Vol. 8(25), pp. 685-700, 8 July, 2014

DOI: 10.5897/AJPP2013.3963
Article Number: E4D4F4346171
ISSN 1996-0816
African Journal of Pharmacy and
Copyright © 2014 Pharmacology
Author(s) retain the copyright of this article
http://www.academicjournals.org/AJPP

Review

Potential involvement of oxidative stress in induction of

neurodegenerative diseases: Actions, mechanisms and
neurotherapeutic potential of natural antioxidants
George Laylson da Silva Oliveira1, Francisco Rodrigo de Asevedo Mendes de Oliveira1 and
Rivelilson Mendes de Freitas1*
Pharmaceutical Sciences, Federal University of Piaui, Teresina, Piaui, 64049-550, Brazil.
Received 1 December, 2013; Accepted 2 July, 2014

Several studies have shown that oxidative damage to various organs of a given organism is involved in
causing various diseases, and in this context, the brain is highly vulnerable to oxidative stress because
of its high metabolic rate, low capacity of cell regeneration, small amounts of enzymatic and non-
enzymatic antioxidants. Oxidative stress is caused by an imbalance in cell redox state, in which there is
excessive production of reactive oxygen species and/or failure of antioxidant defense systems.
Consequently, oxidative stress in brain has shown direct implications in the pathogenesis of several
neuro-degenerative diseases such as Alzheimer's, Parkinson's, Huntington's, Schizophrenia and
amyotrophic lateral sclerosis. In this review, the critical role of oxidative stress in neuro-degenerative
diseases as well as some aspects of antioxidant compounds (phenolic compounds and vitamins)
regarding prevention and/or treatment of Alzheimer's, Parkinson's, Huntington's, Schizophrenia and
amyotrophic lateral sclerosis were evaluated.

Key words: Natural antioxidants, brain, neurodegenerative diseases, oxidative stress.

INTRODUCTION

Oxidative stress causes damage to various cellular and also discussed the use of antioxidants of natural
processes in a deleterious manner, and consequently origin as neurotherapy in diseases such as Alzheimer's,
plays important roles in the development of many Parkinson's, Huntington's, Schizophrenia and
diseases, including those that affect the central nervous amyotrophic lateral sclerosis.
system such as neuro-degenerative diseases. Thus, This review was made based on a literature search
many studies have aimed at researching new treatment using Science Direct (http://www.sciencedirect.com),
strategies using antioxidants as a therapy for neuro- Scopus (http://www.scopus.com), Pub Med
degenerative diseases (Choi et al., 2012; Johri and Beal, (http://www.ncbi.nlm.nih.gov/pubmed), Web of Science
2012; Jin et al., 2013a; Li et al., 2014; Deslauriers et al., (http://wokinfo.com) and SciFinder
2014). This review reports a general view on oxidative (http://cas.org/products/scifindr/index.html). The search
stress in pathophysiology of neuro-degenerative diseases was conducted until May 2014 using the following terms:

