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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5409_Библиотеки_им_академика_М_И_Перельмана.pdf
Dietary Components Consisting of Bioactive Molecules in the Prevention of Neurodegenerative Diseases
BIOACTIVE DIETARY COMPONENTS IN THE PREVENTION
OF NEURODEGENERATIVE DISEASES
As life expectancy increases, the frequency of diseases caused by neuronal degeneration increases. Due
to this increase, it is an urgent need to help people have a healthy body and mind, maintain the quality
of life, and treat and finally hinder age-related diseases. Bioactive compounds are biologically active
compounds obtained from edible sources that can be used as additives in the food and other industries.
These active compounds, which are also called phytochemicals and found in vegetables, fruits, grains,
legumes and tea, play a role in the prevention of many diseases. In recent years, the number of studies
inquiring the effects of these active compounds on neuronal survival has increased. These studies aim
to protect the quality of life and decrease financial problems by preventing the development of neurodegenerative diseases.
Low levels of ROS production help maintain physiological functions, including proliferation, defense
of the body and signal transduction (Singh-Mallah et al., 2019). The brain is especially susceptible to
oxidative stress and neuroinflammation due to the huge numbers of neurotransmitters, neurotransmitter
receptors, ROS-sensitive polyunsaturated fatty acids, and restricted potential of neuronal regeneration.
The chronic neurodegenerative process can be triggered by the vicious circle between oxidative stress,
neuroinflammation, and neurodegeneration. As a result, inhibiting the generation of ROS can diminish
neuroinflammation and vice versa. Generally speaking, since bioactive foods have strong antioxidant,
anti-inflammatory and immunomodulatory properties, they are protective against oxidative stress, which
enables them to prevent development of neurodegenerative diseases (Weaver, 2014). Recently, bioactive molecules have gained more attention, especially in the prevention/delay of cognitive disorders that
develop with age.
Vitamins, carotenoids, and polyphenols are the most important bioactive components present in
fruits and vegetables, and they have the potential to support a healthy metabolism and prevent diseases
(Akhtar et al., 2015). The next sections will go through the synthesis and biological consequences of
these bioactive chemicals, as well as their functions in the prevention of neurodegenerative diseases.
Polyphenols
Oxidative stress and impaired metabolism of certain neurotransmitters such as glutamate, GABA, acetylcholine, dopamine or serotonin play a decisive role in the pathogenesis of neurodegenerative diseases.
It has been shown that biologically active plant polyphenols have a positive effect on the function of the
central nervous system (CNS) through the modulation of metabolism and the effect of some neurotransmitters (Rebas et al., 2020). Considering that the polyphenols are non-toxic, we can assume that they can
be alternatives to the conventional treatment methods of neurodegenerative diseases as well as support.
Neuronal degeneration can occur as a result of excessive production of ROS and proinflammatory
mediators (Uttara et al., 2009; Bhullar & Rupasinghe, 2013). One of the powerful options to prevent
or slow down this formation is to take components with antioxidant and anti-inflammatory properties.
Regular intake of fruits rich in polyphenols can help delay the development of neurodegenerative diseases
by using their strong antioxidant and anti-inflammatory properties (Youdim & Joseph, 2001; Hamaguchi
et al., 2006; Pandey & Rizvi, 2009). Polyphenols are the most abundant and widely dispersed bioactive
molecules. Polyphenols have been shown to have a wide range of biological activities, and numerous
studies have emphasized the positive effects of phenolic compounds, indicating their potential as thera-
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Dietary Components Consisting of Bioactive Molecules in the Prevention of Neurodegenerative Diseases
peutic tools for a number of disorders (Fraga et al., 2019). Some of the polyphenols have neuroprotective
effects and they exert their effect by making changes in some signaling pathways and neurotransmission
(Rahimifard et al., 2017). Polyphenols specifically bind to the TrkB receptor, which phosphorylates the
CREB protein by activating the Ras/ERK 1/2, PI3K/Akt, BDNF and PL-Cy pathways. The transcription of Bcl-2 and antioxidant genes that regulate cell survival is thus increased by CREB, which inhibits
neurodegeneration. Polyphenols also boost neuroprotective efficacy by activating the Keap-Nrf2-ARE
signaling pathway (Uddin et al., 2020).
