzymes (SOD, catalase, and
GSH-Px), the compensatory hyperactivity of the
dopaminergic neurons may become self-destructive. Chronic
administration of L-DOPA would then only exacerbate the
production of destructive ROS [214,215]. The
administration of L-DOPA itself has been postulated to
enhance the accumulation of ROS [216,217]. Hiramatsu et
al. [218] by using electron spin resonance spectrometry have
shown that 10 mM L-DOPA by itself was inactive, whereas
it produced ROS in the presence of 10 mM Fe-
diethylenetriamine-pantaacetic acid, and this effect was
blocked by deprenyl, an inhibitor of MAO-B, which has
been advocated as a symptomatic and protective therapy in
PD [219], as well as MPTP-induced parkinsonism [220].
Another index of oxidative stress in PD might be the
evidence of a robust increase of NF-κB in the nuclei of
dopaminergic neurons in the substantia nigra of PD patients
[59]. This clinical finding is consistent with in vitro data
showing that oxidative stress induced by C
2
-ceramide
treatment causes nuclear translocation of NF-κB in cultured
mesencephalic neurons [59]. More recently, it has been
shown that the neurotoxin 6-OHDA activates NF-κB in
PC12 cells by enhancing intracellular ROS levels [221].
Interestingly, in this experimental moodel, NF-κB seems to
sustain cell survival by stimulating the expression of the
anti-apoptotic proteins bcl-2 and bfl-1 [221]. Moreover, as
already mentioned, the potent green tea polyphenol
antioxidant EGCG exerts a neuroprotective effect in a MPTP
mouse model of PD [88].
When induced by the toxins 6-OHDA or MPTP in
animal models of PD, nigral cell death seems to involve
both necrotic and apoptotic processes. In human PD there
has been some debate about whether key features of
apoptosis could be demonstrated, at least when based on
morphological features or TUNEL (terminal
deoxynucleotidyl transferase-mediated dUTP-fluorescein nick
end-labeling) alone [222,223]. However, the recent
development of techniques involving double labeling with
TUNEL to demonstrate DNA fragmentation in conjuction
with cyanine dye that binds to DNA to provide structural
details, has demonstrated chromatin condensation and DNA
fragmentation whithin the same nuclei in the substantia
nigra of parkinsonian patients [223]. These results indicate
that the number of apoptotic nuclei in the substantia nigra in
PD is greater than that seen in normal aging, consistent with
the 10-fold higher rate of cell loss seen in patients with the
disease [174,224].
Biochemical and Therapeutic Effects of Antioxidants Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 2 101
The progressive nature of PD and the fact that neuronal
degeneration in the substantia nigra is slow and protracted
[225] present opportunities for therapeutic intervention
aimed at blocking or slowing down the degenerative process.
Recent neuroimaging and autopsy data indicated that there is
a preclinical period of 4-5 years before symptoms appear,
and that the rate of cell loss and decline of dopaminergic
function in the striatum is likely to be in the order of 10%
per year, with the disease progressing relatively more rapidly
during the early phases that the more advanced stages of the
disease [176,225]. Both PET and SPECT (single-photon
emission computed tomography) imaging seem to be able to
detect a decline in striatal dopamine function before clinical
symptoms appear [176], which may make it possible to
begin neuroprotective intervention during the preclinical
phase.
The largest neuroprotective trial conducted to date, the
DATATOP (Deprenyl and Tocopherol Antioxidant Therapy
of Parkinsonism) study [226], involved two putative
antioxidant agents, vitamin E and deprenyl [227-229].
