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Chapter 10
Efcacy of Phytochemicals
and Natural Products in the
Management/Treatment of
Neurodegenerative Diseases
Johnson Olaleye Oladele
Kings University, Nigeria
Oluwaseun Titilope Oladele
Osun State University, Nigeria
Taiwo S. Adewole
ABSTRACT
Neurodegenerative illnesses are disorders that cause considerable loss of neurons, both structurally and
functionally, and affect millions of people globally. These disorders include Parkinson’s disease, which
is characterized by the loss of dopaminergic nigrostriatal neurons; Huntington’s disease, characterized by the loss of spiny, medium-sized striatal neurons; and Alzheimer’s disease (AD), characterized
by cerebral atrophy. As a result of current therapeutic procedures and the progressive nature of these
diseases, a number of side effects have emerged, prompting patients to seek alternative treatment. The
concept of neuroprotection concerns the administration of a specific agent, which should reverse some
of the damage or prevent further adverse changes associated with these disorders. The involvement of
medicinal plants and natural products in such situations has proven advantageous due to their manifestation through many cellular and molecular pathways. This chapter focuses on role of phytochemicals
and natural products on major pathological factors in NDs.
Kings University, Nigeria
Oyedotun M. Oyeleke
Kings University, Nigeria
Adenike T. Oladiji
University of Ilorin, Nigeria
INTRODUCTION
Neurodegenerative diseases (NDs) are devastating diseases which adversely altered motor or cognos-
DOI: 10.4018/978-1-6684-5129-8.ch010
Copyright © 2022, IGI Global. Copying or distributing in print or electronic forms without written permission of IGI Global is prohibited.
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Ecacy of Phytochemicals and Natural Products in the Management/Treatment
cible responsibilities and are swiftly emerging a worldwide disease having about 47 million individuals
globally suffering derangement. These diseases are characterized by gradual dysfunction in nerve cells
and neuronal loss. Parkinson’s disease (PD), Alzheimer’s disease (AD), and Huntington’s disease (HD)
are notable types of neurodegenerative diseases (Matilla-Duenas et al., 2014; Oladele et al., 2021a).
NDs represent significant health risks, particularly in the elderly population (Hamer & Chida, 2009).
For example, Parkinson’s disease is the second most common neurodegenerative disease, negatively
impacting 1 to 2% of the persons over the age of 65, while Alzheimer’s disease is the 6th major cause
of mortality in the United States (Bekris et al., 2010; Alzheimer’s Association, 2016).
Alzheimer’s disease (AD) is the most common cause of dementia (Alzheimer’s Association, 2016),
which is defined by a decline in cognitive function, notably memory, and the inability to carry out daily
tasks (Alzheimer’s Association, 2016). The aggregation of neurofibrillary tau tangles (NFTs) and amyloid
beta (Aβ) plaques in the nerve cells which disturb neuronal functional impulses has been recognized as
key in the aetiology of AD. Tau proteins are regulated and enhanced via phosphorylation by phosphatases and glycogen synthase kinase 3β (GSK-3Β) to carry out its biological functions (Mi & Johnson,
2006). Many disorders of the lysosomal system are implicated to ensue owing to dysregulation in the
degradation of tau protein due to multiple phosphorylations, ultimately resulting in the development of
extracellular NFTs which cause a disturbance on the neural network and degenerate to a pathological
state known as Alzheimer’s disease (Murphy & Lii, 2010).