The Blood Brain Barrier (BBB) acts as a barrier to ensure the stability of the physiological environment of the brain tissues and to prevent harmful agents from damaging the CNS. The BBB consists of
endothelial cells that form the inner surface of the capillaries and the tight connections between these
cells (Xie et al., 2019). Gap junction proteins are found in astrocytes, pericytes, and endothelial cells
interconnected via the extracellular matrix, and they work in collaboration in order to regulate the
movement of ions, molecules, and cells between the blood and brain to create a good environment for
proper neuronal function (Pervin et al., 2019). In vivo and in vitro research have documented that some
flavonoids can pass the BBB (Faria et al., 2014).
According to the nature of the carbon skeleton, polyphenols are classified into four main groups:
Phenolic acids, flavonoids, stilbenes and lignans (Scalbert & Williamson, 2000).
Flavonoids
Flavonoids are a group of non-nutrient polyphenolic phytochemicals, which naturally occur as bioactive
compounds and are found in plants. Depending on the oxidation state of the pyran ring, flavonoids can be
classified into six subgroups: anthocyanins, flavanols, flavonols, flavanones, flavones, and isoflavones
(Bhagwat et al., 2014). Anthocyanins include compounds such as petunidin, pelargonidin, peonidin,
malvidin, delphinidin and cyanidin, while genistein and daidzein are classified as isoflavones. These
chemicals are categorized based on their chemical structures and biological activities. Genistein and
daidzein of isoflavones are mainly found in legumes. Resveratrol, especially found in the skin of red
grape, is a non-steroidal polyphenolic compound and is considered a phytoestrogen.
Microglial cells, a major type of brain cell, are glial neurons that can migrate in case of oxidative stress
and inflammation. However, these microglial cells can create cytokines and inflammatory chemicals
like superoxide and nitric oxide in cases of severe oxidative or inflammatory damage. While flavonoids
can activate antioxidant genes such as SOD and GPX through their antioxidant properties (Zaidun et
al., 2018), NF-kB, IL1, IL6 cytokines can inhibit BCL2 (Nam, 2006).In addition, they decrease caspase
activity, and they can activate neurogenesis by activating CREB, BDNF, ERK1/2 (Muhammad et al.,
2019). Since flavonoids are active in many signaling pathways in the central nervous system, and can
pass through the BBB, they have important effects on neuronal survival.
Anthocyanins
Anthocyanins are classified under a large group of compounds known as flavonoids. Anthocyanin molecules are commonly associated with fruits, although they are also found in roots, legumes, vegetables and
grains. In particular, blueberries, blackberries and mulberries are rich sources of anthocyanins (McGhie
& Walton, 2007). Bioavailability and absorption studies have shown that anthocyanins begin to show
their mechanism of action immediately after dietary intake. Various studies have shown that oral micro-
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flora provides beta glucosidase activity, which is also present in the human intestinal epithelium. These
findings suggest that oral microflora, saliva, and the entire oral epithelium may contribute to formation
of bioactive aglycon from major anthocyanins. Therefore, starting from the oral cavity, anthocyanins
interact with enzymes with similar functions and structures throughout the digestive tract. Anthocyanins metabolized by the oral microbiota are also rapidly absorbed in the stomach, but the maximum
absorption site is the intestine (Passamonti et al., 2003; Charron et al., 2007; Charron et al., 2009). The
bioavailability of anthocyanins is affected by the intensive metabolism of bacteria in the colon. Because
it is well known that probiotic bacteria can have a variety of health benefits, the good effects shown after
consuming anthocyanins may be attributed in part to regulation of gut microbiota. The metabolization of
anthocyanins by gut microbiata produces short-chain fatty acids. This situation both causes a decrease
in pH and creates a suitable environment for the proliferation of probiotic bacteria (Zhu et al., 2018). In
this way, anthocyanins have a potential role in modulation of gut microbiota and neuroinflammation. It
is believed that the gut microbiota can positively alter the modulation of the production of toxic proteins
such as tau and amyloid, thereby providing massive benefits for public health (Zilli & Zilli, 2021). It has
been shown that a diet rich in anthocyanin decreases TCK-1 expression in the hippocampus by increas-
ing Pseudoflavonifractor and Sporobacter genera. In addition, it has decreased lippolysaccharide (LPS)
production in fecal microbiota and increased the production of neuroprotective metabolites by changing
tryptophan metabolism (Marques et al., 2018). Many experimental models which prove the benefits of
dietary anthocyanins have shown that anthocyanins are effective in the prevention of various types of
cancer, diabetes, cardiovascular and neurodegenerative diseases by possibly affecting a number of cell
signaling cascades, triggering anti-inflammatory response and controlling gene expression (Hui et al.,
2010; Takikawa et al., 2010; Chen et al., 2015).
