Parkson, Biomolecules-09-00271

biomolecules
Review
Role of Dietary Supplements in the Management of
Parkinson’s Disease
Michele Ciulla , Lisa Marinelli, Ivana Cacciatore and Antonio Di Stefano *
Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, via dei Vestini 31,
66100 Chieti Scalo (CH), Italy
* Correspondence: antonio.distefano@unich.it; Tel.: +39-0871-355-4708

Received: 24 May 2019; Accepted: 9 July 2019; Published: 10 July 2019
Abstract: The use of food supplements or functional food has significantly increased in the past
decades, especially to compensate both the modern lifestyle and the food shortages of the industrialized
countries. Despite food supplements are habitually intended to correct nutritional deficiencies or
to support specific physiological functions, they are often combined with common drug therapies
to improve the patient’s health and/or mitigate the symptoms of many chronic diseases such as
cardiovascular diseases, cystic fibrosis, cancer, liver and gastrointestinal diseases. In recent years,
increased attentions are given to the patient’s diet, and the use of food supplements and functional
food rich in vitamins and antioxidants plays a very important role in the treatment and prevention of
neurodegenerative diseases such as Parkinson’s disease (PD). Natural compounds, phytochemicals,
vitamins, and minerals can prevent, delay, or alleviate the clinical symptoms of PD in contrast to
some of the main physiopathological mechanisms involved in the development of the disease, like
oxidative stress, free radical formation, and neuroinflammation. The purpose of this review is to
collect scientific evidences which support the use of specific biomolecules and biogenic elements
commonly found in food supplements or functional food to improve the clinical framework of
patients with PD.
Keywords: Parkinson’s disease; food supplements; functional food; antioxidants; anti-inflammatory;

neuroprotection; natural compounds
1. Introduction
The use of food supplements has significantly increased over the past decades, especially in the
industrialized countries, with a trend that is expected to increase for the coming years [1]. The reasons
for this growth can be ascribed primarily to the modern times, the industrialization process, and the
food sources, which are now poorer in important nutrients. Moreover, the frenetic lifestyle that people
tend to adopt, as well as the increase of life expectancy and the incidence in chronic diseases provide a
constant attention to the intake of specific nutritional elements to compensate for food shortages.
In recent years, a positive outlook toward the medical nutrition market was assessed, estimating
that the constant use of food supplements has led to the global dietary supplements market at $133.1
billion in 2016 and is projected to accelerate at CAGR (compound annual growth rate) of 9.6%, reaching
$278.02 billion by 2024 [1]. Vitamins-based supplements are projected to account for 48% of the global
share by the end of 2024. The European Food Safety Authority (EFSA) defines food supplements as a
“concentrated source of nutrients or other substances with a nutritional or physiological effect that are marketed
in dose form. A wide range of nutrients and other ingredients might be present in food supplements, including,
but not limited to, vitamins, minerals, amino acids, essential fatty acids, fiber and various plants and herbal
extracts” [2]. In this context, the role of food supplements is to compensate nutritional deficits through
an appropriate consumption of specific components, thus supporting several biological processes.
Biomolecules 2019, 9, 271; doi:10.3390/biom9070271 www.mdpi.com/journal/biomolecules

Biomolecules 2019, 9, 271 2 of 23
It is important to underline that these products are not medicines, since they cannot simulate any
pharmacological activity and treat or prevent the onset of diseases [3]. Indeed, claims relating to food
supplements are strictly regulated by EFSA, which only after a deep evaluation of scientific literature
allows to indicate in which terms the vitamin or more in general the nutrient in question can exert
beneficial nutritional effects [4].
Nevertheless, nutritional supplements are often combined with pharmacological therapies for
many chronic diseases such as cardiovascular diseases, cystic fibrosis, cancer, human immunodeficiency
virus and acquired immune deficiency syndrome, liver and gastrointestinal diseases, and nutritional
status related diseases [5,6]. Moreover, nutrition also plays a very important role in the treatment
and prevention of neurodegenerative diseases, especially in the older age groups [7]. Recently, it
has been highlighted that the consumption of functional food and food supplements can contribute
greatly in the management of age-related diseases such as Parkinson’s disease (PD) [8]. Indeed, natural
compounds, phytochemicals, vitamins, minerals present in the food supplements or fruits, vegetables,
and spices can prevent, delay, or alleviate the clinical symptoms of chronic neurodegenerative diseases,
improving cognitive functions, learning, general brain status, and wellbeing [9].
The purpose of this review is to collect scientific evidences to support the use of specific
biomolecules commonly found in food supplements or functional food in order to improve the
clinical framework of patients with PD. By analyzing scientific literature data, it will be possible to
identify which vitamins, minerals, or different molecules have shown to exert potential properties
useful to counteract or mitigate physiopathological phenomena related to PD, such as oxidative stress
and neuroinflammation.
2. Parkinson’s Disease
PD is a degenerative neurological disorder characterized by the onset motor symptoms such
as tremors, muscle rigidity, slowness in movement (bradykinesia), and stooped posture (postural
instability) [10]. Moreover, non-motor symptoms are also present, including disorders of mood and
affect, apathy, anhedonia and depression, cognitive dysfunction and hallucinosis, sleep disruption, as
well as complex behavioral disorders. PD affects 1–2% of the population at any time, and together
with Alzheimer’s disease (AD), is one of the most common neurologic disorders [11]. PD affects
approximately 1% of individuals older than 60 years, with an increment in the incidence of 5–10 times
from the sixth to the ninth decade of life [12]. Environmental and genetic factors are both involved in
the onset of PD, even if the framework of the disease is not completely elucidated [13]. Regarding the
neuropathological mechanisms, the major evidence is the loss of dopaminergic neurons of the substantia
nigra pars compacta and the locus coeruleus. The first is responsible for motor control, while the latter
is responsible for various psychological effects. One of the most important consequences of neuronal
degeneration is the reduction of dopamine (DA), responsible for numerous biological functions [14].
Furthermore, a brain affected by PD is characterized by the presence of Lewy bodies and Lewy
neurites [15]. Lewy bodies consist of protein agglomerations (α-synuclein, parkin, and other proteins)
embedded in the cytoplasm of dead neurons located in several different brain regions. Agglomeration
of α-synuclein starts when soluble monomers initially form oligomers, then progressively continue to
merge and thus form large, insoluble fibrils [16]. Beyond these two major clinical evidences, PD involves
different molecular mechanisms, all related to each other and directly linked to the physiopathology of
the disease, in a sort of vicious circle that exacerbate the neurodegeneration process (Figure 1).
important role in the progression of the disease. The inflammation depends also on the impaired
energy metabolism at the level of the mitochondria, which causes the activation of the microglia and
the relative production of a plethora of pro-inflammatory mediators, including prostaglandins,
cytokines, chemokines, complement, proteinases, reactive species of oxygen (ROS), and reactive
species of nitrogen (RNS) [23,24].
Figure 1. Interaction between the major molecular mechanism involved in the pathogenesis of
Figure 1. Parkinson’s
Interaction between
disease (PD). the major molecular mechanism involved in the pathogenesis of
Parkinson’s disease (PD).
There are evidences that correlate neuronal mitochondrial dysfunction with the pathogenesis
All these evidences
of PD [17,18]. Thislead to the degeneration
dysfunction is associated with of the
dopaminergic neurons,of
abnormal accumulation a α-synuclein,
reduced dopaminergic
which
causes
transmission in anthealteration of normal
motor region ofmitochondrial
the striatum,function, leading tocell
and therefore neuronal
deathdegeneration
[22]. Moreover, and strong
PD causes
oxidative stress [19,20]. The latter is exacerbated in the nervous tissue of patients with PD, especially
the alteration of two other neurotransmission complexes such as the cholinergic and the serotonergic
at the level of nigral dopaminergic neurons, particularly vulnerable to oxidative and metabolic
systems. In particular,
stress [21,22]. The a presence
reduction in the cholinergic
of neuroinflammation and muscarinic
is another receptors
peculiar characteristic was
of PD, whichhighlighted
plays in
patients with PD, with
an important rolenegative consequences
in the progression related
of the disease. Theto cognitive depends
inflammation and motor also onfunctions
the impaired [25]. The
diagnosis energy
of PDmetabolism
is difficult to level
at the define before
of the the symptoms
mitochondria, which causesof thethe disease
activationbecome evident [26].
of the microglia
and the relative production of a plethora of pro-inflammatory
Moreover, most patients with PD also have non-motor symptoms, including disorders of mediators, including prostaglandins,
cytokines, chemokines, complement, proteinases, reactive species of oxygen (ROS), and reactive species
sleep–wake cycle regulation, cognitive impairment disorders of mood and affect, autonomic
of nitrogen (RNS) [23,24].
dysfunction, as Allwell
theseas sensorylead
evidences andtopain [27]. The treatments
the degeneration of dopaminergic available today
neurons, aim to
a reduced restore the level
dopaminergic
of dopamine in the striatum
transmission in the motorin order
regionto of contain the and
the striatum, motor disorders,
therefore and
cell death levodopa
[22]. Moreover, (L-DOPA)
PD causes is still
the gold standard for of
the alteration thetwotreatment of parkinsonism
other neurotransmission [28]. such
complexes Treatment with L-DOPA,
as the cholinergic accompanied by
and the serotonergic
systems. In particular, a reduction in the cholinergic and muscarinic
a series of pharmacological strategies, aims to prevent peripheral dopamine metabolism and receptors was highlighted
in patients with PD, with negative consequences related to cognitive and motor functions [25].
improve its bioavailability, thus reducing motor complications due to its administration, as well as
The diagnosis of PD is difficult to define before the symptoms of the disease become evident [26].
further therapies
Moreover,tomostcontrol non-motor
patients with PD also symptoms mentioned
have non-motor symptoms, before that weigh
including disorders onofthe quality of life
sleep–wake
of the patients with PD
cycle regulation, [29–31].
cognitive In recent
impairment years,
disorders medical
of mood therapies
and affect, autonomichavedysfunction,
been flanked as by
non-pharmacological
well as sensory alternatives
and pain [27]. The such as exercises,
treatments available todaygroupaim totherapies, nutrition
restore the level of dopamineand food
in the striatum in order to contain the motor disorders, and levodopa
supplementation [32–34]. Recently, the management of age-related diseases such as PD has been (L-DOPA) is still the gold
standard for the treatment of parkinsonism [28]. Treatment with L-DOPA, accompanied by a series
associated with consumption of functional food or food supplements. Indeed, a healthy diet rich in
of pharmacological strategies, aims to prevent peripheral dopamine metabolism and improve its
foods containing antioxidants,
bioavailability, thus reducing vitamins and minerals,
motor complications due toor its the use of food
administration, supplements
as well can help to
as further therapies
reduce and/or contrast
to control the symptoms
non-motor of PD andbefore
symptoms mentioned the related
that weigh pathological
on the qualitymechanisms
of life of the[35,36].
patients
with PD [29–31]. In recent years, medical therapies have been flanked by non-pharmacological
3. Oxidative Stress and Neuroinflammation in PD
Oxidative stress, generation of free radicals, and generation of ROS in neurons and glial cells
contribute and play a major role in the pathogenesis of PD and other neurodegenerative diseases
[21,37]. In particular, nigral dopaminergic neurons seem to be particularly vulnerable to oxidative
alternatives such as exercises, group therapies, nutrition and food supplementation [32–34]. Recently,
the management of age-related diseases such as PD has been associated with consumption of functional
food or food supplements. Indeed, a healthy diet rich in foods containing antioxidants, vitamins and
minerals, or the use of food supplements can help to reduce and/or contrast the symptoms of PD and
the related pathological mechanisms [35,36].
3. Oxidative Stress and Neuroinflammation in PD