Parkinson’s disease (PD) is the second most prevalent ND, with two types: sporadic PD (which accounts for more than 90% of cases) and familial PD (which accounts for the remaining 10% of cases),
with over twenty genes linked with this disease (Deng et al., 2017). Autosomal dominant is caused by
aberrations in α-syn or LRRK2 (leucine-rich repeat kinase 2) while mutation in UCHL1 (ubiquitin Cterminal hydrolase 1), Parkin, DJ-1 or PINK1 (PTEN induced putative kinase 1) has been reported to
cause autosomal recessive (Yao et al., 2010; Helferich et al., 2016). Moreover, chromosome 2 and X have
been associated with Parkinson’s vulnerability. The α-Syn is an important protein that plays a critical role
in the molecular pathogenesis of PD in both familial and sporadic forms of the disease (Winslow et al.,
2010). The complicated pathophysiology of neurodegenerative diseases has not been fully understood;
nevertheless, existing data from research and clinical trials demonstrated these diseases are typified by
neuroinflammation, oxidative stress, cell death as well as protein misfolding. As high levels of oxidative stress are commonly documented in the brain areas of individuals suffering from various types of
neurodegenerations, reactive oxygen species (ROS) may play an important role in disease etiology (Dias
et al., 2013; Oladele et al., 2021a).
ROS are chemically reactive molecules that are spontaneously produced within the biological system and play important roles in modulating cellular processes such as stressor responses, cell survival,
and inflammation. Nevertheless, if their levels are not effectively controlled or managed, they can be
harmful to health and contribute to the pathogenesis of a variety of illnesses, including neurological
diseases, cancer, allergies, muscle dysfunction, and cardiovascular problems (Zuo et al., 2013; He &
Zuo, 2015; Oladele et al., 2021c; 2021d). Because of their reactivity, the presence of large concentration
of these reactive species may induce oxidative stress (OS), which is characterized by disruption in the
equilibrium between antioxidant and pro-oxidants in bio-systems, coupled with mitotic catastrophe if
unmanaged (Zuo et al., 2015).
A variety of preclinical experiments have been conducted to determine the role of oxidative stress
in neurodegenerative disorders (St-Pierre et al., 2006; Hensley et al., 2006; Oladele et al., 2020a). ROS
may not be able to cause neurodegenerative diseases on their own, but they can exacerbate disease pro-
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gression by causing damage to key macromolecules and altering mitochondrial functions (Dias et al.,
2013). Remarkably, neurons are prone to oxidative damage due to significant polyunsaturated fatty acid
membrane content, ineffective antioxidant defense, and high oxygen consumption (Rego & Oliveira,
2003). Endogenous antioxidants maintain free radicals and reactive oxygen species generated by NADPH
oxidase (Nox), xanthine oxidase (XO), mitochondria, and at moderately low levels under resting conditions (Zuo et al., 2015). However, aberrations in the mitochondria functions and/or inflammation of the
neurons can modify and disrupt the redox balance (Rego & Oliveira, 2003).
Several indications from cellular, genetic, neuropathological and biochemical investigations have demonstrated that monomeric proteins can misfold, oligomerized, form aggregates and become accumulated
in the brain, which is the major cascade of processes that activate pathological abnormalities associated
with neurodegenerative diseases (Goedert, 2015). The following proteins in neurodegenerative diseases
have reported to involve cerebral misfolded aggregates accumulation: prion proteins in chronic wasting
disease, prion diseases (PrDs) (i.e., Creutzfeldt–Jakob disease (CJD), scrapie, and bovine spongiform
encephalopathy; and TAR DNA-binding protein 43 (TDP-43) in frontotemporal dementia and amyotrophic
lateral sclerosis; dementia with Lewy bodies and multiple system atrophy, alpha-synuclein (α -Syn) in
PD; amyloid-beta (Aβ) in AD; tau in chronic traumatic encephalopathy, frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, and AD. Although the
formation of protein aggregates differs amongst neurodegenerative illnesses, their pathogenic processes
are clearly alike (Soto, 2003). The prophylactic use of natural products and plant derived bioactive agents
in the treatment and management of diseases such as neurodegenerative diseases, cardiovascular diseases,
and cancer have continuously been discovered (Oladele et al., 2017, 2019, 2020a). Plants are sources of
therapeutic chemicals and have played a significant role in human health maintenance over time. Natural
products account for more than half of all current clinical medications, and they play an essential part
novel drug development strategy. The protective potential of phytochemicals in the neuronal system
have been documented (Oladele et al., 2017, 2019, 2020b 2020c). As a result, there is a rising interest in
developing pharmaceutical and nutritional treatments to prevent oxidative stress-induced damage to the
central nervous system, with dietary antioxidants, natural products, and phytochemicals being studied
for their possible neuroprotective properties.