*Corresponding author. E-mail: rivelilson@pq.cnpq.br. Tel: +55 86 3215 5870. Fax: +55 86 3215 5870.
Author(s) agree that this article remain permanently open access under the terms of the Creative Commons Attribution
License 4.0 International License
686 Afr. J. Pharm. Pharmacol.
oxidative stress, reactive oxygen species, reactive
nitrogen species, brain, antioxidants, neurodegenerative
diseases, Alzheimer's disease, Parkinson's disease,
amyotrophic lateral sclerosis, Schizophrenia,
Huntington's disease, phenolic compounds and vitamins.
These words were also used in various combinations,
being considered valid original research article, full text
and that provided the search terms in the title and/or
abstract. The duplicate articles in scientific databases
were excluded and the remaining ones were evaluated
by their eligibility regarding the inclusion and exclusion
criteria, by reading and analyzing title and abstract.
Articles in English published up to 2014 were analyzed.
OXIDATIVE STRESS IN BRAIN
The chemical substances that have one or more unpaired
electrons are considered free radicals, which have as
main characteristic that facility to donate their electrons to
other molecules causing chain reactions and oxidative
damage (Liochev, 2013). Free radicals and related
molecules are classified as reactive oxygen species
(ROS) and reactive nitrogen species (RNS) and a wide
variety of these radicals are produced during normal
metabolism in biological systems, which are counter
balanced by cellular antioxidant mechanisms. However,
the imbalance by excessive ROS and RNS and
decreased antioxidant defense systems at cellular level
cause oxidative stress (Figure 1), which can be induced
to damage by peroxidation of cellular structures, protein
oxidation, DNA damage and inhibition of electron
transport chain in mitochondria (Dasuri et al., 2013).
ROS are represented by a group of chemicals that
include the superoxide anion (O2•-), hydroxyl (HO•),
peroxyl (RO2•), hydroperoxyl (HO2•), lipid hydroperoxide
(LOOH), hypochlorous acid (HClO), singlet oxygen (O2)
and hydrogen peroxide (H2O2). RNS produced in cells
are represented by nitric oxide (NO) and peroxynitrite
(ONOO•) (Roberts et al., 2010; Koskenkorva-Frank et al.,
2013). The superoxide anion, hydroxyl and hydrogen
peroxide are the main ROS. Among these, the
superoxide anion is formed due to reduction of molecular
oxygen by various enzymatic systems (enzymes in the
electron transport chain in mitochondria, xanthine
oxidase, cyclooxygenase and NADPH-oxidase). In turn,
the enzyme superoxide dismutase (SOD) converts the
superoxide anion into molecules of hydrogen peroxide.
Hydrogen peroxide in other reactions, in the presence of
transition metals (iron and copper) is converted into a
very reactive ROS, the hydroxyl radical (Milenkovic et al.,
2013; Koskenkorva-Frank et al., 2013). One of the main
mechanisms responsible by production of ROS in cells of
the brain tissue is illustrated in Figure 2.
Several studies have considered that oxidative damage
to various organs of a given organism is involved in the
onset of various diseases. In this context, the brain is an
organ highly vulnerable to oxidative stress due to its high
metabolic rate, which accounts for 20% of oxygen
consumption (Sultana et al., 2013). In addition, the brain
has low capacity for cellular regeneration, small amount
of antioxidant enzymes (catalase, superoxide dismutase,
glutathione peroxidase and glutathione reductase) and
antioxidant non-enzymatic (reduced glutathione, -
tocopherol and ascorbic acid) and as in any other tissue,
oxidative stress in brain can damage the neurons by
peroxidation of poly-unsaturated fatty acids (arachidonic
acid and docosahexaenoic acid) in cell membrane,
oxidative damage to DNA, RNA, proteins and induction of
apoptosis (Figure 3) (Nunomura et al., 2012; Smith et al.,
2013).
Peroxidation of the cell membrane has as consequence
the increase of stiffness, decreased activity of membrane
bound enzymes, deficiency of membrane receptors and
alters the permeability. ROS and RNS can also attack
directly the proteins of the lipid membrane and cause
fragmentation of proteins, cross-links between proteins
and the formation of carbonyl, which contributes to the
integrity of the cell membrane and interferes with various
cellular processes. ROS and RNS can still attack the
nucleic acids causing the crosslinking of the protein-DNA,
modification of DNA bases, breakage and mutations in
the DNA chain (Sultana et al., 2013).
OXIDATIVE STRESS AND NEURODEGENERATIVE
DISEASES
Oxidative stress and Alzheimer's diseases
Alzheimer's disease (AD) is clinically characterized by
progressive memory loss and severe cognitive function
decline. The accumulation of extracellular amyloid protein
deposited senile plaques and intracellular neurofibrillary
tangles made of abnormal and hyper-phosphorylated tau
protein, regionalized neuronal death, loss of synaptic
connections in selective brain regions, proliferation of
astrocytes and microglia activation, and define neuro-
pathologically the AD. In addition, the oxidative stress
and mitochondrial dysfunction are related to the
development of AD (Gubandru et al., 2013).
Mitochondria are responsible for ATP production,
oxidative phosphorylation, cell cycle control, cell growth
and apoptosis (Chaturvedi and Beal, 2013). Thus, a
problem in energy metabolism contributes to reduced
production of ATP, beyond the generation of excessive
ROS, such as superoxide, hydroxyl radicals and
hydrogen peroxide. The literature describes the
mitochondrial damage induced by ROS and vascular
hyperfusion as key initiators for the development of AD
(Butterfield et al., 2006; Aliev et al., 2010; Massaad et al.,
2009; Parihar and Brewer, 2007; Kovacic and
Somanathan, 2012; Schrag et al., 2013).
Indeed, oxidative imbalance and significant increase of
its bio-products have been consistently reported in AD.
Thus, the products generated from oxidized biomolecules
 Oliveira et al. 687

Figure 1. Representation of oxidative stress.