The accumulation of inflammatory factors act quite importantly in the development of neurodegenerative diseases. In a mice model of Alzheimer’s disease (AD), anthocyanins can effectively cause
a decrease in expression levels of inflammatory factors, thus Ap1-42 peptide can positively affect the
development of inflammation. Furthermore, anthocyanins can reduce the expression of the AD-activated
nuclear factor kappa B. (NF-KB) (Poulose et al., 2012). On top of that, anthocyanin administered for
14 days has prevented LPS-induced oxidative stress, neurodegeneration and neuroinflammation in the
cortex of adult mice (Khan et al., 2016). About the effect of anthocyanin on cognitive function, it has
been documented that following sixteen weeks of daily supplementation, blood oxygen level-dependent
activation was increased in the left middle frontal gyrus, left pre-central gyrus, and left inferior parietal
lobe in participants supplemented with anthocyanin-rich blueberry. These data show the increased neural
response during working memory challange with cognitive decline in older adults treated with blueberry
(Boespflug et al., 2018). Overproduction of ROS and proinflammatory mediators is often associated with
neuronal degeneration. Therefore, the cognitive protective effects of anthocyanins are largely attributed
to their antioxidant and anti-inflammatory properties.
It is clear that anthocyanins positively affect cognitive and motor functions with their regulatory
effects on neuronal survival. It has been shown that anthocyanins can easily pass the BBB where they
stimulate the communication between cells and neuronal regeneration (Manolescu et al., 2019) and can
be localized in some parts of the brain, affecting signaling pathways at the molecular level, and thus
inhibiting or slowing down the formation of neurodegeneration (Spencer, 2010; Rendeiro et al., 2015).
Therefore, consumption of purple fruits should be a part of a healthy lifestyle.
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Dietary Components Consisting of Bioactive Molecules in the Prevention of Neurodegenerative Diseases
Flavanols
Flavanols contain compounds such as catechin, gallocatechin, epicatechin, epicatechin gallate, epigallocatechin, and epigallocatechin gallate (Ottaviani et al., 2020). Since flavanols directly interact with
neurons at the molecular level by generating signaling that increases connections between neurons,
antioxidants have been demonstrated to promote brain performance and memory at all ages, as well as
enhance and protect brains in older adults (Cox et al., 2015). Amyloid-β (Aβ) formation is observed
from the early stages of many neurological diseases, including AD. Studies have shown that flavanols
have a protective effect against neurodegeneration, so early use can lessen the risk of developing the
disease (Mandel et al., 2008). Catechins, which is a subgroup flavanols, are found in many fruits and
vegetables such as tea, cocoa, grapes. Green tea, which contains catechins, has been shown to regulate
cognitive abilities and protect against aging of the brain (Pervin et al., 2019). Catechin can be consisted
of four different structures: (+) catechin, (-) catechin, (+) epicatechin, and (-) epicatechin. The (-) epiform (-) epigallocatechin gallate (EGCG) is the most abundant catechin in green tea (Unno & Nakamura,
2021). EGCG is a flavanol with very strong antioxidant properties. EGCG can inhibit the aggregation
of amyloidogenic proteins such as Aβ monomers, α-syn, and calcitonin, which are important in many
neurological diseases (Bieschke et al., 2010). It has been demonstrated that following administration of
300 mg EGCG, the activities of alpha, beta, and theta brain waves increased in EEG activity (Scholey
et al., 2012). This result shows that EGCG can prevent stress-related oxidation, regulate cognition, and
has a relaxing and refreshing effect. Catechins in green tea is effective in the development of long-term
memory (Pervin et al., 2019), and spatial working memory (Unno & Nakamura, 2021), and thus catechins
can be beneficial for developing new cognition-enhancing drugs.