Vitamin E had no significant effect at the doses used, but
deprenyl slowed the early progression of symptoms and
delayed the emergence of disability by an average of nine
months. However, being an MAO-B inhibitor, this drug has
symptomatic effects of its own, which has confounded
interpretation of the results [227]. Interestingly, animal
studies have suggested that the neuroprotective effect is not
dependent on MAO-B inhibition per se, but rather on an
antiapoptotic effect of the metabolite desmethyl-deprenyl,
possibly acting on protein transcription [224,230]. Before
the completion of the DATATOP large study (n = 800), an
open trial with high dosages of α-tocopherol and ascorbate,
administered to a small group of early PD patients (n = 15),
found that this combination of natural antioxidants delayed
by 2.5 years the time necessary to begin the therapy with L-
DOPA [231]. There are many alternative antioxidative
approaches that may be considered in future clinical trials,
including free-radical scavengers, GSH, GSH enhancing
agents, ion chelators and drugs that interfere with oxidative
metabolism of DA. Interestingly, the classic directly acting
DA receptor agonists may belong to the last group: by
stimulating DA autoreceptors, these drugs reduce DA
synthesis, turnover and release, so that less L-DOPA is
needed [232]. In addition, some of these compounds have
direct antioxidant effects [233,234]. More recently, the DA
receptor agonist pramipexole has been used as a
monotherapy for the treatment of PD, and it has been shown
that it may have neuroprotective effects [235].
AMYOTROPHIC LATERAL SCLEROSIS
Amyotrophic lateral sclerosis (ALS) is a fatal paralytic
neurodegenerative disorder of unknown cause, mainly
characterized by a progressive loss of motor neurons in the
cerebral cortex, brainstem and spinal cord. ALS is a
progressive disease that invariably leads to death within
approximately 3 to 5 years from the onset of symptoms
[236]. The annual worldwide annual incidence rates for ALS
range between 0.4 and 1.8 per 100,000 population and the
prevalence rates range between 4 and 6 per 100,000
population, with an overall male predominance [237].
Although most cases are sporadic, about 5-10% are familial,
with inheritance following an autosomal dominant pattern.
About 15-20% of patients with familial ALS (FALS), which
is clinically indistiguishable from the more common
sporadic ALS, carry mutations in the gene encoding for the
free radical scavenging enzyme SOD-1 [238-240]. Over 50
different SOD-1 mutations have been documented in FALS
patients [241]. Transgenic mice have been generated that
express mutant forms of SOD-1 found in FALS cases,
including gly
93
→ ala (G93A) [242-244] and gly
37
→ arg
[245], which develop motor neuron disease and death within
4-6 months if the mutant enzyme is expressed at sufficient
levels. Studies of FALS patients with mutations of SOD-1
indicates that SOD-1 activity is decreased 20 to 50%
[239,246]. This suggested initially that the disease was due
to ROS-induced damage resulting from structurally defective
enzyme with reduced activity [239]. However, no deletions
of SOD-1 gene have been found in FALS families, which
implies that expression of the mutant protein is required for
pathogenesis. Studies in transgenic mice suggest that, rather
than causing a loss of function, the mutations of SOD-1 in
FALS patients cause a gain of function that results in
neuronal degeneration [244,247]. Because transgenic mice
expressing wild-type human SOD-1 with comparable
elevation of brain SOD activity do not develop motor
neuron disease [244,245] and in fact, show enhanced
resistance to oxidative stress [248,249], disease is due to
expression of the mutant protein and not to elevation of
SOD activity in the brain [250-252]. Several investigators
have found increased levels of ROS in animals models of
ALS [253-255]. Consistent with animal data, a number of
clinical studies indicate that oxidative stress may be
involved in the pathology of ALS, as suggested by increased
levels of oxidative damage products, such as protein
carbonyls, 4-HNE, 8-OHdG, and nitrotyrosine
[17,41,48,255-258]. In addition, fibroblasts from ALS
patients were found to be more sensitive to oxidative stress
[259]. Moreover, immunohistochemical studies have shown
that NF-κB is strongly activated in astrocytes of the spinal
cord of ALS patients, probably as a consequence of the
oxidative stress [61]. Thus, the occurence of oxidative stress
and activation of NF-κB is a common characteristic of AD,
PD, and ALS. In this regard, it is noteworthy that overlap
syndromes with clinical and pathological features of
dementia, ALS and PD have been described [260]. It is also
important to mention that degeneration of midbrain DA
neurons occurs in a mouse model of ALS [261].