Figure 2. Representation of ROS/RNS in cells of nervous tissue by reduction of

molecular oxygen to water in mitochondrial electron transport chain, which consists of
four multimeric complexes (I, II, III and IV) and two conveyors of electrons (Coenzyme Q
and Cytochrome C). Complexes I and III are the major sources of production of free
radicals.
688 Afr. J. Pharm. Pharmacol.
Figure 3. Oxidative damage caused by ROS and RNS to various biomolecules.
are stable and used as markers of ROS. Moreover,
exogenous antioxidants and antioxidant enzymes can
indirectly measure the levels of ROS. In that sense, in
lipid peroxidation, significant levels of reactive aldehydes
may be evidenced, including 4-hydroxynonal,
malondialdehyde (MDA), and 2-propenal (acrolein) and
are chemically and metabolically stable iso-prostanoids
including F2-isoprostanes and F4-neuroprostanes (Wang
et al., 2013a; Gubandru et al., 2013; Sultana et al., 2013).
Several investigations show that in the oxidation of
proteins, the most investigated markers are carbonyls
and 3-nitrotyrosine, final product of the interaction of
peroxy nitrite with tyrosine residues (Aksenov et al.,
2001; Castegna et al., 2002; Good et al., 1996; Tohgi et
al., 1999; Butterfield et al., 2001; Castegna et al., 2003;
Reed et al., 2009).
In the oxidation of the genetic material (DNA/RNA), the
hydroxyl deoxyguanosine 8-(8-OHdG) and 8-
hydroxyguanosine (8-OHG) are the main markers, which
are the products of oxidation of guanine (Mecocci et al.,
1994; Nunomura et al., 1999; Shan et al., 2003; Ding et
al., 2005; Honda et al., 2005). Besides the increase these
toxic products of biomolecules, significant reduction of
antioxidants and antioxidant enzymes can be verified.
Study reveals that plasmatic levels of antioxidants such
as albumin, bilirubin, uric acid, lycopene, vitamin A,
vitamin C and vitamin E are decreased in patients with
AD. Similar results can be shown with antioxidant
enzymes such as superoxide dismutase, catalase,
glutathione peroxidase and hemeoxigenase, in different
brain regions (Wang et al., 2013; Foy et al., 1999; Kim et
al., 2006). Despite continued efforts, current therapeutic
strategies are limited to those that soften the symptoms
without impeding the progress of the disease. Thus, there