Flavanones
Among the flavanones, naringenin, hesperidin, naringin, eriodicytol are the ones which have been
widely studied for their effects on neuroprotection, apoptosis, and synaptic dysfunction. Naringenin, a
flavanone, is commonly found in fruits, especially citrus fruits, bergamot, tomatoes, and lemons. In addition to their anti-inflammatory, immunomodulatory, antiproliferative and antioxidant effects, they are
good neuroprotectors, and therefore many studies have investigated their function in neuronal survival
(Dobrzynska et al., 2020; Bhia et al., 2021). One study has shown that administration of naringenin
to propofol-exposed mice suppressed neurodegeneration, prevented apoptosis, and enhanced learning
memory response (Zou et al., 2020). However, since the bioavailability of naringenin is low and its dis-
solution is difficult, some researchers have opted for nanocoating of naringenin. In a study on ischemic
experimental animals, naringenin was coated with chitosan and administered intranasally. In cerebral
ischemic rats, neurobehavioral activity improved and infarct volume decreased. These results have shown
that naringeninin exhibits a strong neuroprotective effect against oxidative stress (Ahmad et al., 2020).
In a comparable study using the SH-SY5Y cellular model of Parkinson’s disease, naringenin was found
to have improved neuroprotective and antioxidant properties against 6-OHDA-induced neurotoxicity
(Md et al., 2019).
Another compound found in flavanones and closely related to neuronal survival is hesperidin. It is
found in citrus fruits such as orange and grapefruit. In a study with streptozotocin (STZ)-treated mice,
hesperidin has exerted a protective effect against STZ-induced memory impairment and neuronal apoptosis (Hajizadeh Moghaddam et al., 2020). Another study has demonstrated the neuroprotective effect
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of hesperedin against neuroinflammation, neurodegeneration, synaptic dysfunction, LPS-induced glial
activation and memory problems in mice (Muhammad et al., 2019). Eriodictyol, another flavonoid com-
pound, has been shown to alleviate memory impairment and Aβ accumulation and Tau phosphorylation
by activating the Nrf2/HO-1 signaling pathway via vitamin D receptor (VDR) mediated mechanism (Li
et al., 2022). Its effect on suppressing the neurodegeneration, especially in AD, suggests that it can be
used for a new treatment approach.
Flavones
Among the most important flavones are luteolin, chrysin, apigenin and tangeritin. The effects of these
flavones on neuronal survival have been documented by both in in vivo and in vitro studies. It has been
shown that luteolin, one of the flavones, has decreased the levels of tumor necrosis factor-α (TNF-α),
prostaglandin E2 (PGE2), IL-1β and nitric oxide (NO), and resulted in an antioxidant, anti-inflammatory
and neuroprotective phenotype by affecting the microglial transcriptome (Kempuraj et al., 2021). In vivo
experiments have shown that apigenin can alleviate hypoxic-ischemic brain injury by down-regulating
apoptosis via the PI3K/Akt/Nrf2 signaling pathway (Wilms, 2005). Similarly, in the presence of CD40
ligation, luteolin and apigenin inhibited interferon-gamma-induced microglial TNF- and IL-6 production
(Rezai-Zadeh et al., 2008). In a study conducted with rats with traumatic brain injury (TBI), chrysin has
been shown to improve vestibular dysfunction, reduce memory-related problems and anxiety/depression.
It has also been observed that chrysin has anti-inflammatory and anti-apoptotic effects (Rashno et al.,
2020). According to a similar study, fisetin administration lowered neuronal cell death and apoptosis,
elevated B-cell lymphoma 2 (Bcl-2), decreased Bcl-2-related X protein (Bax) and caspase-3 expression
after TBI, resulting in a neuroprotective effect (Zhang et al., 2018). Tangeretin, a flavon that is found
in the peel of the citrus fruits, has antiasthmatic, antioxidant, anti-inflammatory and neuroprotective
properties. One study has shown that tangeretin can be used as a therapeutic strategy against ischemic
reperfusion injury, as it increases the activity of superoxide dismutase, decreases the levels of ROS and
malondialdehyde, and ameliorate the injury (Wu et al., 2019). In addition, its neuroprotective effect has
been emphasized in neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases (Braidy
et al., 2017).
Flavonols
Neurodegeneration associated flavonols can be classified as: kaempferol, quercetin, myricetin.It has
been shown that Kaempferol acts specifically on the mitochondrial Ca
is able to cross the BBB in animals with traumatic brain injury which were treated with Kaempferol
(Parent et al., 2020). Kaempferol has suppressed the expression of numerous pro-inflammatory proteins
in brain ischemia reperfusion rat models by decreasing the phosphorylation and nuclear translocation of
the transcription factor NF-KB p65 (Li et al., 2019).
