Molecules 26 05327 With Cover

4.6 6.
Review
Therapeutic Potential of Natural

Products in Treating
Neurodegenerative Disorders and
Their Future Prospects and
Challenges
Md. Habibur Rahman, Johny Bajgai, Ailyn Fadriquela, Subham Sharma, Thuy Thi Trinh,
Rokeya Akter, Yun Ju Jeong, Seong Hoon Goh , Cheol-Su Kim and Kyu-Jae Lee
Special Issue
Plant Derived Natural Products and Age-Related Diseases
Edited by
Prof. Dr. Manuela Bartolini and Prof. Dr. Luiz Antonio Soares Romeiro
https://doi.org/10.3390/molecules26175327
molecules
Review
Therapeutic Potential of Natural Products in Treating
Neurodegenerative Disorders and Their Future Prospects
and Challenges
Md. Habibur Rahman 1,2,† , Johny Bajgai 1,† , Ailyn Fadriquela 3 , Subham Sharma 1,2 , Thuy Thi Trinh 1,2 ,
Rokeya Akter 2 , Yun Ju Jeong 1 , Seong Hoon Goh 1 , Cheol-Su Kim 1 and Kyu-Jae Lee 1, *
1 Department of Environmental Medical Biology, Wonju College of Medicine, Yonsei University,

Wonju 26426, Gangwon-do, Korea; pharmacisthabib@yonsei.ac.kr (M.H.R.); johnybajgai@yonsei.ac.kr (J.B.);
subhamsharma047@gmail.com (S.S.); tththuy@hpmu.edu.vn (T.T.T.); joj2337@naver.com (Y.J.J.);
forget419@hanmail.net (S.H.G.); cs-kim@yonsei.ac.kr (C.-S.K.)
2 Department of Global Medical Science, Yonsei University Graduate School,
Wonju 26426, Gangwon-do, Korea; rokeyahabib94@gmail.com
3 Department of Laboratory Medicine, Yonsei University Wonju College of Medicine, Yonsei University,
Wonju 26426, Gangwon-do, Korea; ailynfadriquela@gmail.com
* Correspondence: medbio9@gmail.com; Tel: +82-33-741-0331
† These authors contributed equally to the work.
Abstract: Natural products derived from plants, as well as their bioactive compounds, have been

extensively studied in recent years for their therapeutic potential in a variety of neurodegenerative
Citation: Rahman, M.H.; Bajgai, J.; diseases (NDs), including Alzheimer’s (AD), Huntington’s (HD), and Parkinson’s (PD) disease. These
Fadriquela, A.; Sharma, S.; Trinh, T.T.;
diseases are characterized by progressive dysfunction and loss of neuronal structure and function.
Akter, R.; Jeong, Y.J.; Goh, S.H.; Kim,
There has been little progress in designing efficient treatments, despite impressive breakthroughs
C.-S.; Lee, K.-J. Therapeutic Potential
in our understanding of NDs. In the prevention and therapy of NDs, the use of natural products
of Natural Products in Treating
may provide great potential opportunities; however, many clinical issues have emerged regarding
Neurodegenerative Disorders and
Their Future Prospects and
their use, primarily based on the lack of scientific support or proof of their effectiveness and patient
Challenges. Molecules 2021, 26, 5327. safety. Since neurodegeneration is associated with a myriad of pathological processes, targeting
https://doi.org/10.3390/ multi-mechanisms of action and neuroprotection approaches that include preventing cell death and
molecules26175327 restoring the function of damaged neurons should be employed. In the treatment of NDs, including
AD and PD, natural products have emerged as potential neuroprotective agents. This current review
Academic Editors: Manuela Bartolini will highlight the therapeutic potential of numerous natural products and their bioactive compounds
and Luiz Antonio Soares Romeiro thatexert neuroprotective effects on the pathologies of NDs.
Received: 29 July 2021

Keywords: neurodegenerative diseases; natural products; alzheimer’s disease; parkinson’s disease;
Accepted: 27 August 2021
therapeutic potential; oxidative stress; neuroinflammation
Published: 2 September 2021
Publisher’s Note: MDPI stays neutral