is growing demand for a treatment capable of protecting
neurons and inhibiting oxidative damage, may be an
effective alternative evidenced in natural antioxidants
(Bonda et al., 2010).
Oxidative stress and Parkinson's diseases
Parkinson's disease (PD) is a chronic neurological
progressive disease and associated with a loss of
dopaminergic neurons in the compact part of the
substantia nigra (SN), clinically characterized by cardinal
symptoms, resting tremor, rigidity, brady kinesia and
postural instability. In addition to dopamine depletion, PD
is neuropathologically defined by the deposition of Lewis
bodies and Lewis neurites in vulnerable neurons. The
etio-pathogenesis of PD is still not fully understood. In
most cases the disease is eventual: a multifactorial
idiopathic disease, seems to arise from a combination of
genetic susceptibility and environmental exposures
(Perfeito et al., 2013; Dickson et al., 2009; Halliday et al.,
2011; Hauser and Hastings, 2013).
Some environmental toxins are involved in the process
of oxidative stress, including paraquat, rotetone, maneb
and MPTP (1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine). The MPTP, for example, crosses the
blood-brain barrier due to their lipophilicity and is oxidized
to a toxic substance, MPP+ (1-methyl-4-
phenylpyridinium) by monoamine oxidase in glial cells.
MPP+ is accumulated in mitochondria of dopaminergic
neurons. The MPP+ inhibits mitochondrial complex I,
causing break in electron transport chain and as a result
the reduction in ATP production and increased production
of ROS (Subramaniam and Chesselet, 2013; Chen and
Le, 2006).
Moreover, evidence shows an association between
oxidative stress and mitochondrial DNA (mtDNA)
mutations with the onset of PD. Associated with constant
exposure to ROS, the lack of protection by histones, and
limited DNA repair mechanisms, make mtDNA particu-
larly vulnerable to oxidative damage, which can lead to
harmful mutations. As a result, a positive feedback is
generated by the accumulation of these mutations, which
can gradually cause a reduction in the efficiency of the
electron transport chain (ETC) stimulating decreased
ATP production and increased production of ROS,
followed by eventual cell death (Yan et al., 2013; Sanders
and Greenamyre, 2013).
In addition, ROS can irreversibly damage protein, for
example, amino groups in side chains of specific amino
acids can be modified to carbonyl groups (Greenamyre
and Sanders, 2013). It recently shows an association be-
tween elevated levels of protein carbonyls and increased
oxidative stress (Hyun et al., 2002). Another study
showed damage of mitochondrial complex I subunit in PD
brains related to high levels of protein carbonyl (Keeney
et al., 2006).
Oliveira et al. 689
Similarly, the oxidized lipids can exercise deleterious
effects on neuronal function and lead to PD. In general,
lipids involved in membrane fluidity and permeability, can
store energy that participate in inflammatory processes
and in apoptosis signaling. The poly-unsaturated fatty
acids are more prone to lipid peroxidation, particularly in
the brain there is a large amount of two of these, the
arachidonic acid and docosahexaenoic acid. After the
adipose tissue, the organ with the highest lipid content is
the brain and thus, it is very prone to lipid peroxidation
(Ruipérez et al., 2010; Bochkov et al., 2002; Roberts II
and Fessel, 2004; Chen et al., 2008). Evidence supports
an association between lipid peroxidation and PD (Hyun
et al., 2002; Hoepken et al., 2007; Lee et al., 2001).
Oxidative stress and Huntington's diseases
Huntington disease (HD) is a progressive neuro-
degenerative disorder characterized by presence of
emotional and movement disorders and dementia (Ayala-
Peña, 2013). HD has autosomal dominant transmission
with the mutant gene termed IT15, responsible for the
disease located on chromosome 4. The mutation respon-
sible by this disease consists in an excessive number of
abnormal tri-nucleotide cytosine-adenine-guanosine
(CAG). The mutant gene encodes a protein called
huntingtin, which interacts with several proteins that are
involved in transcription, cell signaling and intracellular
transport. As a result of repeated CAG, may be
polyglutamine expansion located near the N-terminus of
protein molecule. The expanded poly-glutamine chains
lead to fragmentation of protein, which tends to accumu-
late inside the neuron. The aggregation of protein
fragments causes changes in neuronal functioning and
possibly plays a role in neuronal death process (Goldberg
et al., 1994; DiMauro and Schon, 2008; Harjes and
Wanker, 2003; Cattaneo et al., 2005; Ha et al., 2012).
It is known that oxidative stress is mediated by
increased ROS, including superoxide, hydrogen peroxide
and hydroxyl radical. These ROS impair cell function by
degrading proteins, lipids and nucleic acids and
consequently, there is a vicious cycle of mitochondrial
oxidative damage in Huntington's diseases. In context of
mutant Huntington expression, the ROS overproduction
causes accumulation and exhaustion of mtDNA damage
and reduced mitochondrial bioenergetics.
Simultaneously, the mutant Huntington affects mtDNA
repair, avoiding the accumulation of human apurinic/
apyrimidinic endonuclease (APE1) in mitochondria, which
further contributes to mitochondrial damage. As a result,
the mtDNA damage leads to exacerbated mitochondrial
dysfunction and possible neuro-degenerative diseases. In