While quercetin is abundantly found in asparagus, onions, red leaf lettuce, cherries, apples and
strawberries, it is also found in many fruits and vegetables, even in low amounts. Due to its very strong
antioxidant capacity, many in vivo and in vitro studies have been conducted to investigate its function in
neurodegenerative diseases. Quercetin’s bioavailability is low and it has a lipophilic compound (Andres
et al., 2018). It can cross the blood-brain-barrier so that it can exert its neuroprotective effects. It has
been demonstrated that the conjugated forms of isorhamnetin-3-O-glucuronide (methylquercetin-3-O-
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2+
uniporter (mCU) channel and
Dietary Components Consisting of Bioactive Molecules in the Prevention of Neurodegenerative Diseases
glucuronide) and Quercetin-3-O-glucuronide accumulate in cerebral tissue after oral administration of
quercetin (Babaei et al., 2018). Quercetin exerts a protective effect against MPP+-induced oxidative
stress in dopaminergic neurons (Bournival et al., 2009), protect neurons against LPS-induced microglial toxicity and attenuate neurodegeneration in PD mouse models (Boyina et al., 2020), and improve
cognitive abilities (Sriraksa et al., 2012). It has been reported that, in neuronal-microglial cell cultures,
LPS-induced TNF-α and IL-1 gene production was suppressed in glial cells, and inflammatory-induced
neuronal death was reduced (Bureau et al., 2008). In addition, another study has suggested that admin-
istration of quercetin 40mg/kg for 16 weeks in the APPswe/PS1dE9 transgenic mouse model of AD may
reduce ROS production, mitochondrial dysfunction, plaque formation, and improve cognitive deficits
(Babaei et al., 2018). These findings suggest that quercetin acts as a pro-antioxidant in the brain and
could be employed as a nutraceutical in the treatment of neurodegenerative diseases.
Myricetin is a light yellow flavonol that is commonly found in fruits and vegetables such as apple,
mulberry, strawberry, spinach, aloe and carrot. Due to its strong antioxidant effects, myricetin has been
shown to provide clinical benefit in the treatment of neurodegenerative diseases. Myricetin has antioxidant, anti-inflammatory and anti-tumor effects (Pluta et al., 2021). It has been shown that myricetin
reduces infarct volume caused by cerebral ischemia and improves cerebral and mitochondrial function
(Wu et al., 2016). One study showed that myricetin lowered endothelial permeability and inflammation
in a brain cell model of oxygeneglucose deprivation and reoxygenation, and considerably contributed
to BBB function via activating the eNOS/NO pathway (Zhang et al., 2019). Nevertheless, quercetin and
myricetin can be used efficiently to preventing DNA damage induced in lymphocyte cell lines or human
lymphocytes (Wilms et al., 2005).
Isoflavones
Isoflavones have biological effects on neuronal systems. They are a type of phytoestrogen, naturally occurring compounds in plants that serve as the main source of protein in many soy products and standard
rodent feeds. The steric structure of these molecules is comparable to that of steroidal compounds. They
have the ability to bind to the human estrogen receptor (ER) and thus perform a number of estrogenic
or anti-estrogenic actions (Duncan et al., 2003). A number of studies have focused on different isoflavones such as daidzein and genistein and their function in neuronal survival. Phytoestrogens have direct
effects on androgen receptors in the brain, and they can affect neural circuit activities when combined
with their ER actions. The activation of second messengers associated with plasticity in the hippocampal synapse was reduced in male mice which were fed a low phytoestrogen diet. This diet caused
a significant reduction in long-term potentiation (LTP) in the ventral hippocampus, as well as reduced
intermale aggressiveness, changes in territorial marking behavior, and a general disruption of social
behavioral patterns (Gorzkiewicz et al., 2021). ER expression and localization are dynamic processes,
varying according to cell type, hormonal condition, area of the brain, and neurological function. Both
ERa and ERb are highly expressed in the brain and have a distribution pattern that corresponds to their
roles in cognition and reproduction. Some clinical studies have revealed that changes in estrogen levels
in the postmenopausal period cause negative effects on the cognitive level (Spencer et al., 2008; Vargas
et al., 2016). Isoflavones can ameliorate neurological deficits and reduce brain infarct volume in rats
using the ER pathway alone, as well as reduce neural death induced by oxygen-glucose deprivation plus
reoxygenation (OGD/RO) and L-glutamate treatment in neuron cell lines in a dose-dependent manner
(Gu et al., 2021). The offspring of pregnant rats fed with an isoflavone-rich diet have better learning
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and memory development (Lephart et al., 2002), and their brains are protected against oxidative stress
and neuronal apoptosis (Yan et al., 2019).