with regard to jurisdictional claims in
1. Introduction
published maps and institutional affil-
iations. A variety of chronic progressive central nervous system disorders triggered by de-
terioration and eventual loss of neurons are implicated in neurodegenerative diseases
(NDs) [1]. Recently, aging of the population has contributed to the increase in NDs [1–3],
and age-related diseases including NDs are becoming extremely important due to their ir-
reversibility, lack of effective treatment, and accompanied social and economic burdens [4].
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
Parkinson’s disease (PD), well-characterized by loss of dopaminergic nigrostriatal neurons;
This article is an open access article
Huntington’s disease (HD), which causes loss of spiny, medium-sized striatal neurons; and
distributed under the terms and
Alzheimer’s disease (AD) induced by diffuse brain atrophy, are generally known as NDs.
conditions of the Creative Commons Some disorders were often referred to as NDs, including primary dystonia or tremor [5,6].
Attribution (CC BY) license (https:// Patients with NDs manifest with a wide variety of symptoms that often overlap and range
creativecommons.org/licenses/by/ from memory and cognitive impairment to impairment of the person’s ability to walk,
4.0/). communicate, and breathe; these patients often have certain clinical characteristics, such
Molecules 2021, 26, 5327. https://doi.org/10.3390/molecules26175327 https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 5327 2 of 20
as gradual progression over the years, even reaching decades [4]. Furthermore, oxidative
stress, neuroinflammation, dysfunction in mitochondria, dysfunctional protein misfolding
and agglomeration, and other biological processes have been linked to neurodegenera-
tion [4,7,8]. These biological pathways have been implicated in the development of NDs
and their pathogenesis. To date, extensive research has attempted to explain the process
and potential therapeutic goals in the battle against NDs [9]. Neuroprotection strategies and
relative mechanisms, therefore, function best by interaction with the pathophysiological
transition process to interrupt or postpone the neurodegeneration process [4,10,11]. Natu-
ral products are known and have been used for their medicinal properties since ancient
times. Natural products and their bioactive compounds have been extensively researched
and analyzed in recent years, with a focus on biological processes, nutritional principles,
potential health, and therapeutic benefits. In recent decades, numerous studies have con-
firmed the protective effects of natural products and their bioactive compounds against
a variety of diseases, including cardiovascular diseases, diabetes, reproductive diseases,
cancers, and NDs [12–14]. Natural products for the treatment of NDs have emerged as
potential neuroprotective agents. This current review highlights the therapeutic potential
of numerous natural products and their bioactive compounds that exert neuroprotective
effects on the pathologies of NDs.
2. Potential Therapeutic Targets of Natural Products against

Neurodegenerative Diseases
The mechanism of neuronal damage and death has been investigated for several years,
from the organ level to the molecular level. Neurotransmitter accumulation in the brain
tissue, particularly glutamate, often leads to excessive brain injury, which can overstimu-
late nerves and cause neuronal death [15]. According to the World Health Organization
figures from 2012, more than 35.6 million people suffer from dementia worldwide, with AD
accounting for 60–70% of this population [16]. So far, the pathogenesis of AD has not been
fully elucidated. The late onset of sporadic AD, the most prevalent type of the disease, is
responsible for genetic vulnerability and environmental factors [17]. To summarize, natural
products have recently received increasing interest as alternative or integrative treatment
agents against AD and other NDs [18,19]. PD’s neuropathological characteristic consists
mainly of the accumulation of intracellular protein aggregates, Lewy bodies, and Lewy
neuritis, consisting mainly of the mistreated and aggregated forms of alpha-synuclein pro-
tein and the gradual loss of nigrostriatal neurons [20,21]. Mutations in the gene coding for
the copper/zinc superoxide dismutase-1 (SOD1) enzyme are linked to amyotrophic lateral
sclerosis [22,23]. In addition, HD is a hereditary autosomal dominant neurodegenerative
condition marked by adult-onset motor dysfunctions, mental disorders, and cognitive
loss [24–26]. Moreover, HD is associated with an unstable cytosine–adenine–guanine (CAG)
expansion in the huntingtin gene on chromosome 4 [27]. Different biological processes,
including oxidative stress and neuroinflammatory and mitochondrial dysfunctions, have
been involved in the development and pathogenesis of NDs (Figure 1) [28,29]. Oxidative
stress has been emphasized in the progression of AD, PD, and other NDs. In addition,
oxidative stress leading to free radical attack on neural cells plays a role in calamitous neu-
rodegeneration [1,30]. However, oxidative stress is caused by an imbalance in the formation
of reactive oxygen species (ROS) and a lack of antioxidant defense capacity, resulting in
cellular damage, DNA repair system impairment, and mitochondrial dysfunction [10,31].
Oxidative stress also aggravates amyloid-beta (Aβ) generation and aggregation and pro-
motes tau protein phosphorylation that can cause a vicious pathogenic cycle for AD [32,33].
Neuroinflammatory pathways include both the innate and the adaptive immune systems
of the central nervous system in connection with neurodegeneration. Furthermore, the
pathophysiology of NDs can also include neuroinflammation [34,35]. The main component
of the innate immune response is the microglia in the central nervous system. Microglia
cause morphological changes in response to pathological changes in the nervous system,
and activated microglia secrete a variety of inflammatory mediators including cytokines,
chemokines, and cytotoxic molecules. These inflammatory mediators allow astrocytes to
Molecules 2021, 26, 5327 3 of 20
respond to the reparation and survival of the secondary inflammatory or growth factor
repair response [36–38]. Mitochondria are the place of oxidative phosphorylation that
help to maintain low cytosol Ca2+ concentration [39]. Excessive Ca2+ absorption and ROS
development lead to a decline inmitochondrial membrane functionand the opening of mi-
tochondrial pores [40]. Several environmental toxins are identified as complex I inhibitors
and cause ND-related characteristics [41,42]. The direct association between mitochondrial
dysfunction and PD [43,44] was deduced from a discovery of complex I deficiency in
the substantia nigra of patients who had died with PD [43,44], followed by evidence of
mitochondrial defects in skeletal muscles, platelets, and lymphoblasts in a proportion
of cases [45]. The mitochondrial deficiency within the brain appeared to be confined to
the substantia nigra. These mitochondrial functional changes occur early prior to the
death of the neuron. In the caspase-independent process, the apoptotic factor is converted
into the nucleus and results in fragmented DNA or chromatin condensation [46,47]. As
neurodegeneration is associated with multifactorial pathological mechanisms, multiple
action mechanisms are a promising strategy in ND prevention and therapy.
Figure 1. Different biological processes, including oxidative stress and neuroinflammatory and mitochondrial dysfunctions,
have been involved in the development and pathogenesis of NDs.
3. Neuroprotective Activities of Numerous Natural Products