addition, oxidative damage to nuclear DNA also
contributes to mitochondrial dysfunction and contributes
to activation of DNA repair processes that may lead to
expansion of the CAG repeat (Mochel and Haller, 2011;
690 Afr. J. Pharm. Pharmacol.
Johri and Beal, 2012; Ayala-Peña, 2013). Furthermore,
oxidative modification of proteins (protein carbonyl) and
lipids (malondialdehyde and 4-hydroxynonenal) are also
increased in HD in the brain (Beal and Browne, 2006).
Relevant characteristics that support the relationship
between oxidative stress and HD, can be evidenced by
accumulation of several markers, such as lipofuscin
derived from peroxidation of unsaturated fatty acids, 3-
nitrotyrosine acids (nitrated protein) as well as 8-hydroxy-
2-deoxyguanosine (OH8dG) in mtDNA (Dhillon and
Fenech, 2013).
Oxidative stress and Schizophrenia
Schizophrenia is a chronic debilitating neuro-
degenerative disorder and is characterized by several
positive symptoms such as delusions, hallucinations,
disorganized speech and negative symptoms, including
deficits in cognitive and social capacity and blunted affect
(Yao and Keshavan, 2011). The initial pathophysiology of
schizophrenia collaborates to increase the generation of
reactive oxygen species in the brain (Bitanihirwe and
Woo, 2011). In addition, genetic evidence demonstrates
that decreased capacity of synthesizing antioxidant
enzymes, such as glutathione (GSH) under conditions of
oxidative stress favor the appearance of schizophrenia
(Gysin et al., 2007; From et al., 2009). As previously
discussed, excessive ROS cause damage to important
macromolecules such as DNA, proteins and lipids. It can
affect the genetic material by modifying gene expression,
protein oxidation, making them non-functional and
peroxidative damage in lipids, which results in damage to
cell membrane and cell organelles (Wu et al., 2013).
Additionally, dopamine, an auto-oxidizable neuro-
transmitter, has a dihydroquinone structure that can be
oxidized by molecular oxygen to form hydrogen peroxide
and o-quinone. Thus, the catecholamines oxidation
combined to deficient antioxidant system in the brain,
produces an excess of free radicals resulting in oxidative
stress (Bošković et al., 2011).
Oxidative stress and amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is one of the major
neurodegenerative disorders regarding the
neuromuscular junction. The disease is characterized by
selective degeneration of upper motor neurons
(corticospinal) and lower (spinal and bulbar), which
results in pathological mis-communication between nerve
and muscle (Pansarasa et al., 2013). The majority of ALS
cases are of unknown etiology (sporadic). However, the
identification of mutant genes that predispose to these
disorders has provided the means to better understand
its pathogenesis. It is known that this condition occurs in
a change mutant gene that encodes Cu/Zn superoxide
dismutase type 1 (SOD1), enzyme that removes free
radicals and protects cells (motor neurons) from oxidative
stress (Halter et al., 2010; Rosen et al., 1993). Studies
have shown that SOD1 in its mutant version can cause
mitochondrial dysfunction. The accumulation of SOD1
aggregates in membrane of mitochondria can cause
blockage of proteins import, excessive ROS production
and eventual cell death by apoptosis (Vijayvergiya et al.,
2005; Mattiazzi et al., 2002; Takeuchi et al., 2002).
NATURAL ANTIOXIDANTS WITH
NEUROTHERAPEUTIC POTENTIAL
Recently, natural antioxidants have gained great
importance in treatment or prevention of diseases such
as cancer, diabetes, cardiovascular and mainly neuro-
degenerative disorders. Scientific studies have already
developed and discussed in preceding paragraphs
demonstrate that the generation of ROS and RNS have
direct implications in neurodegenerative diseases such
as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis
and Huntington's disease. Thus, there is great interest in
studies aiming to investigate the therapeutic potential of
natural antioxidants for preventing or controlling oxidative
stress in neurodegenerative diseases, since it is known
that brain tissue is vulnerable to oxidative damage by
having abundant lipid content and relative scarcity of
antioxidant enzymes when compared with other tissues
(Figure 4).
Antioxidants such as vitamins, phenolic compounds
and flavonoids have been extensively investigated as
potential therapeutic agents in vitro and in vivo for
prevention of neurodegenerative diseases (Ebrahimi and
Schluesener, 2012; Choi et al., 2012). Most of these
antioxidant compounds can be found in fruits, vegetables,
plants or synthesized, and the antioxidant mechanisms
can act by induction of gene expression of endogenous
antioxidant defense systems (activation of nuclear factor
kappa B, NF-kB), regulation of ROS and RNS, interaction
with oxidative pathways and the capacity to chelate metal
ions responsible for the formation of free radicals (Dajas,
2012) (Figure 5).
VITAMINS
Vitamins C, A, E and B6 shown in Figure 6, are
substances with high capacity to remove ROS and RNS
in vitro and in vivo studies, and therefore can act in
prevention of oxidative stress and possible treatment for
neurodegenerative diseases such as Alzheimer's and
Parkinson's disease (Table 1). For example, studies
performed by Ahmed (2012) in mice provided important
evidence that dietary supplementation with vitamins
slows the progression of neurodegenerative diseases like
Alzheimer's.
 Oliveira et al. 691