Genistein is a natural isoflavone compound found mainly in legumes, with antioxidant, anti-aging,
anti-inflammatory, anti-senile dementia and anti-tumor effects (Jiang et al., 2021). Besides being an
enzyme inhibitor and regulator of peroxisome proliferation, it also affects genes that control cell growth
through its effects on natural killer cell function (Sarkar & Li, 2003). By revealing the mechanisms
underlying its anti-inflammatory effects, it has been found that genistein can inhibit the expression of
proinflammatory factors, which are induced by β-amyloid (Jiang et al., 2021), Additionally, genistein
can activate cAMP/CREB-BDNF-TrkB-PI3/Akt signaling pathway and exert neuroprotective effects
(Jiang et al., 2017).
Daidzein, another isoflavones, is known with its neuroprotective and neurotrophic effects. It has been
shown that neurons of dorsal root ganglion can stimulate neurite outgrowth depending on Src kinase,
PKCδ and ERK (Extracellular regulated kinase) signaling pathways (Yang et al., 2012). Nevertheless, a
study on rats has shown that daidzein has reduced cell death in rat cortical neurons caused by exposure
to oxygen-glucose deprivation and improved synaptic function in terms of increased synaptic vesicle
recycling in nerve terminals (Hurtado et al., 2012). In addition, the association of daidzein with neurotensin 1 and interleukin-10 receptors, its neuroprotective properties and positive effects on cognitive
processes have been documented (Alo et al., 2021).
Stilbenes
Resveratrol is a stilbene found in a variety of plants such as grapes, blueberries, raspberries, and peanuts.
Resveratrol exerts neuroprotective effects in experimental models of Alzheimer’s disease and Parkinson’s disease, but is chemically unstable when exposed to high temperatures, pH changes, UV light, or
certain enzymes. Due to its rapid metabolism and low bioavailability, its application in the clinic is quite
limited. To overcome these restrictions, resveratrol can be carried in nanocarriers to extend the half-life
and aid pass through the BBB. Reservatrol was encapsulated using a variety of nanomaterials, including liposomes, lipid and polymeric nanoparticles. To recognize their targets in the brain, some of these
nanocarriers have been engineered with targeting molecules (Liu et al., 2020; Siddiqui et al., 2021).
Resveratrol has been shown to protect neurons by activating ERK-induced CREB regulation, triggering
the release of glial cell-derived neurotrophic factor (GDNF), BDNF and NGF, and suppressing the levels
of IL-1, IL10, and NF-κB (Anastacio et al., 2014), and resveratrol potentially protects neurons by taking
part in neuroinflammation in this way (Granzotto & Zatta, 2011; Yang et al., 2014). Oral treatment of
resveratrol has inhibited microglia activation related to the cortical Aβ plaques formation in a mouse
model of cerebral deposition, reducing the proinflammatory action of Aβ on macrophages (Capiralla et
al., 2012). Furthermore, in an age-related mouse model of AD (SAMP8), long-term dietary resveratrol
consumption was linked to decreased tau hyperphosphorylation, cognitive impairment and amyloid load,
which showed the neuroprotective effect of this compound (Capiralla et al., 2012).
Carotenoids
A variety of organisms such as bacteria, fungi, plants and algae contain carotenoids, a family of red,
orange and yellow pigments. Although carotenoids are especially found in green leafy vegetables, they
are also found in eggs, corn, milk and some fish species (Bohm et al., 2021). As people show more
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Dietary Components Consisting of Bioactive Molecules in the Prevention of Neurodegenerative Diseases
interest and increase awareness for natural foods, interest in natural colorants such as carotenoids that
can be used in food industry also increases, both because they have coloring properties and they are
strong antioxidants. The neuroprotective effects of dietary carotenoids, including beta-carotene, lutein,
lycopene, astaxanthin and fucoxanthin, have been demonstrated by various studies (Park et al., 2020).