A number of natural products have been suggested by Srivastava et al. as traditional
pharmacological agents for the treatment of NDs [48]. The use of natural products for the
treatment of NDs is widely reported in the literature, as they show different neuroprotective
activities. Figure 2 summarizes a wide range of possible therapeutic effects of various
natural products for combating NDs.
Molecules 2021, 26, 5327 4 of 20
Figure 2. Therapeutic effects of numerous natural products for combating NDs.
3.1. Luteolin
Luteolin (Lu) is a crystalline yellow flavonoid, common in the plant families Bryophyta,
Pteridophyta, Pinophyta, and Magnoliophyta. The food sources of Lu are carrot, onion,
celery, olive oil, peppermint, thyme, and oregano [49]. Some Lu molecules have a range
of pharmacological properties, including antioxidant, anti-inflammatory, anti-microbial,
anti-cancer, and neuroprotective properties [50,51]. These various pharmacological and an-
tioxidant effects are combined with its ability to scavenge oxygen and nitrogen species [52].
A study showed that Lu (20–100 µM) effectively attenuated zinc-induced tau hyperphos-
μ
phorylation not only through its antioxidant activity, but also through the regulatory
mechanisms of the tau phosphatase/kinase system [48]. The decrease in intracellular
ROS production increased SOD activity, and the restoration of mitochondrial membrane
permeabilization has inhibited caspase-based apoptosis [53]. In addition, the amyloid
precursor protein (APP) expression was down-regulated and decreased the secretion of
Aβ [54]. In addition, Lu enhanced the nuclear factor erythroid 2-related factor 2 (Nrf2)
routeβ and induced the activation of the neuronal cell extracellular signal-regulated ki-
nase (ERK1/2) [55,56]. One of the study reported the concentration of Lu (10–20 µM)
increased the neuronal survival, which acts with greater efficacy and equalμpotency than
vitamin E [49].
3.2. Quercetin
Quercetin (QCT) is known as a flavonoid in a wide range of food products, such
as capers, apples, tomatoes, pasta, green tea, and black and red wines [48]. QCT is a
potent herbal antioxidant and is one of the most common flavonoids in edible plants [57].
One study reported the therapeutic efficacy of QCT in improving learning, memory, and
cognitive functions in AD [58]. Pharmacologically, QCT has anti-cancer, anti-viral, anti-
inflammatory, and anti-amyloid effects [48]. QCT has been described to induce the gradual
removal of end products associated with plasma with a recorded half-life of 11–28 h,
enabling the body to generate QCT daily [59]. The risk of neurotoxicity can increase through
a rise in the number of QCT aglycons entering the central nervous system parenchyma in
Molecules 2021, 26, 5327 5 of 20
liposome preparations or by allowing higher blood–brain barrier (BBB) permeability [60].