Oxidative stress, generation of free radicals, and generation of ROS in neurons and glial cells
contribute and play a major role in the pathogenesis of PD and other neurodegenerative diseases [21,37].
In particular, nigral dopaminergic neurons seem to be particularly vulnerable to oxidative stress mainly
because of the long axons and millions of synapses, which require high energy to work properly [38].
Besides high energy, increased levels of dopamine and its metabolites can also cause oxidative stress [39].
Finally, the mitochondrial dysfunction naturally leads to an increased level of oxidative stress, with a
depletion of lysosome and the establishment of a vicious cycle in which the first increases the alteration
of the latter and vice versa [40].
At the same time, the antioxidant defensive mechanism in the brain is poor and thus limits its
protective action against free radical attack, especially during the progression of neurodegenerative
conditions, in which the cell’s antioxidant capacity is further reduced. Antioxidants are able to scavenge
free radicals and reactive species, giving a beneficial therapeutic effect in PD by preventing the onset of
apoptotic cell death and neuronal degeneration of the dopaminergic nigrostriatal pathway.
On the same level, neuroinflammation plays an important role in the pathogenesis of PD,
highlighting an increased activation of microglia and the amplification of proinflammatory and toxic
mediators [41]. In particular, the presence of α-synuclein insoluble fibrils activates glial cells and other
immune/inflammatory cells, with the subsequent release of inflammatory cytokines, chemokines, and
neurotoxic mediators, which induce neurodegeneration in dopaminergic neurons [42]. Moreover, toxic
insoluble fibrils also have direct proinflammatory activity in PD, contributing to neurodegeneration
and neuronal cell death (Figure 1) [43]. Finally, peripheral immune and inflammatory cells migrate
to the brain through the defective blood brain barrier (BBB), increasing neuroinflammation either
directly or through glial and neuronal cells [41]. The intake of anti-inflammatory compounds from
food supplements or functional food can lead to the suppression or reduction of neuroinflammation,
ameliorating PD symptoms and reducing the extent of neurodegeneration.
4. Natural Compounds Useful in the Prevention and Management of PD

Scientific evidences have shown that numerous molecules and natural compounds are able to
mitigate the symptoms of PD by counteracting the physiopathological mechanisms which dominate
the disease, such as oxidative stress and neuroinflammation. Furthermore, some molecules have
shown to possess neuroprotective and neuro-modulatory properties.
Table 1 displays the analyzed molecules, describing for each compound the beneficial effects
demonstrated experimentally and the performed mechanism that support a positive incidence in the
treatment of PD.
Table 1. Summary of the beneficial effects and the involved mechanisms for the examined compounds.
Molecule Beneficial Effects Mechanism Ref.