Various drugs which can act by reducing oxidative stress
have been used as potential therapeutic agents in transgenic
mice expressing the mutated human SOD-1 enzyme. Thus,
polyamine- or putrescine-modified catalase, an antioxidant
enzyme that removes hydrogen peroxide and has good
permeability at the blood-brain barrier, increases the survival
of transegenic mice bearing the human mSOD-1
G93A
[262,263]. Moreover, the copper chelator and thiol
compound penicillamine, the copper chelator trientine,
carboxyfullerenes, vitamin E and N-acetylcysteine have been
reported to increase the survival time in this mouse model
and/or delay the onset of the disease to a small extent [264-
267]. The drug riluzole, which inhibits glutamate release at
presynaptic terminals, also extends lifespan slightly in
human mSOD-1
G93A
transegenic mice [267]. Interestingly,
riluzole, which is used clinically in patients with ALS
102 Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 2 Di Matteo and Esposito
[268], has been shown to have direct antioxidative effect on
cultured cortical neurons [269]. However, no clear evidence
for a beneficial effect of α-tocopherol, selegiline, N -
acetylcysteine or an antioxidant cocktail has been obtained in
humans [270-272].
Li et al. [273] have recently reported that blockade of
caspase-1 and caspase-3 activity by N-benzyloxycarbonyl-
Val-Asp-fluoromethylketone (zVAD-fmk), prolongs the
survival of transgenic mice expressing the human mSOD-
1
G93A
, which begin to develop ALS symptoms at the mean
age of about 3 months. These findings open new
perspectives for the use of caspase inhibitors as potential
therapeutic agents in the treatment of ALS and other
neurodegenerative diseases. However, because of the low oral
bioavailability and limited brain penetrance, zVAD-fmk was
delivered by intracerebral administration. Thus, the
physicochemical characteristics of zVAD-fmk might limit its
clinical usefulness. Based on these findings and on the
hypothesis that in transgenic mice expressing the human
mSOD-1
G93A
an increased formation of ROS occurs, we
decided to treat them with lyophilized red wine (which is
rich in antioxidant compounds), dissolved in the drinking
water which was freely available to the animals. This
treatment regimen caused a significant reduction in the
overall mortality of the treated mice, as compared with
control animals. Thus, lyophilized wine prolonged by 6%
the survival of mSOD1
G93A
mice [274]. In the first series of
experiments, the onset of treatment was variable, and
ranging from 43 to 66 days of age [274]. We have recently
repeated the experiments on mSOD1
G93A
mice which were
treated with the same concentration of lyophilized red wine,
but the treatment was started earlier, i.e. 30-40 days from
birth. By using this protocol we have found that
administration of lyophilized red wine significantly
increased the mean survival time by 15%, as compared with
control transgenic mice given drinking water only. The
calculated concentration of polyphenolic compounds,
expressed as gallic acid equivalent (GAE), was 4824 mg/L.
Considering that each mouse drank about 4 ml of liquid
daily, it is possible to calculate the daily intake of GAE,
which was about 20 mg per mouse. It is tempting to
speculate that the mechanism of neuroprotection exerted by
lyophilized red wine on mSOD1
G93A
mice might be due to
its ability to inhibit caspase-3 acvity. This hypothesis is
based on in vitro experiments showing that lyophilized red
wine (5 µg/ml) caused a significant inhibition of caspase-3
activity on primary cultures of rat cerebellar granule neurons
[79]. However, it is presently impossible to establish
whether the effect of lyophilized red wine on caspase-3 is
direct or mediated by inhibition of ROS formation.
Furthermore, ex vivo experiments aimed at investigating the
inhibitory effect of lyophilized red wine on activated
caspase-3 in mSOD-1
G93A
mice are necessary to confirm our
hypothesis.
CONCLUSIONS
There is growing evidence that oxidative stress may play
an important role in the pathogenesis of AD, PD, and ALS.