Dietary carotenoids are antioxidants that work against oxidative stress with their free radical scavenging properties. Carotenoids are essential precursors for the production of retinoids such as vitamin A in
humans. Carotenoids are also associated with many developmental processes. Some carotenoids have
other biological activities for human health. Carotenoids have been associated with reduced incidence of
various chronic diseases such as cardiovascular diseases and neurodegenerative diseases such as stroke
(Bohm et al., 2021).
While lycopene is exclusively found in red tomato varieties and watermelon, it is also found in certain
amounts in other red vegetables and fruits. Studies on the therapeutic effects of carotenoids in human
diseases have received a lot of attention in recent years and due to its efficacy and safety, lycopene is
among the top investigated carotenoids. It protects hippocampal neurons against apoptosis, inhibits
pro-apoptotic proteins, and protects anti-apoptotic proteins (Qu et al., 2011). Lycopene is thought to
be one of the most powerful anti-inflammatory phytochemicals, as it can lower oxidative stress in vivo
through chain-breaking mechanisms and by donating electrons. Lycopene has been demonstrated to have
modulatory effects on a variety of neurodegenerative disorders. It has been suggested that lycopene’s
neuroprotective effect is related to its capacity to permeate the blood-brain barrier and scavenge ROS
(Ugbaja et al., 2021). In vivo and in vitro experiments have shown that lycopene, through the Nrf2/
NF-kB signaling pathway, can reduce apoptosis and inflammation in neurons and the nervous system,
eventually alleviating hypoxic ischemic brain injury, thus lycopene can be an effective alternative to
other drugs (Fu et al., 2020). The β-(beta) carotene is one of the best-known food carotenoids and is
occasionally found in certain foods along with α-carotene. The β-carotene can be detected in carrots,
mangos, and apricots, while α-carotene is typically found in carrots and pumpkin. The β- carotene is
the most abundant provitamin A carotenoid in foods and is a natural molecule (Stutz et al., 2015). It is
known that β-carotene is highly absorbed in the body and metabolized in humans.
It has been shown that β-carotene has improved neural functions and cognitive performance and re-
duced ROS production in TBI rat model (Chen et al., 2019). In addition, it has been shown that β-carotene
supports neural plasticity and increases cognitive abilities (Avraham et al., 2019; Hira et al., 2019).
Lutein, a dihydroxy derivative of β -carotene, is present in a variety of yellow and orange fruits and
flowers, as well as green vegetables. It has been shown that it has a neuroprotective effect especially
in retinal degeneration and is important in preventing age-related macular degeneration, which is the
prominent cause of blindness (Ozawa et al., 2012). Fucoxanthine was found to alleviate traumatic brain
injury induced secondary brain injury, including brain lesion, cerebral edema, neurological deficits, and
neuronal apoptosis (Zhang et al., 2017).
Astaxanthin, which crosses the blood brain barrier with its special structure, has been shown to reduce
cognitive impairment in in vivo and in vitro models of neurodegenerative diseases (Galasso et al., 2018).
Astaxanthin is the main form of carotenoid detected in marine animals such as salmon, shrimp, lobster
and crabs, and other microorganisms. Astaxanthin has β-carotene and its antioxidant capacity 10 times
higher than lutein, therefore it is referred to as super vitamin E (Higuera-Ciapara et al., 2006). This may
be due to its molecular structure, which includes hydroxyl and keto.
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Vitamins
Vitamins offer an apparent advantage to prevent neurodegenerative diseases and preserve cognitive
functions. Both water- and fat-soluble vitamins significantly prevent PD and AD. The effects of the use
of vitamins A, B, C, D and E in appropriate doses on neurodegeneration and cognitive processes have
been shown in different studies.
Vitamin A or retinoid derivatives have been frequently advocated as treatment agents for AD and
psychiatric disorders such as schizophrenia. Vitamin A, through its primary metabolite retinoic acid, has
been shown to have profound effects on behavior in post-embryonic and adult life and brain physiology.
One of the classic hallmarks of human aging is reduced cognitive function, which has been shown in
animal models after inadequate vitamin A supplementation (Biyong et al., 2021).