Coenzyme Q10, due to its 1,4-benzoquinone structure, is a powerful antioxidant acting as a free radical scavenger. Since it is also a
Antioxidant
oenzyme Q10 redox component of the electron transport chain of mitochondria, it may exert neuroprotection through the modulation of [44–50]
Neuroprotection
mitochondrial activity in neuronal cells.
Antioxidant The dithiolane ring, with its oxidized and reduced forms, makes lipoic acid a potent antioxidant. As an anti-inflammatory agent, it
Lipoic acid Anti-inflammatory inhibits NF-kappaB and inflammatory cytokines like TNF-α. Neuroprotection is given by enhancing the intracellular levels of [51–54]
Neuroprotection cysteine, thus increasing the glutathione levels.
Antioxidant The thiol group of N-acetyl-cysteine can act both as a direct antioxidant and as a glutathione precursor. It increases the mitochondrial
N-acetyl-cysteine [55–60]
Neuroprotection complex I and IV activities and prevents reactive species of oxygen (ROS) accumulation in neuronal cells.
Vitamin E Antioxidant Vitamin E acts as a scavenger of several ROS by donating a hydrogen atom to free radicals, thus reducing their reactivity and toxicity. [61–66]
Antioxidant Carvacrol induces the production of antioxidative enzymes and modulates oxidative stress. The anti-inflammatory effect is exerted by
Carvacrol Anti-inflammatory reducing the production of pro-inflammatory cytokines. Carvacrol is also able to inhibit the acetylcholinesterase activity, with positive [67–69]
Neuromodulation effects on memory and cognitive performance in PD.
Antioxidant Curcumin is an excellent free radical scavenger thanks to the phenolic rings and diketone groups. It protects mitochondrial complex I
Curcumin Anti-inflammatory from enzyme nitration and subsequent inhibition, reducing mitochondrial disfunction. Anti-inflammatory and neuroprotective [70–78]
Neuroprotection actions are exerted by modulation of chemokines which mediate the inflammatory cascade.
Omega−3 Antioxidant Omega-3 fatty acids reduce ROS formation acting as free radical scavengers. They also decrease chemotaxis of neutrophils and
[79,80]
fatty acids Anti-inflammatory monocytes, as well as the production of pro-inflammatory cytokines.
Whey protein Antioxidant Since whey protein is an excellent source of cysteine, it can increase the production of glutathione, thus reducing oxidative stress. [81,82]
Antioxidant Vitamin D3 inhibits oxidative stress, reduces free radical formation, and decreases neurotoxicity by enhancing autophagy signaling
Vitamin D3 [83–87]
Neuroprotection pathways. Neuroprotection is exerted by reducing the endothelial dysfunction observed in patients with PD.
Antioxidant Creatine is able to contrast free radicals and ROS acting as antioxidant. Moreover, it can stimulate mitochondrial activity through the
Creatine [88–91]
Neuroprotection production of phosphocreatine, thus modulating the production of ATP and the energy homeostasis in the brain.
Melatonin has interesting antioxidant properties, probably related to the indole group. The antioxidant activity is also performed by
Melatonin Antioxidant [92–96]
preventing the antioxidative catalysts lowering in neuronal cells.
Niacin Antioxidant Niacin and its active form nicotinamide reduce oxidative stress. Neuroprotection is reached since they are involved in the biosynthesis
[97–102]
(Vitamin B3 ) Neuroprotection of nicotinamide adenine dinucleotide (NAD), an essential cofactor for the ATP production at the mitochondrial complex I level.
Vitamin C is an excellent antioxidant, suitable in reducing ROS levels, lipid peroxidation, and oxidative stress. It is also useful in
Vitamin C Antioxidant [103–106]
regenerating other antioxidants.
Antioxidant The α,β-unsaturated ketone moiety makes 6-shogsol a good free radical scavenger. It possesses anti-inflammatory properties by
6-shogaol Anti-inflammatory reducing the production of prostaglandin E and pro-inflammatory cytokines such as TNF-α and interleukin-1β. Neuroprotection is [107–109]
Neuroprotection assessed by inhibiting microglial activation.
β-carotene is an excellent free radical scavenger. The high number of conjugated double bonds in its structure confers to this
β-carotene Antioxidant [110–113]
compound’s peculiar antioxidant properties.
Lycopene is an excellent free radical scavenger. The high number of conjugated double bonds in its structure confers to this
Lycopene Antioxidant [114–118]
compound’s peculiar antioxidant properties.
Flavonoids Antioxidant The antioxidant activity of flavonoids depends upon the arrangement of functional groups on the 15-carbon skeleton. Beside the free
Quercetin Anti-inflammatory radical scavenger capacity, they regulate the overproduction of inflammatory cytokines, reducing pro-inflammatory mediators and
[119–122,125–128,134–136]
Epigallocatechin-3-gallate Neuroprotection conferring to neuroprotection. This last property is exerted also through the increment of striatal dopamine and the modulation of cell
Ginkgo Biloba extract Neuromodulation survival/cell cycle genes, which increase neuronal survivability.
4.1. Coenzyme Q10

Coenzyme Q10 (CoQ10, Figure 2), also known as ubiquinone, is a 1,4-benzoquinone that is
ubiquitous in animals and most bacteria. Its natural sources are foods such as tuna or salmon, organ
meats, and whole grains, but recently food supplements rich in CoQ10 have also become popular.
CoQ10 is a component of the electron transport chain and participates in the aerobic cellular respiration,
which generates energy in the form of ATP. This molecule acts not only as an important electron carrier
in the electron transport chain, but also as a free-radical scavenging antioxidant [44]. In particular,
several in vitro studies showed that CoQ10 has neuroprotective effects in multiple models of neuronal
toxicity. It was also highlighted that oral supplementation of CoQ10 can reduce the loss of dopamine
and dopaminergic axons in the striatum in 1-year-old mice treated with MPTP-induced mouse model
of PD (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP) [45,46]. Nevertheless, the role of CoQ10
in the management of PD is controversial.
Shults and collaborators in 2002 conducted a phase II trial, comparing placebo and three dosages
of CoQ10 (300, 600, and 1200 mg/day) in a prospective, randomized, double-blind study with 20
subjects in each group [47]. The authors found that the high dosages of CoQ10 were safe and well
tolerated, with a reduction of disability for patients treated with the coenzyme compared to placebo,
inducing a slowdown of the progressive deterioration of function in PD.
Moreover, Muller et al. in 2003 performed a monocenter, parallel group, placebo-controlled,
double-blind trial to determine the symptomatic response of daily oral application of 360 mg CoQ10
during 4 weeks of treatments [48]. Results suggested that an oral CoQ10 supplementation provides
moderate beneficial effect in PD patients.
On the contrary, Storch et al. in 2007 performed a clinical study applying the same protocol and
the same maximum dosage as of the Shults’ study (1200 mg/day) but did not find any appreciable
benefits in mid-stage PD after three months of treatment [49].
More recently, meta-analysis was done to highlight the qualitative and quantitative conclusions
about the efficacy of CoQ10 for the treatment of PD [50]. Final results showed that CoQ10 was safe and
well tolerated in PD patients but did not present evidence of clinical benefits. Additional trials are
required to confirm the role of CoQ10 in slowing the progressive deterioration of function in PD.
4.2. Lipoic Acid