In this context, this chapter present a review on the pathogenesis of selected neurodegenerative diseases focusing oxidative stress, neuroinflammation, apoptosis and protein misfolding and aggregation
as major pathological factors in neurodegenerative diseases. The role of phytochemicals and natural
products on these major pathological indices was also discussed.
PATHOGENESIS OF NEURODEGENERATIVE DISEASES
Inflammation in Pathogenesis of Neurodegenerative Diseases
Inflammation is part of the body’s complex physiological response to harmful stimuli or assault induced
by intrinsic or extrinsic causes. This defensive strategy, however, might be harmful if it is not well coordinated/ deployed. In NDs, inflammation can be caused by misfolded protein aggregation, the build-up
of improperly changed cellular components, the reaction to chemicals released after neuronal injury, and
incorrect modulation of inflammatory regulatory mechanisms (Wyss-Coray & Mucke, 2002). Microglia
are tightly connected with neurons producing A inAlzheimer’s disease.A depositsin thebrain, onthe
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other hand, are believed to be connected with an inflammatory response that results in elevated levels
of vital defense proteins and transcription factors (Akiyama et al., 2000).
Microglial cells communicate with one another via a family of receptors known as pattern recognition
receptors (PRRs) which includes Toll-like receptors (TLRs). TLRs connect with invar molecular motifs
confirmed by infectious pathogens’ pathogen associated molecular patterns (PAMPs) or endogenous
danger-associated molecular patterns (DAMPs) released by injured tissues. A, 𝛼-synuclein,and microtubule-associated protein tau are among the DAMPs that have been found. Microglia and astrocytes can
express a variety of TLRs, which when activated can increase the secretion of proinflammatory cytokines
such as TNF-𝛼 and IL-6, as well as chemokines such as IL-8 (Bsibsi et al., 2002; Amor et al., 2010).
Increased proinflammatory cytokines levels are frequent in the cerebrospinal fluid, blood, and
post-mortem brain tissue of PD patients, as they are in AD (Akama & Van Eldik, 2000; Swardfager
et al., 2010). Following 𝛼-synuclein activation, microglia release inflammatory cytokines and activate
inflammation-mediating enzymes such as matrix metalloproteinases (MMPs) (Lee et al., 2010; Glass et
al., 2010). A component of leucine-rich repeat family, pyrin domain containing 3 (NLRP3), and inflammasomes, nucleotide-binding domain is expressed by activated microglia. Inflammasomes promote various
inflammatory reactions, including the maturation of IL-1 , which has been showedin animal models to
aggravate the course of AD and PD (Singhal et al., 2014). As a result, nonsteroidal anti-inflammatory
medications have been anticipated to possess beneficial roles (Krause & Muller, 2010).
The protective function of microglia on neurons, cytokines, and other CNS inflammatory and immunological pathways is also well understood (Cappellano et al., 2013). Microglia, for example, play a
function in removing apoptotic cells and debris in the CNS. There is additional evidence that microglia
enhance fibrillar A removal via micropinocytosis (Takada etal., 2003). Chronic stimulation of microglia, on the other hand, may result in the loss of this protective feature, resulting in amplified secretion of
various cytokines that suppress phagocytosis and other processes needed for cell survival (Al-Nuaimi
et al., 2012). Utilizing current information, the revolutionary idea of “neuroinflammation” attempted to
clarify the function of inflammation in the cause of Alzheimer’s disease coupled with other neurodegenerative diseases. Nevertheless, the debate over beneficial or harmful significance of inflammation to
the CNS of neurodegenerative disease patients is still unanswered. Owning to this, “A unified opinion
was introduced, indicating that in pathophysiological scenarios, inflammation can play both beneficial
and detrimental roles, based on regional conditions and the timeframe of inflammatory processes and
shutting-off systems.” (Cappellano et al., 2013).