QCT has been reported to act as a memory booster in a Zebrafish model with scopolamine-
induced impairment of memory, potentially improving cholinergic neurotransmission [57].
Further toxicological studies are, therefore, necessary to investigate the risk/beneficial
effects of natural products such as QCT [61]. Aβ-mediated apoptosis in hippocampal
cultures was significantly reduced at lower doses of QCT (5–20 µM); however, cytotoxicity
was induced at high doses (40 µM) [62]. QCT (10 µM) demonstrated anti-amyloidine effects
by inhibiting the formation of Aβ fibril [57]. The ability of QCT to cross the BBB and the
quantities of QCT and its metabolites in the brain tissue are crucial considerations for its
possible in vivo application. QCT reaches the brain, according to in vitro experiments using
BBB models [63,64]. Furthermore, QCT and alpha-tocopherol coadministration has been
found to promote QCT transport across the BBB [65]. Dihydroquercetin, also known as
taxifolin, is a flavonoid commonly found in onions [66]. Treatment with taxifolin prevented
spatial memory defects caused by oligomeric Aβ in the wild-type mice hippocampus [67].
In taxifolin-treated cerebral amyloid angiopathy mice, higher blood Aβ levels have been
detected, suggesting that Aβ clearance from the brain to bloodwas made easier [68].
3.3. Resveratrol
Resveratrol (RSV) belongs toa class of polyphenolic stilbene compounds [69]. RSV is
one of the most important red wine flavonoids in grapes, nuts, and other fruits [70]. About
12.5% of participants experienced headaches in the short dose study of RSV, but showed no
serious adverse effects [71]. Many studies have reported cardiovascular, anti-cancer, anti-
viral, blood-glucose-decreasing, and side effects of RSV [72–74]. RSV (10 and 20 mg/kg)
primarily works by scavenging ROS as a strong antioxidant by enhancing glutathione
(GSH) [75]. The loaded lipid core RSV nanocapsules are elevated compared with free RSV
in brain tissue [76]. The gastrointestinal lumen absorbs RSV well, but due to its rapid
metabolism and removal, it has poor bioaccessibility [77]. In different forms, the binding
of RSV (50 µM) to Aβ was greater, but it was more strongly attached to monomeric Aβ
1–40 than to its fibrillary form [78]. By induction of non-amyloidogenic APP cleavage,
RSV reduced Aβ and increased the clearance of Aβ [79]. RSV (100 and 200 µM) can also
inhibit C-reactive protein and ERK1/2 mitogen-activated protein kinase (MAPK)[80]. RSV
(2.5–40 mg/mL) inhibited the inflammatory response to lipopolysaccharide by reducing
inflammatory factors, such as nitric oxide, tumor necrosis factor-α (TNF-α), interleukin
(IL)-1β, and IL-6 of astrocytes [81]. Nuclear factor-kappa B (NF-κB) elimination led to
a decreased downstream TNF-α and IL-6 levels [82]. A meta-analysis showed that RSV
significantly decreased Profile of Mood States (POMS) including vigor and fatigue but
had no significant effect on memory and cognitive performance [83]. However, other
studies have shown that the BBB plays an important role in Aβ clearance and that its
breakdown can result in ineffective clearance [84]. RSV increased claudin-5 expression and
decreased the receptor for advanced glycation end products in vivo [85], protecting the
BBB integrity [86].
3.4. Apigenin
Apigenin (AP) belongs to a subgroup of flavonoids, flavones, based on a skeleton of
2-phenylchromen-4-one (2-phenyl-1-benzopyran-4-one) [87]. To date, very little evidence
suggests that AP in a normal diet promotes in vivo adverse metabolic reactions. AP has anti-
inflammatory, antioxidant, and anti-cancer characteristics [88]. It is also a strong inhibitor of
the enzyme metabolizing several prescription drugs in the body, cytochrome P450 [89]. AP
is a highly soluble and intestinally permeable flavonoid. Different transport processes in
the intestine can well absorb AP; however, the duodenum is the main absorption site [90].
It also functions as a cell growth, anti-carcinogenic, and enzyme inhibitor, as well as
antigenotoxic, anti-inflammatory, and free radical scavenging [91]. In addition, in a double
transgenic mouse model of AD (APP/PS1), a review of the neuroprotective potential of AP
Molecules 2021, 26, 5327 6 of 20
suggested that apigenin could enhance AD-associated memory impairment, decrease the
load of Aβ plaque, and inhibit oxidative stress [92].
3.5. Genistein
Genistein is one of the most commonly known isoflavone found in numerous soy
products and has been investigated for its antioxidant, anti-inflammatory, and proapop-
totic properties; estrogen receptor affinity; protein tyrosine kinase (PTK) inhibition; and
other cellular and physiological functions [93]. Current evidence strongly indicates that
soy isoflavones protect against a variety of chronic conditions including atherosclerosis,
postmenopausal estrogen deficiency, and hormonally based breast or prostate cancer [94].
Recently, some researchers have found the neuroprotective activity of genistein. A study
reported that genistein (100 µM) was found to be effective against toxicity induced by the
Aβ31-35 peptide in primary neuronal cells obtained from newborn Wistar rats [95]. It has
been confirmed that genistein, a phytoestrogen able to cross the BBB, has antioxidants
from ultraviolet light and chemical insults. Another research reported that in cultured
hippocampal neurons, genistein has a neuroprotective effect against Aβ25-35-induced
apoptosis [96]. Exposure to aged Aβ25-35 for 24 h has been shown to double the DCF
fluorescence strength compared with controls for 24 h [97]. Emerging evidence indicates
that estrogen and estrogen-like chemicals have beneficial effects on ND, especially PD.
Interestingly, genistein exhibited a preventive effect on neuronal degeneration caused by
increased oxidative stress [98]. In addition, genistein can cross the BBB [99], and it has
proven to be safe for a long time (over 1 year) in the clinical trial at concentrations up to
150 mg/kg/day.
3.6. Hesperidin
Flavanone-glycosides rich in citrus fruit, lemon, sweet orange, and grapes are also
called hesperidin (C28 H34 O15 ) [100]. Hesperidin administration for 16 wks helped boost
learning and memory function by increasing the recognition index in the transgenic mouse
model of APPswe/PS1dEE [101]. It corrects mitochondrial disorders caused by Aβ by
lowering levels of malondialdehyde and hydrogen peroxide and restoring GSH deple-
tion and total antioxidant ability (T-AOC). A protein kinase that has a prominent role
in mitochondria and AD functions is glycogen synthase kinase-3β (GSK-3β). It has an
important impact on the protein tau hyperphosphorylation and the mitochondrial tar-
get [102]. Increasing oxidative damage triggers the activation of this protein kinase. By
inhibiting the restoration of this kinase, hesperidin theoretically rescued cognitive deficits
and showed mitochondrial neuroprotective effects. It was the potential mechanism by
which hesperidin lowered the Aβ1-40 level [100]. Hesperidin also inhibited learning and
memory impairments resulting from aluminum chloride (AlCl3 )-induced AD, functioning
as an acetylcholinesterase inhibitor. In the rat hippocampus and brain cortex, hesperidin
attenuated APP expression through the NF-κB-dependent pathway and suppressed Aβ1-
40 and β-and γ-secretase levels [49,103]. The neuroprotective role of hesperidin was
reported in the signals of up-regulating B-cell lymphoma 2 (Bcl2) and down-regulating
Bcl-2-associated X protein (Bax) [104–106]. In addition, hesperidin has been reported to
have neuroprotective effects in many neurological disorders, such as cerebral ischemia,
HD, and PD, at 50 and 100 mg/kg oral doses [107]. The hesperidin of citrus flavonoid has
neuroprotective effects andmay pass through the BBB. Hesperidin inhibits the release of
glutamate and exercises an excitotoxic neuroprotection in rat hippocampus with kainic
acid [108].
3.7. Uncaria Rhynchophylla