Figure 4. Number of publications addressing antioxidants and neurodegenerative diseases,

published between 2003 and 2013. Source: Pubmed and Science Direct.

Figure 5. Main antioxidant mechanisms against ROS/RNS.SOD (superoxide dismutase), CAT

(catalase), GPx (glutathione peroxidase).

Vitamins C and E are natural compounds well known
for their high antioxidant capacity in in vitro and in vivo
experimental models. Once there is an involvement of
ROS and RNS in neurodegenerative diseases, vitamins
C and E have been considered as potential therapeutic
agents for neurodegenerative diseases such as
Alzheimer's, Parkinson's, Huntington's and amyotrophic
lateral sclerosis (Heo et al., 2013). For example, Miyake
et al. (2011) investigated the relationship between intake
of antioxidant vitamins and risk of Parkinson's disease in
Japan using data from a case-control study of hospital-
based multicenter.This study included 249 patients with
Parkinson's disease and results indicated that a higher
intake of vitamin E might be associated with a reduced
risk of Parkinson's disease. In another epidemiological
study involving 6 patients bearer of Alzheimer's disease,
Morris et al. (2005) demonstrated that ingestion of vitamin
E could contribute to preventing the neurodegenerative
692 Afr. J. Pharm. Pharmacol.
Figure 6. Chemical structures of vitamins C, B6, E and A.
disease.
Even considering the pharmacological potential of
Vitamin C, there are conflicting scientific studies on its
potential in treatment of various neurodegenerative
diseases, including Alzheimer's disease. For example, in
the study of Arlt et al. (2012) involving the 12 patients
with Alzheimer's disease, was observed that supplemen-
tation with vitamin C did not have significant effect on the
prevention of Alzheimer's disease over 1 year. In another
study involving 57 patients with Alzheimer's disease and
treated with vitamin E, it has been observed that the
oxidative stress was not inhibited when it was considering
the oxidized glutathione levels (Lloret et al., 2009).
Vitamins addressed in Figure 6 are part of human diet
and are considered substances with high antioxidant
capacity. Thus, these antioxidant properties have attrac-
ted great attention for the treatment of neurodegenerative
diseases, but studies to date are contradictory regarding
the therapeutic potential for neurodegenerative diseases.
PHENOLIC COMPOUNDS
Phenolic compounds have one or more hydroxyl groups
bonded to a benzene ring, being chemical constituents
found in a wide variety of plants and which are
represented by a variety of classes of compounds that
can be divided according to their chemical structures.
Among these classes, there are phenolic acids
(hydroxybenzoic acids (C6-C1) and hydroxycinnamic
acids (C6-C3), flavonoids (C6-C3-C6, which includes antho-
cyanins, flavonols, flavones, flavanones and isoflavones),
stilbenes (C6-C2-C6), lignans (C6-C3-C6-C3) and
curcuminoids (C3-C6-C3-C1-C6)) (Figure 7) (Cheynier et al.,
2013).
Antioxidant capacity of phenolic compounds occurs
primarily by elimination of free radicals, chelation capacity
and modulation of enzymes, as well as their effects on
cell signaling pathways and gene expression, being these
mechanisms dependent on the chemical characteristics
of the compounds (De Mello and Fasolo, 2014). Animal
studies, clinical and epidemiological, support the critical
role of phenolic compounds in the prevention and
treatment of various diseases such as neurodegenerative
disorders (Table 2).
Among the studies of phenolic compounds approached
in Figure 7, quercetin (flavonoid) has been shown to be
promising in treating various neurodegenerative diseases
(Jazvinšćak et al., 2012; Pandey et al., 2012; Denny
Joseph and Muralidhara, 2013). In a model of induced
Huntington's disease in rats, treatment with quercetin at a
dose of 25 mg/kg was able to reverse the inhibition of
mitochondrial electron transport chain, restore ATP
levels, prevent the mitochondrial dysfunction by inhibiting
oxidative stress and increase the SOD and CAT activities
(Sandhir and Mehrotra, 2013). In other in vitro and in vivo
studies, quercetin has demonstrated a role in therapeutic
strategies to treatment of neurodegenerative diseases in
clinical settings to provide neuroprotection related to
suppression of oxidative stress, improvement in
behavioral function, reduction in infarct volume, cerebral
edema and cell injury. In contrast, some studies contra-
dict the neuroprotective potential of quercetin and other
flavonoids (Ossola et al., 2009; Huebbe et al., 2010).
In another study, Mansouri et al. (2013) examined the
neuroprotective effect of gallic acid (phenolic acid) at a
dose of 30 mg/kg (orally, once daily for 26 days) on cog-
nitive changes and oxidative stress in the brain induced
 Oliveira et al. 693

Figure 7. Chemical structures of classes of phenolic compounds.

694 Afr. J. Pharm. Pharmacol.

Table 1. Main vitamins with therapeutic potential for the treatment of neurodegenerative diseases.