In the nervous system, vitamins B1, B6, and B12 have diverse neurospecific activities. Due to their
various biochemical effects as coenzymes, all of these are essential for the preservation of normal neurological processes (Calderon-Ospina et al., 2020).
It has been demonstrated that atrophy of brain regions related to cognitive functions (such as hippocampus, parahippocampal gyrus, inferior parietal lobule and cerebellum) can be slowed down after
high-dose vitamin B administration (vitamin B6 20 mg, vitamin B12 0.5 mg, folic acid 0.8 mg) to
elderly individuals (Douaud et al., 2013). Vitamin B6 is a water-soluble cofactor that participates in
many functions. Individuals suffering from mild cognitive impairment have high homocysteine levels,
and it has been shown that it can reduce dementia rates by bringing homocysteine levels back to normal
levels (Cheng et al., 2016).
Insufficient vitamin B12 and folate levels are associated with brain atrophy, cognitive decline, and
dementia. As a result of a 5-year study, it has been found that individuals with low plasma vitamin B12
levels had greater brain volume loss (Vogiatzoglou et al., 2008). Supplementing with vitamin B12 may
have a neuroprotective effect in people who have low amounts of the vitamin. Low levels of vitamin B12
in the elderly should be studied in clinical trials as a modifiable cause of brain shrinkage and cognitive
impairment.
Vitamin C, commonly known as ascorbic acid, is a water-soluble vitamin found mostly in fresh vegetables and fruits. It plays an active role in metal ion metabolism, tyrosine degradation and conversion
of cholesterol, carnitine, steroid hormones and neurotransmitters into bile acids (Lh & Ahluwalia, 1997;
Rumsey & Levine, 1998). Vitamin C is a micronutrient for the central nervous system. It also plays a
role in neurotransmitter synthesis and cognitive function (May, 2012).
Vitamin D is expressed in both the embryo and the adult brain. With its neuroprotective properties,
it has a very important role in the connection of neuronal circuits, both via direct and indirect routes. It
has been proposed that it is important for neuron growth, survival, and proliferation, and hence could be
used to treat a variety of neurodegenerative diseases (AlJohri et al., 2019). Low serum levels of vitamin
D have been associated with sleep disorders, multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s
disease, autism spectrum disorders, cognitive decline in patients affected by schizophrenia and elderly
individuals (Bivona et al., 2019). Taking vitamin D daily may contribute to the preservation of cognitive
abilities by preventing neurodegeneration.
Vitamin E can be found in corn, soybean, safflower, and cottonseed oil, as well as green leafy vegetables and wheat germ. One of its tasks is to act as an antioxidant and scavenger of free radicals (Uneri
et al., 2006). Dose adjustment, on the other hand, is critical. Vitamin E at high amounts (above 3000
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Dietary Components Consisting of Bioactive Molecules in the Prevention of Neurodegenerative Diseases
IU/day) is hazardous and has been linked to a variety of symptoms including gastrointestinal cramps,
exhaustion, and diarrhea (Farina et al., 2017).
Oxygen free radicals are very reactive because they contain oxygen atoms with unpaired electrons. They
can harm proteins, DNA, and cell membranes unless they are immediately ‘quenched’ by antioxidants.
They are waste products of the body’s metabolism and can also be caused by radiation exposure. Unless
they are quickly ‘quenched’ by antioxidants, they can damage the cell membrane, DNA and proteins.
They are the by-products of the body’s metabolism and can also be produced by exposure to radiation.
CONCLUSION
Neurodegenerative risk factors are directly affected by changes in eating habits, lifestyle, physiological,
and environmental factors. Fruits and vegetables have long been renowned for their health advantages. In
addition, studies on the bioactive components of fruits and vegetables, as well as their physiological and
metabolic objectives, have become more popular. The importance of studies on these areas has increased
since it was recognized that bioactive components can be employed in the prevention and treatment of
certain diseases. Changing the lifestyle in a positive way and consuming better and healthier foods that
contain bioactive molecules on a regular basis can help protect our neurons and avoid the development
of neurodegenerative diseases.
We believe that more detailed and comprehensive research is required to enlighten the effects of
bioactive components in foods and to find the proper levels for the treatment of all diseases. If we want
to help people in social and financial context, we should start taking preventive steps as soon as possible
before the disease develops. To conclude, the government and social media should urge people consume
bioactive food components in their regular diet.
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