The herb Uncaria rhynchophylla, part of the Rubiaceae family, is used in traditional
Chinese medicine. Uncaria rhynchophylla extract is made up of alkaloids, rhinchophylline,
hirsutine, hirsuteine, corynanthine, corynoxine, and dihydrocorynantheine [109,110]. The
most widely studied and named neuroprotective compositions among the alkaloids are
Molecules 2021, 26, 5327 7 of 20
rhinchophylline and isorhynchophylline [111,112]. In addition, the neuroprotection effect

of Uncaria rhynchophylla has been reported in an experimental PD model [113]. Shim et al.
documented that Uncaria rhynchophylla reduced neuronal cell death and ROS production,
restored GSH levels in PC12 cells in case of toxicity of caspase-3 and 6-hydroxydopamine
(6-OHDA) cells, and reduced the neuronal loss in the substantia nigra dopaminergic rats
induced by 6-OHDA [113,114]. In the 1-methyl-4-phenylpyridinium (MPP+ ) induced
SH-SY5Y and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse cell models,
Uncaria rhynchophylla has been found to improve cell viability, attenuate dopaminergic
neuronal significant nigra and striatum lowering, and inhibit heat-shock protein 90 and
autophagy [115]. All these results, taken together, indicate that Uncaria rhynchophylla
demonstrates neuroprotective activity through multiple mechanisms of neuronal defense
against damage, which may be attributable to the beneficial combined action of the ac-
tive compounds in Uncaria rhynchophylla. These antioxidant compounds inhibit the anti-
inflammatory effect by inflammatory mediation and the anti-apoptotic effect, modulating
the event and preventing the activation of the caspase and decreasing ROS generation
and improving the antioxidant protective mechanism. Rhynchophylline is an alkaloid
found in certain Uncaria species (Rubiaceae). However, recent studies revealed that isorhyn-
chophylline can easily pass the BBB. These observations suggested that isorhynchophylline
may be an anti-inflammatory substance used to treat NDs [116,117].
3.8. Marine Macroalgae

Marine macroalgae are plant-like organisms, typically referred to as seaweed, that
commonly live in coastal areas. The three groups can be categorized as brown (Phaeo-
phyceae), red (Rhodophyceae), and green algae (Chlorophyceae) [118]. Phenolic com-
pounds, proteins, peptides, pigments, amino acids, and phenols are also found in a variety
of bioactive materials [119]. Numerous studies find that algae and bioactive compounds of
various algae have a health impact [118,120,121]. In addition, Pangestuti et al. showed that
carotenoids have a high radical scavenging function and are present in marine algae as a
major antioxidant [122]. Furthermore, another study found that marine extracts increase
cell viability, decrease oxidative stress, have a healthy mitochondrial membrane potential,
and decrease caspase-3 activities. This indicates the neuroprotective effects and the antioxi-
dant properties of these algae [123]. Silva et al. suggested the possibility of mediating this
neuroprotective action with antioxidant compounds in algae extracts [123]. However, the
researchers’ concern about the potential use for pharmaceuticals, particularly when new
drug delivery systems are being developed, recently attracted their attention to marine sul-
fated polysaccharides [124,125]. The biological activities of sulfated polysaccharides have
been identified in various studies [126,127]. In the meantime, Undaria pinnatifida fucoidan
improved cell viability, prevented apoptosis via inhibition of activation of caspase-3, and
enhanced dense antioxidant systems in Aβ (25–35), SOD activity, and GSH materials in
PC12 cells with neurotoxicity [128]. The fucoidans have a reduced aggregation of Aβ (1–42),
decreased cytotoxicity (1–42), and PC12 hydrogen peroxide caused by Aβ, decreased Aβ-
induced apoptosis (1–42), and improved the role of neuritis outgrowth [129,130]. Moreover,
the possibility of developing marine algae components as neuroprotective agents has not
been investigated because of the BBB.
3.9. Cyanobacteria
Cyanobacteria are prokaryotic, photosynthetic, self-producing species that are closely
related to bacteria and are commonly referred to as blue-green algae. They are members of
the Oscillatoriaceae family. Researchers have been very attentive to their potential phar-
macological properties and advantages for various medical conditions [120,131]. Spirulina
platensis is a multicellular planktonic, alkaliphilic cyanobacterium. It has been widely
studied and recognized for its proper nutritional components. Subsequently, it may protect
itself against dopaminergic neuronal loss triggered by MPTP in substantia nigra. Spirulina
platensis has anti-inflammatory and antioxidant properties that help it defend against PD
Molecules 2021, 26, 5327 8 of 20
caused by 6-OHDA [132,133]. However, evidence suggests that polysaccharides derived

from Spirulina platensis have an antioxidant effect on dopaminergic neurons and dopamine
levels, rather than inhibition of monoamine oxidase B [134]. These findings showed
that Spirulina maxima extract improved cognitive impairment by inhibiting Aβ accumu-
lation [135]. In addition, the neuroprotective role of Spirulina maxima (Sp.) against MPTP
neurotoxicity, used as a model of PD [122]. Other studies have shown that Spirulina maxima
extract has protected against memory damage caused by scopolamine in mice [136,137].
These results show that, via antioxidant activity, Spirulina maxima exert its neuroprotective
impact [136]. In addition, oral administration of c-phycocyanin, a component of Spirulina,
has an effect in the hippocampus, because it crosses the BBB [138]. These studies have
shown collectively that cytoprotective activity against neurodegeneration is demonstrated
by different mechanisms of action, primarily by antioxidants.
4. Role of Other Natural Products in Neurodegenerative Diseases