Lipoic acid (LA, Figure 2) is a compound naturally synthesized in the human body and also found
in several foods. It has potential therapeutic value since it exhibits antioxidative and anti-inflammatory
activity, as well as it inhibits free radical formation [51].
Zhang et al. in 2018 investigated not only the antioxidant and anti-inflammatory properties of LA
in an in vivo mouse model of PD, but they also assessed the capacity of LA to reduce the dyskinesia side
effects related to the L-DOPA administration [52]. The 6-OHDA-lesioned rats (6-hydroxydopamine,
6-OHDA) were treated with LA (31.5 mg/kg or 63 mg/kg) in combination with L-DOPA treatment,
highlighting that LA reduces L-DOPA-induced dyskinesia in a dose-dependent manner without
compromising the anti-PD effect of the drug. Moreover, LA reduced the level of malondialdehyde,
a product of lipid peroxidation, and upregulated the glutatione (GSH) activity, a clear indication of
the positive antioxidant effects. The authors concluded that LA can be recommended as a promising
disease-modifying therapy when administered with L-DOPA.
Jalali-Nadoushan and Roghani investigated the effect of this compound (at doses of 50 and
100 mg/kg) in a 6-OHDA-induced mouse model of PD, highlighting that LA significantly attenuated
rotations on behavioral testing in particular at a dose of 100 mg [53]. These results confirm that LA can
partially afford neuroprotection against 6-OHDA neurotoxicity due to the attenuation of oxidative
stress burden.
Li et al. tested the antioxidant and anti-inflammatory properties of LA on a lipopolysaccharide
(LPS)-induced inflammatory PD model [54]. After the treatment with LPS, in order to induce the
microglia activation, mice were treated with LA once a day at 100 mg/kg. Results showed important
mg/kg) in a 6-OHDA-induced mouse model of PD, highlighting that LA significantly attenuated
rotations on behavioral testing in particular at a dose of 100 mg [53]. These results confirm that LA
can partially afford neuroprotection against 6-OHDA neurotoxicity due to the attenuation of
oxidative stress burden.
Li et al. tested the antioxidant and anti-inflammatory properties of LA on a lipopolysaccharide
(LPS)-induced inflammatory PD model [54]. After the treatment with LPS, in order to induce the
microglia activation, mice were treated with LA once a day at 100 mg/kg. Results showed important
improvement in
improvement inmotor
motordysfunctions,
dysfunctions,a areduction
reductionin in α-synuclein
α-synuclein accumulation,
accumulation, andand a reduction
a reduction of
of the
the pro-inflammatory
pro-inflammatory molecules
molecules activation,
activation, suggestingsuggesting thatexert
that LA may LAa significant
may exertneuroprotective,
a significant
neuroprotective, anti-neuroinflammatory,
anti-neuroinflammatory, and anti-oxidativeand anti-oxidative
effect, thus becomingeffect, thus becoming
a promising agent fora halting
promising
the
agent for halting
progression of PD. the progression of PD.
4.3. N-Acetyl-Cysteine
N-acetyl-cysteine (NAC, Figure 2) is an N-acetylated N-acetylated derivative of the the sulphurated
sulphurated cysteine
cysteine
amino acid. The -SH group is able to actively contrast ROS, conferring antioxidant properties to the
molecule [55]. At the same time, NAC and its analogues contribute to the physiological physiological antioxidant
activity by acting as a GSH precursor
precursor [56,57].
[56,57].
Potential protective properties of NAC in the management of PD were assessed assessed in animal
animal
model studies, demonstrating a sensible reduction of oxidative damage by increasing mitochondrial
complex
complex II and
and IVIVactivities
activitiesand
andpreventing
preventingROS ROSaccumulation,
accumulation,leading
leadinginin
this way
this way to to
thethe
protection of
protection
dopamine-induced cell death
of dopamine-induced cell death [58]. [58].
Holmay
Holmay et et al.
al. in
in2013
2013investigated
investigatedthe thepotential
potentialantioxidant
antioxidant properties of NAC
properties of NAC by measuring
by measuringthe
level of GSH in patients with PD before and after its administration [59]. Results
the level of GSH in patients with PD before and after its administration [59]. Results showed that showed that after
intravenous injection
after intravenous of NAC,
injection there was
of NAC, therea boost
was ainboost
antioxidant GSH levels
in antioxidant GSHinlevels
the brain andbrain
in the blood of
and
PD patients,
blood of PD making
patients, possible
makingthe compensation
possible of the hypothesized
the compensation deficiency and
of the hypothesized lower GSH
deficiency andactivity
lower
in
GSHPD.activity in PD.
Monti
Monti etetal.
al.in
in2016
2016highlighted
highlightedthe potential
the protective
potential properties
protective of NAC
properties in PD
of NAC inusing an in an
PD using vitro
in
and
vitroinand
vivo
in model
vivo model [60]. [60].
The The
first first
model revealed
model an increased
revealed an increaseddopaminergic
dopaminergic neurons
neurons survival in
survival
cells treated
in cells withwith
treated rotenone compared
rotenone comparedto placebo. The clinical
to placebo. study study
The clinical confirmed the protective
confirmed effects
the protective
previously observedobserved
effects previously with an increased dopaminedopamine
with an increased transportertransporter
binding in binding
the caudate
in theandcaudate
putamen in
and
the PD group treated with NAC, and no measurable changes in the control
putamen in the PD group treated with NAC, and no measurable changes in the control group. group.
Figure 2. Chemical structures of the examined natural compounds.

Figure 2.
4.4. Vitamin E
4.4. Vitamin E
Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four
Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four
tocotrienols; abundant in vegetable oils, whole-grain cereals, butter, and eggs. They are involved in
tocotrienols; abundant in vegetable oils, whole-grain cereals, butter, and eggs. They are involved in
several human biological functions, with the alpha-tocopherol (Figure 2) as the main form of vitamin
E, preferentially absorbed and accumulated in human body. It acts as an antioxidant, scavenger of
several ROS, including hydroxyl and peroxyl radicals, and it is able to inhibit lipid peroxidation [61].
Some clinical trials were carried out to better understand the potential neuroprotective properties of
this molecule in the management of PD, but the results are controversial [62].
Fahn tried to administer a combination of ascorbate and vitamin E to patients with early PD
in a first pilot open-labeled trial [63]. The primary end point of the trial was the progression of the
disease until patients needed treatment with L-DOPA or a dopamine agonist compared to control,
and results showed that patients who received the antioxidants combination extended the time when
L-DOPA became necessary by 2.5 years, suggesting that the progression of PD may be slowed by the
administration of vitamin C and E.
Zhang et al. documented the occurrence of PD within two large cohorts of men and women who
completed detailed and validated semiquantitative food frequency questionnaires, highlighting that
supplementation with antioxidant vitamins is not associated with the risk of PD, but it is significantly
reduced among men and women with high intake of dietary vitamin E [64].
Nevertheless, in another clinical trial, Scheider and collaborators took into consideration the
possible role of long-term dietary antioxidants intake in PD onset [65]. Results showed that vitamin
E did not show evidence of benefits in either improving the clinical features of PD or delaying the
functional decline.
A large clinical trial was conducted to examine the benefits of deprenyl (selegiline) and
alpha-tocopherol in slowing the progression of PD (DATATOP study, Deprenyl and tocopherol
antioxidative therapy of parkinsonism) [66]. The observation indicated that deprenyl delay the time of
disability development, while alpha-tocopherol produced no benefits. Additional trials are still needed
to confirm the role of vitamin E in slowing the progressive deterioration of function in PD.
4.5. Carvacrol
Carvacrol (Figure 2) is a phenolic monoterpene found in numerous aromatic plants including
basil, rosemary, thyme, and oregano. The last possesses the highest percentage of carvacrol-enriched
essential oil. Several studies investigated the properties of this monoterpene, highlighting the numerous
pharmacological properties, including antibacterial, antifungal, anti-inflammatory, antioxidant, and
neuro-modulatory action [67,68]. As a neuro-modulatory agent, the ability to also regulate the activity
of dopaminergic neurons has made the use of carvacrol for the treatment of PD interesting.
Haddadi et al. experimentally assessed the effect of carvacrol in a mouse model of PD [69].
The animals were treated with 6-OHDA to induce the onset of the typical symptoms of PD, and
subsequently different tests were carried out to determine the motor and cognitive abilities of the
treated animals. In particular, the apomorphine-induced rotation test showed that treatment with
carvacrol exerted no differences between the treated and the untreated group. Regarding the passive
avoidance memory test, the treatment of mice with carvacrol at concentrations of 25 mg/kg showed
clear improvements compared to the control group. Finally, the tail-flick test showed no difference
between the carvacrol-treated group and the control. The authors concluded that carvacrol showed
improved cognitive impairments without having effects on pain and motor symptoms.
4.6. Curcumin
Curcumin (diferuloylmethane, Figure 2), is a polyphenol extracted from the rhizome of Curcuma
longa, a plant widely distributed in Asia. The powder, derived from the rhizome, is used as a spice
and as a natural remedy in traditional oriental medicine. The properties that curcumin boasts include
antioxidant, anti-inflammatory, and neuroprotective activities, which can have a positive impact on the
treatment of PD [70].
Wang et al. carried out an analysis of the scientific literature, collecting 113 studies concerning
curcumin and PD [71]. Among these, specific inclusion criteria led to assessing 13 studies as relevant
in relationship to the effects that curcumin can exert in animal models of PD. In particular, the
three major findings that the authors described are that curcumin can perform anti-inflammatory,
antioxidant, and antiapoptotic action. The anti-inflammatory properties were highlighted in five
studies, where curcumin attenuated the DNA damage caused by numerous metals and reduced the
presence of pro-inflammatory cytokines [72–76]. The antioxidant properties presented in several
neuroprotection to the brain tissues in the examined animal models of PD [73,78].
4.7. Omega-3 Fatty Acids