Apoptosis in Pathogenesis of Neurodegenerative Diseases
The morphology of apoptosis is defined by the sequence of chromatin condensation, nuclear contents
splitting, cell shrinking, and disintegration into minute pieces surrounded by membrane structures.
Apoptotic cells are opsonized in vivo by surrounding cells without generating inflammation because the
integrity of plasma membranes and cell organelles is conserved and the release of intracellular components is inhibited throughout the suicide program.
Apoptosis may take place locally without having destructive effects on neighbouring healthy cells,
as against necrosis, which is characterized by spontaneous cell enlargement and subsequent plasma
membrane breakdown. Necrosis frequently causes significant secondary cell rupture in close tissue as a
result of the inflammatory response caused by cell rupture. Because necrosis and apoptosis differ biochemically and physically, they were once classed as two distinct types of cell death. There is mounting
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evidence that this difference is not really that clear, and that traumatic cell death, at the very least, can
be seen as a link between them (Martin, 2001). Apoptosis is a physiological process that provides for the
preservation of a constant size and cell number in actively dividing tissues such as the intestinal mucosa,
skin, and the immune system, as well as the development of the peripheral and central nervous systems.
During synapse development, for example, neuronal death is common (Mattson, 2000). Furthermore,
the supply of neurotrophic factors, which promote the survival and proliferation of neurons, appears to
be significant for the fate of the particular neuron, due to activation of anti-apoptotic pathways (Mattson
& Lindvall, 1997).
Many acute and chronic neurological disorders are characterized by the degeneration of one or more
nerve cell types. Many of the prerequisites for apoptotic cell death are met as chronic neurodegenerative diseases advance. As a result, developing new therapeutic options for neurodegenerative illnesses
necessitates an insight into the molecular mechanisms underpinning neuronal cell death. Extrinsic and
intrinsic apoptosis pathways exist, as do diverse prospective interaction networks between them. The
intrinsic pathway is directly related to the quality, integrity, operations and feature of mitochondria within
the cell, meanwhile the extrinsic pathway is induced by cell surface mediator of tumour necrosis factor
(TNF) family cytokine receptors (Reed, 2000).
Major Mediators of Neuronal Apoptosis
The physiological and chemical alterations associated with apoptosis are propagated by a unique class
of subcellular cysteine proteolytic enzymes called caspases (cysteine aspartyl-specific proteases), which
catalyze their substrates at specific aspartate side chains (Alnemri et al., 1996). Removal of such residues
also results in caspase activation. As a result, caspases, coupled with key cellular biomolecules, can
self-activate. More or less 14 distinct members of these enzymes have been identified with 11 of them
being found in the human genome (Reed, 2002). Based on their amino-terminal properties, they are
normally classified as upstream initiator caspases or downstream effector caspases (Reed, 2000). Caspases initiating this cascade may self-interrelate via their elongated inactive-domains; however, function
of the short inactive-domain in efferent enzymes have not been fully elucidated. Caspase-8, a protein
that initiates the extrinsic signalling pathway, has a death propagating domain at its amino-terminus
that it associates with and is activated by similar proteins propagating such activities (12 death effector
proteins has been identified). Representative member of these protein family (FADD) also possesses a
death domain whose interaction with TNF family death receptors have been well reported (Reed, 2000).
Even though the induction of capase-8 in nerve cells by various death signals are documented (Velir
et al., 1999), the triggering of ensuing programmed cell death by specific ligands and receptors is yet
ascertained. Remarkably, the p75 nerve growth factor receptor (p75NGFR) comprises an altered death
domain (Liepinsh et al., 1997), and its activation can induce apoptosis in neurons under certain conditions
(Bredesen et al., 1998). Nevertheless, it should be highlighted that developmental and disease-specific
activation mechanism may differ greatly, especially since adult neurons no longer exhibit this growth
factor (Hu et al., 1998; Hirsch et al., 2000).