NDs exhibit some common characteristics despite specific clinical and etiopathogenic
differences, such as irregular protein deposition, abnormal cellular transports, mitochon-
drial deficits, inflammation, intracellular Ca2+ overload, unregulated ROS generation, and
excitotoxicity [4,139]. In the pathogenesis of all essential NDs, reactive astroglia and/or
microglia are also involved [140,141]. Several natural substances have been suggested for
treating NDs to complete and/or help conventional pharmacological agents [4]. Their
use on NDs is commonly identified as a consequence of several different neuroprotective
activities reported in the literature [142–144]. The main objectives include mitochondrial
dysfunction, inflammation, oxidative stress, and protein malfunction among the natural
products [145–147]. Some animal products, such as omega-3 fatty acids, inhibit cell toxicity
and have anti-inflammatory effects in the treatment of AD [148]. Plant-based products,
such as lunasin, polyphenols, alkaloids, and tannins, are possible therapeutic candidates
for AD [149]. Resveratrol and flavonoids appear to be dietary additives that have obvious
neuroprotective and other beneficial effects on human cognitive disability [69,150]. Al-
though natural products can be extracted from different biological sources, it is not trivial
to turn them into therapies. The challenges can include concerns about their stability and
neuro-availability, difficulties in properly defining and quantifying the active principle,
and, lastly, difficulties in organizing large-scale clinical trials to evaluate these complex
products [151]. The capacity to defend against neurodegeneration has been evaluated in
several differentnatural products. Tables 1 and 2 provide a description of natural products
and their bioactive compounds with various neuroprotective functions, depending on the
disease being treated. Natural products and their bioactive substances with neuroprotec-
tive function in the treatment of AD are represented in Table 1. Similarly, PD treatment
currently includes medicines such as Levodopa, primarily catalytically converted into
dopamine by dopa decarboxylase in the brain, resulting in its therapeutic effects [152,153].
There is evidence that correlates neuronal mitochondrial dysfunction with the pathogenesis
of PD [154,155]. However, this dysfunction is associated with the abnormal accumulation
of α-synuclein, which causes an alteration of normal mitochondrial function, leading to
neuronal degeneration and strong oxidative stress [156,157]. In addition, the presence
of neuroinflammation is another peculiar characteristic of PD, which plays a significant
role in the development of the disease. However, the inflammation depends also on the
impaired energy metabolism at the level of the mitochondria impairment that causes the
activation of the microglia and the relative generation of a plethora of pro-inflammatory
mediators, including prostaglandins, cytokines, chemokines, complement, proteinases,
ROS, and RNS [158]. Moreover, most patients with PD also have non-motor symptoms,
including disorders of the sleep–wake cycle regulation, cognitive impairment disorders of
mood and affect, autonomic dysfunction, as well as sensory impairmentand pain. Recently,
the management of age-related diseases, such as PD, has been associated with consumption
of functional food or food supplements. Certainly, a healthy diet rich in foods containing
antioxidants, vitamins, and minerals or the use of food supplements can help to reduce the
Molecules 2021, 26, 5327 9 of 20
symptoms of PD and the related pathological mechanisms [158]. Mucunapruriens belongs

to the family Leguminosae and is a twiner with trifoliate leaves, purple flowers, and pods
covered with hairs. Seeds from Mucuna pruriens (Atmagupta) have been described as
a useful therapeutic agent in different diseases of the human nervous and reproductive
system, including PD in the ancient Indian medical system, Ayurveda [158]. Mucuna
pruriens exhibited twice the anti-parkinsonian activity compared with synthetic levodopa,
suggesting that Mucuna pruriens may contain unidentified antiparkinsonian compounds
in addition to levodopa, or that it may have adjuvants that enhance the efficacy of lev-
odopa [159]. Another therapy involves anticholinergic drugs that can block the excitability
of cholinergic nerves by striatal cholinergic receptors; it has also been shown that they
can suppress dopamine reuptake to increase the activity of dopaminergic neurons [160].
Natural products and their bioactive substances with neuroprotective function in the treat-
ment of PD are shown in Table 2. The therapeutic potential of medicinal plants has been
studied and evaluated in scientific circles. Numerous medicinal plants extract used in the
clinical trial and their outcomes are shown in Table 3. In conclusion, as complementary
or integrative therapeutic agents against AD, PD, and other NDs, natural products have
recently gained greater attention [161].
Table 1. Representative natural products and their bioactive substances with neuroprotective activity in the treatment of
AD related disease model.
Name of Plant Part Name of Model Neuroprotective Mechanisms References