Omega-3 fatty acids have as main feature, a double bond, located three atoms far from the last
methyl group, which is part of the backbone in their polyunsaturated structure (Figure 3). Omega-3
are present in certain foods such as cold-water fish (salmon) and fish oils, walnut, edible seeds and
flaxseed oil, as well as dietary supplements in which fish oil is formulated as soft gel capsules. These
studies,ofdemonstrated
types fatty acids are the ability of curcumin
important to reduce
constituents in vivo lipid
of animal the ROS levels, lipidand
metabolism, peroxidation,
they playandan
NO generation [72,76,77]. Finally, the antiapoptotic properties have been identified
important role in the human diet and in human physiology, contributing to lower the levels of in two studies,
where curcumin
cholesterol and LDL reduced the pro-apoptotic
(low-density cellular
lipoproteins) proteins
in the level, conferring neuroprotection to the
blood [79].
brainBeside
tissuesthese
in thealready
examined
knownanimal modelsTaghizadeh
functions, of PD [73,78].
et al. evaluated the effects of omega-3 fatty
acids and vitamin E co-supplementation on clinical signs and metabolic status in patient with PD,
4.7. Omega-3 Fatty Acids
assessing a randomized clinical trial conduced in double-blind against a control group [80]. The
treated group fatty
Omega-3 received
acidsomega-3
have as fatty
mainacids (1000
feature, mg) inbond,
a double combination with atoms
located three vitamin farEfrom
(400 the
IU) last
for
three
methylmonths. Resultsis showed
group, which that
part of the omega-3infatty
backbone their acids and vitamin
polyunsaturated E co-supplementation
structure (Figure 3). Omega-3led toare
a
significant improve in the selected rating scale used to assess the stage of PD. Furthermore,
present in certain foods such as cold-water fish (salmon) and fish oils, walnut, edible seeds and flaxseed
co-supplementation
oil, as well as dietarydecreased
supplements high-sensitivity C-reactive
in which fish oil protein
is formulated as and increased
soft gel capsules. total antioxidant
These types of
capacity
fatty acidscompared with constituents
are important the placebo,of demonstrating that omega-3
animal lipid metabolism, fatty play
and they acidsanand vitamin
important E
role
co-supplementation in people with PD had favorable effects not only on the development
in the human diet and in human physiology, contributing to lower the levels of cholesterol and LDL of PD
symptoms, but
(low-density also in the management
lipoproteins) of ROS production and oxidative stress reduction.
in the blood [79].
Chemical structures
Figure 3. Chemical structures of the principal polyunsaturated fatty acids omega-3.
Beside
4.8. Whey these already known functions, Taghizadeh et al. evaluated the effects of omega-3 fatty
Protein
acids and vitamin E co-supplementation on clinical signs and metabolic status in patient with PD,
Protein
assessing obtained by
a randomized whey
clinical are
trial a mixture
conduced of differentagainst
in double-blind lactoglobulins, serum[80].
a control group albumin, and
The treated
immunoglobulins, and more importantly, it is an excellent dietary source of cysteine.
group received omega-3 fatty acids (1000 mg) in combination with vitamin E (400 IU) for three months.Several studies
highlighted
Results showed the that
capacity
omega-3of whey protein
fatty acids andtovitamin
increase GSH, suggesting that
E co-supplementation ledthis
to acomplex mixture
significant improveis
capable of boosting GSH synthesis, thus reducing oxidative stress [81].
in the selected rating scale used to assess the stage of PD. Furthermore, co-supplementation decreased
Tosukhowong
high-sensitivity et al. inprotein
C-reactive 2016 conducted a placebo-controlled,
and increased double-blind
total antioxidant capacity studywith
compared on PD
the patients
placebo,
to investigate the
demonstrating effects
that of whey
omega-3 fattyprotein supplementation
acids and on plasma GSH, plasma
vitamin E co-supplementation amino
in people acids,
with and
PD had
the unified Parkinson’s disease rating scale modifications [82].
favorable effects not only on the development of PD symptoms, but also in the management of ROS
production and oxidative stress reduction.
4.8. Whey Protein

Protein obtained by whey are a mixture of different lactoglobulins, serum albumin, and
immunoglobulins, and more importantly, it is an excellent dietary source of cysteine. Several studies
highlighted the capacity of whey protein to increase GSH, suggesting that this complex mixture is
capable of boosting GSH synthesis, thus reducing oxidative stress [81].
Tosukhowong et al. in 2016 conducted a placebo-controlled, double-blind study on PD patients to
investigate the effects of whey protein supplementation on plasma GSH, plasma amino acids, and the
unified Parkinson’s disease rating scale modifications [82].
Results showed a significant increase in plasma concentration of reduced GSH, plasma branched
chain amino acids (BCAA), and essential amino acids in the whey-supplemented group only. The rate
possible implication in the muscular and endocrine apparatus, as well as in the central nervous
system, with a positive attitude as neuroprotective agent in the management of PD [83].
Wang et al. studied the neuroprotective effects of vitamin D3 against 6-OHDA-lesioned mice in
vivo and in vitro [84]. Results showed that the pretreatment with vitamin D3 for eight days
significantly
Biomolecules 2019,restored
9, 271 locomotor activity in the lesioned mice. Neurochemical analysis determined a
10 of 23
protection from oxidative stress and reduction in depletion of DA neurons in mice treated with the
vitamin compared to the control.
of disease
Jang modification was notthe
et al. investigated significantly
protective, ameliorated in either group,effects
autophagy-modulating indicating that
of an wheyform
active protein of
supplementation significantly increases plasma reduced glutathione
vitamin D₃ in an in vitro model of PD [85]. Result showed that the treatment with the vitaminin patients with PD with no
significant
reduced ROS changes
levelsinand
clinical outcomes.
increased the levels of intracellular signaling proteins associated with cell
survival.
4.9. Vitamin D3
Moreover, some clinical studies suggest that vitamin D3 has a positive effect on PD.
Vitamin
The first D 3 (cholecalciferol,
evidence was describedFigure by4) is endogenously
Evat et al. in a study produced
of 2008, inwhen skin
which theislevel
exposed to the
of vitamin
UV-B
D3, in rays
55% from the sun.
of patients withOnly
PD,awasfewinsufficient
foods suchcompared
as cod liver to oil,
36%tuna, carp, salmon,
of a control fat cheeses,
population [86]. and
mushrooms contain vitamin D . Thus, it can be ingested directly from food
Knekt et al. carried out3 a cohort study on the Finnish population, collecting information supplements. Between the
liposoluble
regarding the steroids
onset belonging
of PD and to the groupatof
measuring vitamin
the D, the
same time thevitamin
levels of D325-hydroxy
is one of the most important
vitamin D, which
since it is involved
is a serum indicator inof
different physiological
the vitamin processes,inamong
D3 concentration the body,them the most
from known
1978–1980 is the
until thecalcium
end of
absorption and the bone growth regulation. Recently, several studies highlighted
2007 [87]. The results showed that higher levels of vitamin D3 are related to a lower risk of a possible implication
in the muscular
developing and endocrine
PD, giving apparatus,
an important as well
indication of as
theinpotential
the central nervous system,
neuroprotective withof
activity a positive
vitamin
attitude as neuroprotective
D3 against this disease. agent in the management of PD [83].
Figure 4. Chemical structures of the examined natural compounds.
Wang et al. studied the neuroprotective effects of vitamin D3 against 6-OHDA-lesioned mice
in vivo and in vitro [84]. Results showed that the pretreatment with vitamin D3 for eight days
significantly restored locomotor activity in the lesioned mice. Neurochemical analysis determined a
protection from oxidative stress and reduction in depletion of DA neurons in mice treated with the
vitamin compared to the control.
Jang et al. investigated the protective, autophagy-modulating effects of an active form of vitamin
D3 in an in vitro model of PD [85]. Result showed that the treatment with the vitamin reduced ROS
levels and increased the levels of intracellular signaling proteins associated with cell survival.
Moreover, some clinical studies suggest that vitamin D3 has a positive effect on PD.
The first evidence was described by Evat et al. in a study of 2008, in which the level of vitamin D3 ,
in 55% of patients with PD, was insufficient compared to 36% of a control population [86].
Knekt et al. carried out a cohort study on the Finnish population, collecting information regarding
the onset of PD and measuring at the same time the levels of 25-hydroxy vitamin D, which is a serum
indicator of the vitamin D3 concentration in the body, from 1978–1980 until the end of 2007 [87].
The results showed that higher levels of vitamin D3 are related to a lower risk of developing PD, giving
an important indication of the potential neuroprotective activity of vitamin D3 against this disease.
4.10. Creatine
Creatine is a nitrogenous guanidine molecule that occurs naturally in vertebrates and helps to
supply energy to muscle and nerve cells (Figure 4). This molecule usually is used by athletes to
increase maximum power and performance in high-intensity anaerobic repetitive work, but there are
also evidences of antioxidant properties, mitochondrial dysfunction reduction, and neuroprotective
properties in in vitro and in vivo models of PD [88].
Matthews et al. assessed the neuroprotective effect of creatine in a MPTP-induced mouse
model of PD [89]. Results showed that oral supplementation with either creatine or cyclocreatine
produced significant protection against MPTP-induced dopamine depletions in mice, with a decreased
dopaminergic neurons degeneration.
Yang et al. examined whether a combination of CoQ10 with creatine can exert additive
neuroprotective effects in a MPTP mouse model of PD [90]. After administration of MPTP, the treatment
with the two antioxidant molecules significantly reduced lipid peroxidation and pathologic α- synuclein
accumulation in the neurons of the MPTP-treated mice, producing additive neuroprotective effects.
Despite these positive results, Bender et al. conducted a two-year placebo-controlled randomized
clinical trial on the effect of creatine in 60 patients with PD, highlighting that creatine improves patient
mood and led to a smaller dose increase of dopaminergic therapy but had no effect on the disease
modification [91]. Further clinical trial may clarify clinical benefits of creatine in the treatment of PD.
4.11. Melatonin
Melatonin is a hormone produced in the pineal gland (Figure 4), and it is involved in
synchronizing the circadian rhythms including sleep–wake timing, blood pressure regulation, and
seasonal reproduction. Moreover, several studies described the capacity of melatonin to exert relevant
antioxidant properties [92].
In particular, Antolin et al. described the capacity of melatonin to act as an antioxidant in a
MPTP-induced mouse model of PD [93]. Results showed that melatonin can prevent neuronal cell
death, contrasting the damage induced by chronic administration of MPTP, and preventing neuronal
degeneration in the nigrostriatal pathway by counteracting induced oxidative and nitrative stress.
Dabbeni-Sala et al. demonstrated the neuroprotective action of melatonin in a 6-OHDA animal
model of PD [94]. The authors observed the protective activity of melatonin in the treated-mice, with
an increased activity of mitochondrial oxidative phosphorylation enzymes and a reduction of neuronal
oxidative stress disorders.
Finally, two studies indicated that the administration of melatonin in mice was ineffective in
protecting nigral dopaminergic neurons from MPTP-induced toxicity. Results for both studies indicated
that the neuronal enzymatic levels and DA concentration were not different from melatonin-treated
mice versus control [95,96].
4.12. Niacin (Vitamin B3 )