However, in spite of the large body of experimental data
showing the protective effect of antioxidants in in vitro
models of neurodegeneration and in some animal models,
there is still limited evidence for a neuroprotective effect of
antioxidants in the treatment of neurodegenerative disorders
in humans. There may be several reasons for this discrepancy
between pre-clinical and clinical data. Thus, it is conceivable
that the therapeutic regimen used so far (e.g., one or two
antioxidants) might not be sufficient to halt the
neuropathologic process. As pointed out by others, a more
efficient strategy would be the use of multiple antioxidants
in the treatment of AD, PD, and ALS [97]. In this regard, it
is important to point out that one possible advantage of the
use of extracts of fruits, vegetables or beverages (such as red
wine, green tea or ginkgo biloba) in the treatment of
neurodegenerative disorders, is that they often contain
multiple antioxidant compounds which can potentiate each
other. Particularly important would be the use of lyophilized
red wine [274] which is provided with strong antioxidant
capacity [69-71]. Moreover, one possible limitation of the
neuroprotective strategy (including antioxidant
administration) might be consequent to the fact that when
overt symptomatology of AD, PD, and ALS occurs, a
certain amount of neuronal death has already occurred. Thus,
the neuroprotective agents (including antioxidants) can, at
best, only rescue the surviving neurons, an effect which
might not be sufficient to attenuate the neurologic
symptomatology. It is therefore important to start the
therapeutic intervention at an early stage of the disease
process. In this regard, it is interesting to note that some
epidemiological studies have shown that dietary habits can
inflence the incidence of neurodegenerative disorders. In
particular, it was found that a diet rich in vitamin E can
reduce the risk for PD [66,72], and that moderate wine
consumption may decrease the risk for AD [64,65].
However, there are still few and controversial [63,75]
epidemiological data on this important point, which might
be partly due to the intrisic difficulties in performing
epidemiological surveys regarding the dietary habits of large
populations. Nevertheless, it is desirable that future studies
aimed at investigating the relationship between dietary
antioxidant intake and the relative risk for neurodegenerative
disorders such as AD, PD, and ALS will throw more light
on this very important aspect of public health.
ACKNOWLEDGEMENTS
This work was supported in part by the Italian MIUR
(Ministero Istruzione Università Ricerca) DM 623/96 –
2002, and L 488/92 Project N° S209-P/F.
ABBREVIATIONS
Aβ =Amyloid β-peptides
AD = Alzheimer's disease
ADNF = Activity-dependent neurotrophic factor
ALS =Amyotrophic lateral sclerosis
CAPE = Caffeic acid phenethyl ester
DA = Dopamine
DATATOP = Deprenyl and tocopherol antioxidant therapy
of parkinsonism
EC =(—)-Epicatechin
Biochemical and Therapeutic Effects of Antioxidants Current Drug Targets - CNS & Neurological Disorders 2003, Vol. 2, No. 2 103
ECG =(—)-Epicatechin-3-gallate
EGC =(—)-Epigallocatechin
EGCG = (—)-Epigallocatechin-3-gallate
FALS = Familial amyotrophic lateral sclerosis
GAE = Gallic acid equivalent
GSH = Glutathione
GSH-Px = Glutathione peroxidase
4-HNE = 4-Hydroxy-2-trans-nonenal
HVA = Homovanillic acid
IAPs = Inhibitor-of apoptosis proteins
IKKs = IkB kinases
MAO-B = Monoamine oxidase B
MMSE=Mini-Mental State Examination
MPP
+
= 1-Methyl-4-phenylpyridinium
MPTP = 1-Methyl-4-phenyl-1,2,3,6-
tetrahydropyridine
NAC = N-acetyl-L-cysteine
NF-kB = Nuclear factor-kB
NGF = Nerve growth factor
NMDA = N-methyl-D-aspartate
6-OHDA = 6-Hydroxydopamine
8-OHdG = 8-Hydroxy-2’-deoxyguanosine
PAQUID = Personnes Agees Quid
PBN = α-Phenyl-tert-butyl nitrone
PD = Parkinson’s disease
PET = Positron emission tomography
PUFA = Polyunsatured fatty acids
ROS = Reactive oxygen species
SOD-1 = Cu/Zn superoxide dismutase
SOD-2 = Mn superoxide dismutase
SPECT = Single-photon emission computed
tomography
TBARS = Thiobarbituric acid reactive substances
TUNEL = Terminal deoxynucleotidyl transferase-
mediated dUTP-fluorescein nick end-
labeling
zVAD-fmk = N-benzyloxycarbonyl-Val-Asp-
fluoromethylketone.
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