Yacon (Poepp. and endl.) (Smallanthus
Rat Memory deficits prevented [162]
sonchifolius) extract of the leaf
Short and long-term memory
Natural safflower aqueous extract Rat [163]
improved
Methanolic extract of Lactucacapensis thunb. Lowering the degree of lipid
Rat [164]
leaves peroxidation and protein oxidation
Improvement in the quality of life
Turmeric powder Human [165]
and behavioral symptoms
Tabernaemontana divaricata root extract Mouse Prevented memory loss [166]
Coconut oil enriched Mediterranean diet Human Enhanced cognitive features [167]
Osmotin, a protein derived from Nicotiana Increased conduct of random
Mouse [168]
tabacum alternation
Reduced production of intracellular
Germinated brown rice SH-SY5Y cells [169]
ROS
Improvement in functions of memory,
Isolated from Huperzia serrata is Huperzine A Human [170]
cognition, and actions
Huperzine A isolated from Huperzia serrata Rat Reduce oxidative damage [171]
Table 2. Representative natural products and their bioactive substances with neuroprotective activity in the treatment of PD
related disease model.

Smith ethyl acetate extract Zingiber zerumbet
Rat Prevention of neuronal damage [172]
(L.)
Enhanced motor control and alteration in
Urticadioica Linn. ethyl acetate fraction. Rat [173]
oxidative protection
Apium graveolens L. Mouse Improved behavioral disorder caused by MPTP [174]
Tribulus terrestris extract Mouse Improved the proportion of viable neurons [175]
Restored locomotive operation behavioral
Ethanol extract of Tinospora cordifolia Rat [176]
changes caused by 6-OHDA
Dihydromyricetin (DHM) (Ampelopsis Mitigated the deficit in the balance of movement
Mouse [177]
grossedentata) caused by the MPTP
Molecules 2021, 26, 5327 10 of 20
Table 2. Cont.

Agaropentaose, an agaro-oligosaccharide
Inhibited potential loss of mitochondrial
monomer that is isolated from red algae SH-SY5Y cells [178]
membrane
hydrolysates of agarose
Restored development of cholinesterase in the
Capsicum annuum L. extract Mouse [179]
brain
β-Caryophyllene, a cannabinoid compound
originating from a plant known as Rat Lipid peroxidation inhibited [180]
phytocannabinoids
Viride var. of Coeloglossum. Extract from
Mouse Prevented neuronal dopaminergic loss [181]
bracteatum
Boswellic acids Rat Motor functions improved [182]
Rosmarinic acid isolated from callus of Perilla
Rat Increased tyrosine hydroxylase numbers [183]
frutescens
Inhibited tyrosine hydroxylase-positive neuron
Olive leaf extracts (Olea europaea L.) Rat [184]
depletion
Oxalis corniculata extract Mouse Improved preservation and retrieval of memory [185]
In the striatum, decreased proinflammatory
Curcuminoids (Curcuma longa (L.) rhizomes) Mouse [186]
cytokine and complete nitrite production
Supplementation of fish oil (rich in omega-3 Reduced loss of substantia nigra neurons and
Rat [187]
polyunsaturated fatty acids) nerve terminals in the striatum)
Improved the number of dopaminergic neurons
Germinated brown rice Rat [188]
that survive
Table 3. Numerous medicinal plant extracts used in clinical trials and their outcomes.
Plant Species Type of Clinical Study Clinical Outcomes Reference

Salvia officinalis Randomized, double-blind Significantly improved cognitive function [189]
Randomized, placebo-controlled, Resveratrol was safe and well-tolerated.
Resveratrol double-blind, multicenter 52-wk Resveratrol and its major metabolites penetrated [190]
phase 2 trial the blood–brain barrier to have CNS effects
Longitudinal, 3 monthly Focal electroretinograph↑ amplitude and
Ginkgo biloba L. follow-ups over a 12-month sensitivity amplitude that stabilized after 3 months [191]
period independent of genotype
Longitudinal, open-label study, 8 Focal electroretinograph saffron treated
Crocus sativus L. monthly follow-ups over a 29 age-related macular degeneration patients: Visual [192]
(±5)-month period function remained stable
24 older adults with physical or
Curcumin longa Improve physical function and cognitive function [193]
cognitive impairment
The effect of C. Sativus similar to imipramine in the
Crocus sativus Depressant patients [194]
treatment of mild to moderate depression
Improvement of all asthmatic symptoms, chest
Nigella sativa Asthmaticpatients [195]
wheeze and pulmonary function test values
Randomized, double-blind
Centella asiatica Improved memory function [196]
placebo-controlled trial
Double-blind, placebo-controlled
Bacopa monnieri trial in 38 healthy volunteers Significantly improved cognitive function [197]
(aged 18–60 years)
Prospective, randomized, Significantly improved executive functions in
Withania somnifera [198]
double-blind, placebo-controlled adults with mild cognitive impairment
Molecules 2021, 26, 5327 11 of 20
5. Limitations, Future Prospects, and Challenges