B vitamins are a class of water-soluble vitamins that play important roles in cell metabolism, with
a relevant role as enzyme cofactors in multiple biochemical pathways in all tissues. Good sources for
B vitamins include legumes (pulses or beans), whole grains, potatoes, bananas, and above all meat.
Probably the most popular use of vitamins is as metabolism booster, mainly for the athletes, and for the
elderly which may need to supplement the intake of B vitamins because of problems in absorption and
increased needs for energy production [97]. Among the vitamins B, niacin is an essential component
for the human metabolism, its active form nicotinamide is the precursor of coenzymes NADH and
NADPH, which are essential to produce ATP, and its deficiency leads to pellagra (Figure 4). Since
a part of PD physiopathology is related to mitochondrial dysfunction and cellular energy failure, it
was highlighted that niacin, due to its role in numerous metabolic pathways, has neuroprotective and
antioxidant functions at low doses [83].
Jia et al. studied the effects of nicotinamide on mitochondrial function and oxidative stress in
MPP+ -induced cellular model of PD (1-methyl-4-phenylpyridinium, MPP+ , a neurotoxin that acts by
interfering with oxidative phosphorylation in mitochondria) [98]. Result showed that nicotinamide
significantly protected human cells from an MPP+ toxicity, increasing cell survival and antioxidant
generation, and reducing DNA damage.
Anderson et al. examined the potential of nicotinamide in a MPTP-induced mouse model of
PD [99]. Among the different doses of nicotinamide administrated (125, 250, or 500 mg/kg i.p.), only
the highest dose showed the recovery of striatal DA levels and neuroprotection in the animals treated
with MPTP.
In clinical studies, a positive correlation was demonstrated between a high niacin diet and the
reduced risk of PD [100]. Of interest is the case in which niacin, orally administrated for three months
(500 mg twice daily), significantly improved rigidity and bradykinesia in a patient with idiopathic
PD, though the original purpose was to treat hypertriglyceridemia [101]. Nevertheless, the adverse
effects (unacceptable nightmares and skin rash), did not allow to prolong and better understand the
framework of this result.
Finally, a population-based case-control study evaluated the nutrient intake as a risk factor for
PD, failing in noticing a remarkable clinical efficacy of niacin though the study was conducted only
in people aged ≥50 years in metropolitan Detroit [102]. More clinical observations are warranted to
verify the efficacy as well as side effects of niacin in PD.
4.13. Vitamin C
Vitamin C (ascorbic acid, Figure 4) has an important role in the human body since it is involved
in numerous physiological functions. Moreover, it is an excellent antioxidant, useful in reducing the
presence of ROS, lipid peroxidation, and oxidative stress [103]. The main food sources of vitamin C
are vegetables and fruits, especially citrus fruits and paprika; in recent years more and more food
supplements rich in vitamin C have emerged in the market.
The antioxidant activity of vitamin C can have important implications in the management of PD, as
confirmed by Sershen et al., which demonstrated in vivo that ascorbic acid (100 mg/kg) administration
prior to MPTP treatment can reduce ROS derivatives involved in MPTP neurotoxicity [104].
Seitz et al. carried out a study on the possible correlation between vitamin C and L-DOPA/dopamine
concentrations in an in vitro model of human nerve cells [105]. In particular, the addition of vitamin C
to the culture medium showed an increased production of L-DOPA and dopamine, mainly due to both
an enhancement at metabolic level and involving the gene expression of the enzymes responsible for
producing L-DOPA and dopamine.
Finally, Hughes et al. examined the association between the intake of antioxidants such as vitamin
C and the risk of developing PD [106]. Analyzing more than 1000 cases of patients with PD, it was
observed that the intake of vitamin C can reduce the risk of PD. However, the authors were unable to
confirm this correlation due to the absence of data relating to some years in the follow-up study.
4.14. 6-Shogaol (from Zingiber officinale)