Vitamin Neurodegenerative diseases Mechanisms involved References

Alzheimer's disease
Elimination of ROS Ballaz et al. (2013), Heo et al. (2013), Engelhart et al. (2002), Kontush et al. (2001), Li
Parkinson's disease
Chelating activity et al. (2012), Quinn et al. (2003), Montilla-López et al. (2002), De Oliveira et al. (2012),
1 Huntington's disease
Lipid peroxidation inhibition Morales et al. (1989), Rebec et al. (2006), Heiser et al. (2010), Sivrioglu et al. (2007),
Amyotrophic lateral sclerosis Dadheech et al. (2006), Dakhale et al. (2005), and Arvindakshan et al. (2003)
Inhibition of amyloid-β (Aβ) aggregation
Schizophrenia

Elimination of ROS
2 Alzheimer's disease Hashim et al. (2011) and Nassiri-asl et al. (2012);
Chelating activity

Alzheimer's disease Morrissey and Hill (2011), Ricciarelli et al. (2007), Ahmed (2012), Morris et al. (2005),
Elimination of ROS
Parkinson's disease Viña et al. (2004), Guan et al. (2012), Kontush and Schekatolina (2004); Kalonia et al.
3 Regulation of antioxidant enzymes
Huntington's disease (2010), Peyser et al. (1995), Rao et al. (2003), Dadheech et al. (2006), Sivrioglu et al.
Lipid peroxidation inhibition (2007) and Arvindakshan et al. (2003)
Schizophrenia

Elimination of ROS/RNS
Alzheimer's disease Lee et al. (2009), Ono et al. (2004), Ono and Yamada (2012), Gackowski et al. (2008),
4 Chelating activity
Parkinson's disease Sutachan et al. (2012), King et al. (1992) and Rao et al. (2003)
Inhibition of amyloid-β (Aβ) aggregation

Table 2. Phenolic compounds with therapeutic potential for the treatment of neurodegenerative diseases.

Phenolic compounds Neurodegenerative diseases Mechanisms involved References

Elimination of ROS, chelating activity; Regulation of
Liu et al. (2013), Sandhir and Mehrotra (2013), Zhu et
Alzheimer's, Parkinson's, antioxidant enzymes; Lipid peroxidation inhibition;
1 al. (2013), Huebbe et al. (2010), Ansari et al. (2009),
Huntington's and Schizophrenia Inhibition of amyloid-β (Aβ) aggregation; Attenuation of
Lavoie et al. (2009), and Chakrabortyet al. (2013)
deficits in motor coordination.

Elimination of ROS; Lipid peroxidation inhibition; Inhibition Wang et al. (2012), Javed et al. (2012), Moshahid et
2 Alzheimer's and Parkinson's
of amyloid-β (Aβ) aggregation al. (2012), and Islam et al. (2012)

Zhang et al. (2013), Lee et al. (2013), He et al. (2012),

Alzheimer's, Parkinson's,
Elimination of ROS, Inhibition of amyloid-β (Aβ); Levites et al. (2001), Kim et al. (2010b), Avramovich-
3 Huntington's and Amyotrophic
Modulation of cell signaling pathways Tirosh et al. (2007), Ehrnhoefer et al. (2006), Xu et al.
lateral sclerosis
(2006), and Koh et al. (2006)

Elimination of ROS; Inhibition of amyloid-β (Aβ) George et al. (2013), Ejaz Ahmed et al. (2013),
Alzheimer's, Parkinson's, and
4 aggregation; Inhibition of the aggregation of tau proteins; Teixeira et al. (2013), Dietrich-Muszalska et al. (2012),
Schizophrenia
Lipid peroxidation inhibition. and Lim et al. (2013)

Elimination of ROS; Regulation of antioxidant enzymes; Hamaguchi et al. (2009), Detoma et al. (2011), Zhang
5 Alzheimer's and Parkinson's
Inhibition of amyloid-β (Aβ) aggregation et al. (2011), and Molina et al. (2004)