The capacity of neuroprotection and the development of therapeutic products and
tools, including isolated natural compounds, against various NDs have been naturally
developing. Despite the promising neuroprotective activity in pre-clinical settings, the
translation of promising preclinical investigations to clinical use has proven difficult be-
cause human clinical studies of neurodegenerative disorders have no favorable findings.
Natural products and isolated natural compounds face several challenges and weaknesses
that can compromise their therapeutic efficacy, including poor bioavailability and decreased
water solubility, physical and chemical instabilities, rapid metabolism, and BBB crossing.
These reviews of the literature provide more details [199–201]. However, numerous natural
compounds, including resveratrol [202] and curcumin [203,204], have been reported to
have low bioavailability and limited stability due to degradation or transformation into
inactive derivatives [205,206]. As a result, their efficacy is reduced. In addition, the BBB
prevents access of natural compounds to the brain, thus prevents them to reach their
action site. This limits their distribution to the brain tissue and results in low bioavail-
ability [207]. Nanotechnology and nanocarriers can help improve therapeutic responses
and effectiveness in the delivery of natural products and their isolated compounds, which
will help solve these problems [208,209]. Nanoparticles may be used in the delivery sys-
tem to increase the bioavailability of natural products and their compounds. Polymeric
nanoparticles, nanogels, rigid lipid nanoparticles, crystalline nanoparticles, micelles, and
dendrimer complexes are the most commonly used nanoparticles [210,211]. Several studies
have been published on the use of natural nanoparticles with thesecompounds, such as
epigallocatechin 3-gallate for treating AD [212], rosemary acid for HD [213], curcumin for
brain disease [214].
6. Concluding Remarks
Therapeutic potential for natural products and natural bioactive compounds to be
neuroprotective has been supported by various research studies. Natural products and
important bioactive compounds are needed to prevent and treat various NDs without
causing harmful adverse effects. Since several functional pathways are found in neurode-
generative pathologies, ND prevention and treatment approaches have an important role
to play. For natural products and bioactive substances, it is preferable to use various modes
of action to display neuroprotective effects. Furthermore, the ability of natural products
and their bioactive compounds to cross the BBB is essential for neuroprotective activity.
It is important to develop new methods and techniques, such as nanotechnology, for the
delivery of natural compounds and drugs in order to enhance the role of natural products
and bioactive compounds in ND prevention and therapeutic fields, in order to promote
access to the brain of neuroprotective products.
Author Contributions: Conceptualization, K.-J.L., M.H.R. and J.B.; writing—original draft prepara-
tion, M.H.R.; writing—review and editing, J.B. and A.F.; preparation of the tables and figures, R.A.,
S.S., S.H.G. and T.T.T.; visualization, Y.J.J., C.-S.K.; supervision, K.-J.L. All authors have read and
agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data presented in this study are available within the article (tables
and figures).
Acknowledgments: The authors would like to thank Editage (Cactus communication Korea Ltd.)
for language editing.
Conflicts of Interest: The authors declare no conflict of interest.
Molecules 2021, 26, 5327 12 of 20
Abbreviations
6-OHDA 6-hydroxydopamine
AD Alzheimer’s disease
AlCl3 Aluminum chloride
AP Apigenin
APP Amyloid precursor protein
Aβ Amyloid-beta
Bax Bcl-2-associated X proteins
BBB Blood-brain barrier
Bcl2 B-cell lymphoma 2
CAG Cytosine-adenine-guanine
DHM Dihydromyricetin
DNA Deoxyribonucleic acid
ERK Extracellular signal-regulated kinase
GSH Glutathione
GSK-3β Glycogen synthase kinase-3β
HD Huntington’s disease
IL Interleukin
L-DOPA Levodopa
Lu Luteolin
MAPK Mitogen-activated protein kinase
MPP+ 1-methyl-4-phenylpyridinium
MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
NDs Neurodegenerative diseases
NF-κB Nuclear factor-kappa B
Nrf2 Nuclear factor erythroid 2-related factor 2
PD Parkinson’s disease
POMS Profile of Mood States
PTK Protein tyrosine kinase
QCT Quercetin
ROS Reactive oxygen species
RSV Resveratrol
SOD-1 Superoxide dismutase-1
T-AOC Total antioxidant ability
TNF-α Tumor necrosis factor-α
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4.6 6.

Therapeutic Potential of Natural

1 Department of Environmental Medical Biology, Wonju College of Medicine, Yonsei University,

Received: 29 July 2021

Publisher’s Note: MDPI stays neutral

Molecules 2021, 26, 5327. https://doi.org/10.3390/molecules26175327 https://www.mdpi.com/journal/molecules

2. Potential Therapeutic Targets of Natural Products against

3. Neuroprotective Activities of Numerous Natural Products

Figure 2. Therapeutic effects of numerous natural products for combating NDs.

liposome preparations or by allowing higher blood–brain barrier (BBB) permeability [60].

3.7. Uncaria Rhynchophylla

rhinchophylline and isorhynchophylline [111,112]. In addition, the neuroprotection effect

3.8. Marine Macroalgae

caused by 6-OHDA [132,133]. However, evidence suggests that polysaccharides derived

4. Role of Other Natural Products in Neurodegenerative Diseases

symptoms of PD and the related pathological mechanisms [158]. Mucunapruriens belongs

Name of Plant Part Name of Model Neuroprotective Mechanisms References

Name of Plant Part Name of Model Neuroprotective Mechanisms References

Name of Plant Part Name of Model Neuroprotective Mechanisms References

Plant Species Type of Clinical Study Clinical Outcomes Reference

5. Limitations, Future Prospects, and Challenges

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