Zingiber officinale is an herbaceous plant of the Zingiberaceae, native to the south-east Asia and it
is widely used as a spice and in the folk medicine. Commercialized with the English name of ginger,
it is cultivated throughout the tropical and subtropical area. It produces clusters of white and pink
flower buds that bloom into yellow flowers, with juicy and fleshy rhizomes which contains the active
ingredients of the plant: essential oil (mainly composed of zingiberene), gingerols, shogaol (main
responsible for the pungent taste), resins, and mucilage.
Among these, 6-shogaol (Figure 4) highlighted interesting properties for the treatment of PD [107].
Park and collaborators studied the neuroprotective and anti-inflammatory properties of this
compound in in vitro and in vivo models of PD [108]. Results showed that treatment with 6-shogaol of
rat mesencephalic cells exposed to MPP+ prevented dopaminergic induced cell loss, showing a counted
pathways and to ameliorate the typical PD motor symptoms.
Ha et al. evaluated the anti-inflammatory effects of 6-shogaol in primary microglia cells and in
an in vivo systemic inflammatory model induced by LPS [109]. Results showed significant
neuroprotective effects in vivo in transient global ischemia via the inhibition of microglia, indicating
the positive attitude of ginger to the reduction on neuroinflammation, one of the main pathological
mechanism of PD.
4.15. β-Carotene
neuron cells of 98.37% ± 10.27% compared to the control group. In the same cell cultures, 6-shagaol
was able to suppress
β-carotene MPP+ -induced
(provitamin A, Figureproduction of neuroinflammatory
5) is a vitamin A precursor, since it factors in a dose-dependent
is composed of two retinyl
manner. In vivocan
groups, which studies demonstrated
be broken down in thethe mucosa
capacityofofthe
6-shagaol to reduce
small intestine byMPTP-induced movement
β-carotene dioxygenase to
impairment
form vitamin of mice comparedcan
A. β-carotene to control,
be foundindicating thatorange,
in yellow, this ginger
andextract
green compound is ableand
leafy vegetables to protect
fruits
dopaminergic
(predominant neurons,
in carrots,tomango,
inhibit the PD inflammatory
maize, pathways
lentils, and spinach). Asand
an to ameliorateitthe
antioxidant, cantypical PD
scavenge
motor
singletsymptoms.
oxygen with very high efficiency, and it is also able to inhibit free radical reactions [110]. The
Ha
very low et toxicity
al. evaluated the anti-inflammatory
of β-carotene effectsefficacy
and its potential of 6-shogaol in primaryfree
in scavenging microglia
radicalscells andled
have in an
to
in vivo systemic
several clinical inflammatory
trials assessingmodel
the induced by LPS
antioxidant [109]. Results
preventative showed some
activities, significant neuroprotective
of them also in the
effects in vivo
prevention in contrast
and transientto
global ischemia
the PD via the inhibition of microglia, indicating the positive attitude
disease.
of ginger to the reduction on neuroinflammation,
Yang et al. prospectively related the consumption one of the of main
dietary pathological
β-carotenemechanism of PD.
with the antioxidant
capacity and the reduced PD risk in two population-based cohorts (38.937 women and 45.837 men)
4.15. β-Carotene
[111]. Results suggested that the constant use of antioxidant supplements such as β-carotene can
exertβ-carotene
a protective effect on PD
(provitamin A, through
Figure 5)theis areduction
vitamin Aofprecursor,
oxidativesince
damageit isby neutralizing
composed theretinyl
of two effect
of ROS. which can be broken down in the mucosa of the small intestine by β-carotene dioxygenase
groups,
to formOno et al. assessed
vitamin the incan
A. β-carotene vitro
be potential anti-fibrillogenic
found in yellow, orange, and and fibril-destabilizing
green leafy vegetablesactivities
and fruitsof
β-carotene, inin
(predominant a dose-dependent manner
carrots, mango, maize, [112].and spinach). As an antioxidant, it can scavenge singlet
lentils,
oxygen Finally, Etminan
with very et al. studied
high efficiency, and itthe effect
is also ableoftoβ-carotene
inhibit freeintake
radicalon the risk[110].
reactions of PD Thethrough
very lowa
meta-analysis
toxicity of observational
of β-carotene studies,
and its potential but they
efficacy could notfree
in scavenging highlight
radicalsany
haveprotective effects
led to several from
clinical
β-carotene,
trials probably
assessing due to the
the antioxidant small number
preventative of studies
activities, somethat included
of them data
also in theon dietary intake
prevention of this
and contrast
carotenoid
to [113].
the PD disease.
Figure 5. Chemical structures

Figure 5. structures of β-carotene and lycopene.
of β-carotene lycopene.
Yang et al. prospectively related the consumption of dietary β-carotene with the antioxidant
capacity and the reduced PD risk in two population-based cohorts (38.937 women and 45.837 men) [111].
Results suggested that the constant use of antioxidant supplements such as β-carotene can exert a
protective effect on PD through the reduction of oxidative damage by neutralizing the effect of ROS.
Ono et al. assessed the in vitro potential anti-fibrillogenic and fibril-destabilizing activities of
β-carotene, in a dose-dependent manner [112].
Finally, Etminan et al. studied the effect of β-carotene intake on the risk of PD through a
meta-analysis of observational studies, but they could not highlight any protective effects from
β-carotene, probably due to the small number of studies that included data on dietary intake of this
carotenoid [113].
4.16. Lycopene
Lycopene is an acyclic isomer of beta-carotene, containing 11 conjugated and 2 non-conjugated
double bonds, belonging to the carotenoid group (Figure 5). It is a natural compound that contributes
to the red color of fruits and vegetables. It is found in tomatoes, watermelons, pink grapefruits, and
apricots. Due to the high number of conjugated double bonds, lycopene is one of the most powerful
natural antioxidants. Among the natural carotenoids, it demonstrated to possess in vitro the highest
scavenger capacity against free radicals, 10-fold and 47-fold more effective in quenching singlet oxygen
than alpha-tocopherol and β-carotene, and the ability to counteract ROS of 2-fold and 10-fold compared
to the other antioxidants, respectively [114,115].
Kaur et al. assessed the potential antioxidant activity of lycopene on oxidative stress and
neurobehavioral abnormalities in rotenone induced PD [116]. The authors administrated 10 mg/kg of
lycopne orally to the rotenone-treated rats for 30 days, and results showed an increased activity by 39%
compared to the control. Moreover, lycopene administration decreased the levels of malonilaldehyde,
a measure of membrane lipid peroxidation, increased the levels of GSH by 75.35% and the level of
superoxyde dismutase (SOD) by 12% when compared to control. This was accompanied by a partial
inversion of cognitive and motor deficits in rotenone-treated rats.
Prema and collaborators investigated the neuroprotective activity of lycopene in an in vivo
model of PD [117]. Administration of lycopene (5, 10, and 20 mg/kg per day, orally) protected
MPTP-induced depletion of striatal DA in a dose-dependent manner. Several studies also indicated that
the neuroprotective effect of lycopene could be related to the emendation of mitochondrial disfunction
and neuroinflammation reduction, such as Sandhir et al., which investigated the neuroprotective
effect of lycopene on an in vivo model of 3-nitropropionic acid-induced mitochondrial dysfunctions
and oxidative stress [118]. Lycopene administration exhibited a protective effect on the induced
mitochondrial dysfunctions and oxidative stress, with an important reduction in ROS formation
and lipid peroxidation. These findings provide an evidence for the beneficial effects of lycopene
supplementation, suggesting the therapeutic potential as neuroprotective and a strong antioxidant
Biomolecules 2019, 9, x 15 of 22
natural compound in the management of PD.
suggests that flavonoids may be promising natural products for the prevention of PD and can
4.17. Flavonoids
potentially be employed as therapeutic compounds.
Flavonoids
Among foods are and
a class of plant
food and fungus
supplements thatsecondary metabolites,
contain high quantitieschemically basedthere
of flavonoids, on a 15-carbon
are some
skeleton consisting
that are widely usedofintwo
thebenzene rings
daily diet, so connected by a heterocyclic
that their constant intake can pyrone ring,
prevent thedivided
onset ofinto
PD six
or
subclasses based on their structural variations (Figure 6).
improve the clinical framework of patients who are already suffering from this disease.
Figure 6. Chemical structures of flavonoids.
Common
4.17.1. sources
Quercetin (fromof flavonoids are several foods such as parsley, onions, blueberries and other
Pollen)
berries, black tea, green tea, all citrus fruits, Ginkgo biloba, red wine, and dark chocolate. Alongside
theseQuercetin, (3,30,40,5,7-pentahydroxyl-flavone)
common foods, is a natural
a novel product recently re-evaluated flavonoid,
for human present
nutrition in most
as food plants,
supplement
fruits and vegetables such as broccoli, peppers, red onions, apples, and grapes. The major
is pollen, which has proven to be a rich source of carbohydrates, lipids, proteins, vitamins, and source is
pollen, which presents quercetin in the glycosylated form as the predominant flavonoid among
those present [123]. There are scientific evidences that quercetin possesses anti-inflammatory,
antitumor, immunomodulating, and neuroprotective properties [124].
This last feature was confirmed in an in vivo study carried out by Kumar et al., which evaluated
the neuroprotective effects of quercetin on mice treated with colchicine, which causes cognitive
minerals [119]. Moreover, pollen is one of the major sources of antioxidants, with a phenolic profile
represented by more than 90% of the flavonoids (mostly glycosylated), which also represent the most
abundant molecules among the nutrients that characterize its chemical composition [120].
Flavonoids can provide numerous health benefits due to their biologic effects, which include
antioxidative, anti-inflammatory, antiapoptotic, and lipid-lowering properties, including a reduction
in the risk of PD [121].
In 2018 Jung and Kim provided an overview of the scientific literature concerning the preventive
and protective roles of flavonoids in the management of PD [122]. The authors, following the
classification of flavonoids into the six major subclasses—flavones, flavonols, flavanones, flavanols,
isoflavones, and anthocyanins—described different studies which support the relationship between
the single molecules and PD. The main role that flavonoids can exert in the PD is the protection of
neurons against oxidative stress, the capacity to suppress neuroinflammation, and the ability to interact
with critical neuronal intracellular signaling pathways. These pathways involve protein kinase and
lipid kinase signaling, which strongly affect neuronal function by altering the phosphorylation state of
target molecules and by modulating gene expression. This suggests that flavonoids may be promising
natural products for the prevention of PD and can potentially be employed as therapeutic compounds.
Among foods and food supplements that contain high quantities of flavonoids, there are some
that are widely used in the daily diet, so that their constant intake can prevent the onset of PD or
improve the clinical framework of patients who are already suffering from this disease.
4.17.1. Quercetin (from Pollen)