Table 2. Contd.
Alzheimer's, Parkinson's, and
6
Amyotrophic lateral sclerosis
7 Alzheimer's
8 Alzheimer's and Parkinson's
Alzheimer's, Parkinson's and
9
Huntington's
Alzheimer's, Parkinson's and
10
Amyotrophic lateral sclerosis
11 Alzheimer's
12 Alzheimer's
Alzheimer's, Parkinson's,
13
Huntington's and Schizophrenia
Alzheimer's, Parkinson's,
14 Huntington's and Amyotrophic
lateral sclerosis
by streptozotocin (STZ) (model used to study the
Alzheimer's disease) in rats and the results
showed that the gallic acid attenuated the
cognitive deficits, increased levels of enzymatic
antioxidants (GPx, CAT and SOD) and inhibited
lipid peroxidation by the reduction of the MDA
levels in brain tissue.
Another substance with great therapeutic
potential for treatment of neurodegenerative
diseases is resveratrol (Figure 7), a phenolic non-
flavonoid compound found in grapes and red
Elimination of ROS; Inhibition of amyloid-β (Aβ)
aggregation
Elimination of ROS, chelating activity; Regulation of
antioxidant enzymes; Inhibition of amyloid-β (Aβ)
aggregation
Elimination of ROS; Lipid peroxidation inhibition; Inhibition
of amyloid-β (Aβ) aggregation
Elimination of ROS; Inhibition of amyloid-β (Aβ)
aggregation
Elimination of ROS, chelating activity; Lipid peroxidation
inhibition; Inhibition of amyloid-β (Aβ) aggregation
Elimination of ROS, chelating activity; Regulation of
antioxidant enzymes; Inhibition of amyloid-β (Aβ)
aggregation
Elimination of ROS; Inhibition of amyloid-β (Aβ)
aggregation
Elimination of ROS; chelating activity; Inhibition of amyloid-
β (Aβ) aggregation
Elimination of ROS; Inhibition of amyloid-β (Aβ)
aggregation; Regulation of antioxidant enzymes; Chelating
activity, regulating of expression of SIRT1
wine. This antioxidant compound has been
investigated in different in vitro and in vivo studies
to treatment of Parkinson's disease, Alzheimer's,
Huntington's and amyotrophic lateral sclerosis. In
a model of Parkinson's disease induced in rats, it
was observed that resveratrol (20 mg/kg) in
dopaminergic neurons showed neuroprotective
effect by regulating glutathione, glutathione
peroxidase, glutathione reductase, catalase,
superoxide dismutase and decreasing levels of
thiobarbituric acid reactive substances (TBARS).
Oliveira et al. 695
Bagheri et al. (2011), Baluchne et al. (2009), Liu et al.
(2008), Trieu and Uckun (1999)
Zhao et al. (2013a, b)
Heo et al. (2004), Khan et al. (2012), Ma et al. (2013),
Zbarsky et al. (2005), and Sonia et al. (2013)
Kim et al. (2010a), Sharoar et al. (2012), Filomeni et
al., (2012), Li and Pu (2011), and Lagoa et al. (2009)
Barros et al. (2013), Huang et al. (2013a), and
Fontanilla et al. (2011)
Zhao et al. (2013a, b)
Mori et al. (2013) and Pi et al. (2012)
Wang et al. (2013b), Huang et al. (2013b), Li et al.
(2013), Yu et al. (2013), Agrawal et al. (2012), Du et al.
(2012), Mansouri et al. (2012), Sandhir et al. (2013),
Hickey et al. (2012), Bishnoi et al. (2008) and Lavoie et
al. (2009)
Khan et al. (2010), Jin et al. (2008b), Feng et al.
(2013), Porquet et al. (2013), Ho et al. (2010), Wang et
al. (2011), and Kim et al. (2007)
Furthermore, it was observed decreased carbonyl
protein levels, phospholipase A2 activity and
improvement in content of dopamine (Khan et al.,
2010). Resveratrol also showed neuroprotective
effects in a cellular model of amyotrophic lateral
sclerosis and in a model of Alzheimer's disease in
mice, being observed in the hippocampus a
significant increase of neuronal survival (Kim et
al., de 2007).
Confirming the important role of phenolic
compounds in complementary therapy and/or
696 Afr. J. Pharm. Pharmacol.
prevention of neurodegenerative diseases, the results of
Bournival et al. (2009) have clearly demonstrated that
resveratrol and quercetin are compounds that effectively
protect neurons against apoptotic cascade induced by
oxidative stress.
Most of the works discussed in this article are mainly
supported by data obtained in animal models and thus
more studies regarding the therapeutic potential for
human health are needed to unravel the role of these
antioxidant compounds, which are becoming increasingly
important as alternative or complementary therapies to
neurodegenerative diseases (Figure 4).
CONCLUSION
Based on the literature, there is good evidence that
oxidative stress plays an important role in the
pathogenesis of neurodegenerative diseases such as
Alzheimer's, Parkinson's, Huntington's, Schizophrenia
and amyotrophic lateral sclerosis. In this context, natural
antioxidant compounds with different chemical structures
that neutralize the damaging effects of ROS have been
investigated in preventing neurodegenerative diseases.
Most of the items discussed in this review demonstrated
the efficacy of antioxidant compounds in treatment of
neurodegenerative disorders using animal models or in
small clinical studies. However, some studies showed
contradictory results regarding the therapeutic potential of
antioxidants of natural origin. Thus, new studies approa-
ching clinical applications of antioxidants in the treatment
or prevention of neurodegenerative diseases are needed.
Conflict of interest
The author(s) declare(s) that they have no conflicts of
interest to disclose.
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