Quercetin, (3,30,40,5,7-pentahydroxyl-flavone) is a natural flavonoid, present in most plants,
fruits and vegetables such as broccoli, peppers, red onions, apples, and grapes. The major source is
pollen, which presents quercetin in the glycosylated form as the predominant flavonoid among those
present [123]. There are scientific evidences that quercetin possesses anti-inflammatory, antitumor,
immunomodulating, and neuroprotective properties [124].
This last feature was confirmed in an in vivo study carried out by Kumar et al., which evaluated the
neuroprotective effects of quercetin on mice treated with colchicine, which causes cognitive dysfunction
and oxidative stress [125]. Chronic administration of quercetin showed clear improvements in the
memory of mice, while biochemical assays on nerve cells showed a significant reduction in ROS and
lipid peroxidation.
Sriraksa et al. confirmed the previous findings through an in vivo evaluation of the efficacy
of quercetin in counteracting oxidative stress and memory deficits in 6-OHDA-lesioned rats [126].
Animals were treated with quercetin before and after the establishment of lesion, and they showed
a marked improvement in cognitive functions, as well as a reduction of damage caused by induced
oxidative stress compared to the control group.
4.17.2. Epigallocatechin-3-Gallate (from Green Tea)

Green tea is a variant of tea obtained with non-treated leaves of Camellia sinensis. Like all
commercialized teas, it has Chinese origins, and for centuries it has been consumed in various Asian
regions, from Japan to the Middle East. In recent years, green tea has become more popular also in
the rest of the world, mainly because the several health benefits it claims, including the prevention of
risk cancer, cardiovascular diseases, diabetes, and neurodegenerative diseases [127,128]. Green tea is
rich in flavonoids, among which one of the most important is (-)-epigallocatechin-3-gallate (EGCG), a
compound part of the flavanols subgroup and that presents interesting antioxidant properties, which
can contribute to counteracting the onset of PD [129].
Guo et al. evaluated from the histochemical point of view the neuroprotective effect of green tea
on 6-OHDA-treated mouse model of PD, identifying a marked protection from ROS, a reduction in
lipid peroxidation, and in the intracellular nitrite and nitrates levels [130].
Levites et al. demonstrated the potential free radical scavenger activity of polyphenols of green
tea through an in vivo study on 6-OHDA mouse model of PD [131]. The results showed a reduction
in oxidative stress and an inhibition of the activation of gene promoters that influence cell death in
animals that received green tea extract prior to the treatment with 6-OHDA.
Hellenbrand et al. examined the possible correlation between the ingestion of green tea and the
onset of PD, in a case-control study of the dietary habits of patients with PD compared to a control
group [132]. The results showed a moderate lower risk of developing PD among people who regularly
consume green tea in their diet.
Finally, Siddique et al. studied the role of EGCG on the transgenic Drosophila model of
flies expressing normal human alpha synuclein (h-αS) in the neurons [133]. Results showed that
supplementation with 0.25, 0.50, and 1.0 µg/mL of EGCG delayed locomotor dysfunction in a
dose-dependent manner, as well as reduced the oxidative stress and apoptotic processes in the brain of
the PD model flies.
4.17.3. Ginkgo Biloba Extract

Ginkgo biloba is the only living species in the division Ginkgophyta, used for centuries in the
traditional Chinese medicine. Its extracts, rich in flavonoids and terpenoids, may have beneficial effects
in the management of PD [134].
Wu and Zu investigated the neuroprotective effect of Ginkgo biloba extract on MPTP-treated
mice [135]. The pretreatment of animals with the extract, seven days before the administration of MPTP,
significantly reduced the MPTP-induced neurotoxicity. A possible mechanism of neuroprotection
was the antioxidant properties of flavonoids and ginkgolides against formation of free radicals.
Moreover, fluorometric assays highlighted the capacity of the extract to inhibit in vitro the activity
of monoamine oxidases B (MAO B), further reducing the degeneration or apoptosis of nigrostriatal
dopaminergic neurons.
Rojas et al. confirmed the free radical scavenger activity of Ginkgo biloba extract in a mouse model
of PD [136]. Mice treated prior or after 24 h the administration of MPTP showed a significant decrease
in loss of striatal dopamine levels compared to the control. The authors also determined the oxidative
stress levels by measuring the lipid peroxidation and the antioxidant enzymes activity. After the
administration of Ginkgo biloba extract, the lipid peroxidation was reduced, whereas the activity of
SOD, glutathione peroxidase (GPx), and glutathione reductase was enhanced, indicating that the
neuroprotective action of the extract is related to the free radicals scavenging properties, the reduction
of lipid peroxidation, and the capacity to stimulate several antioxidant enzymes.
5. Conclusions
Healthy ageing, primarily when a neurodegenerative disease is present, is possible by applying
the correct pharmacological therapy, but diet and food supplementation often are a critical factor.
The use of food supplements or functional food has undergone an enormous increment in recent years,
with a wider market that offers diversified products for every type of need. The treatment of PD passes
through a balanced diet, rich in biomolecules potentially useful to reduce the symptoms of the disease,
by contrasting the mechanisms responsible for neurodegeneration. Moreover, a balanced diet and the
use of food supplements based on vitamins, antioxidants, or elements with anti-inflammatory and
neuroprotective properties can effectively act as a complement to the normal pharmacological therapies.
The molecules analyzed in this review have shown to actively contribute in countering the
pathophysiological mechanisms of PD. Most of the molecules examined have a marked antioxidant
capacity, important for combating the oxidative stress characteristic of PD. Other molecules are
useful because they possess anti-inflammatory properties, or because they are able, through different
molecular mechanisms, to induce the neuroprotection of dopaminergic neurons.
Nevertheless, time has a crucial role in the use of natural and/or plant-derived molecules, since
usually they do not show any immediate action or tangible benefit in the short period, but constant
use over a long period of time can bring several benefits in the treatment of several pathologies, in
particular for slow-running neurodegenerative diseases such as PD.
Funding: This study was supported by the Italian Ministry of Education, University and Research (University of
Chieti-Pescara) FAR 2018.
Conflicts of Interest: The authors declare no conflict of interest.
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biomolecules

Keywords: Parkinson’s disease; food supplements; functional food; antioxidants; anti-inflammatory;

Biomolecules 2019, 9, 271; doi:10.3390/biom9070271 www.mdpi.com/journal/biomolecules

3. Oxidative Stress and Neuroinflammation in PD

4. Natural Compounds Useful in the Prevention and Management of PD

Molecule Beneficial Effects Mechanism Ref.

4.1. Coenzyme Q10

4.2. Lipoic Acid

Figure 2. Chemical structures of the examined natural compounds.

4.7. Omega-3 Fatty Acids

4.8. Whey Protein

Figure 4. Chemical structures of the examined natural compounds.

4.12. Niacin (Vitamin B3 )

4.14. 6-Shogaol (from Zingiber officinale)

Figure 5. Chemical structures

Figure 6. Chemical structures of flavonoids.

4.17.1. Quercetin (from Pollen)

4.17.2. Epigallocatechin-3-Gallate (from Green Tea)

4.17.3. Ginkgo Biloba Extract

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