There is a lot of facts arising from research in gene deletion and bio-engineered animals that the
intrinsic signal transduction system is important for neuronal death. Metabolic stress (hypoxia, hypoglycaemia), development of free radicals (oxidative stress), damage of the plasma membrane components,
elevated calcium inflow (excitotoxicity), increased expression of the tumour suppressor gene p53, and
DNA damage (hereditary or induced) could result into mitochondrial alterations leading to the develop-
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ment of small channels in the membrane of mitochondria and a number of cell death-related chemicals
(apoptosis-inducing factor, cytochrome C, SMAC/Diablo) are released.
Bcl-2 family proteins control and moderate changes in mitochondrial function that eventually contribute to cell death. These Bcl-2 family proteins displayed multiplicity (Reed, 2000) in which some are
propagate cell death (e.g., Bid, Bax, Bad) while others mitigate or inactivate this process (e.g., Bcl XL,
Bcl-2). The development of dimers, as well as the balance shift between pro- and anti-apoptotic Bcl-2
family members, may affect a cell’s susceptibility to apoptotic stimuli (Kroemer and Reed, 2000). It has
been demonstrated, for example, that calcineurin dephosphorylates Bad in neurons, hence commencing
the cell death cascade (Wang et al., 1999). Proteins that bind to members of the Bcl-2 family modulate
their functions have garnered significant recognition in recent years. The BAG family is one of these
Bcl-2 binding proteins with antiapoptotic action (Takayama & Reed, 2001). Through their BAG domain,
they all bind to specific molecular chaperone (Hsp70) and link cellular stress responses to the apoptotic
death mechanism. BAG1 has been found in neurons as an important protectant of the neurones and key
modulator in their development (Kermer et al., 2002). In vivo, BAG1 promotes stroke resistance via
boosting Hsp70 expression at the posttranscriptional level (Kermer et al., 2003).
The bifunctional apoptosis regulator (BAR) is another Bcl-2 binding protein with neuroprotective
effects. BAR is a multidomain protein that was initially found as a Bax-mediated cell death inhibitor
(Zhang et al., 2000). It has the ability to block both TNF family death receptor-induced apoptosis and
mitochondria-dependent cell death. BAR’s association with Bcl-2 or Bcl-XL through a specialized domain
may contribute to BAR’s apoptotic-quenching capabilities. Furthermore, this protein has a domain similar
to traditional death propagating domains (dubbed “pseudo DEDs”) which facilitates caspase-8 interaction. As a result, this protein was suggested to function as a linkage protein that connects components
of the receptor-induced and mitochondria-dependent apoptotic mechanisms/ pathways. Conclusively,
the expression of BAR in the nerve cells is quite pronounced where it enhances thriving of these cells
in response to a variety of apoptotic events (Roth et al., 2003).
Cytochrome-c forms oligomeric clusters with Apaf-1 (apoptotic protease activation factor-1) and
caspase-9 after being released from mitochondria into the cytoplasm causing the activation of caspase-9
(Zou et al., 1999). Apaf-1 and caspase-9 interact via a CARD domain (caspase-associated recruitment
domain) that is found in both proteins (Qin et al., 1999). A mechanism known as ‘induced proximity’ is
thought to be responsible for caspase-9 activation (Salvesen & Dixit, 1999). Several inactive caspase-9
proforms are brought into close proximity to one another by attaching to Apaf-1. Because this caspase’s
proform has some protease activity, the interaction of numerous caspase molecules promotes cleavage
and the transition into the fully active form. Aside from procaspases that contain a CARD domain (caspase-1, -2, -4, -5, and -9), the human genome contains at least 20 CARD proteins that either promote or
inhibit apoptosis (Reed, 2000). Active caspase-9 catalyzes the conversion and activates effector caspase-3,
which is in charge of driving the cell death program (Hengartner, 2000).
Aside from Bcl-2 and CARD proteins that have apoptosis- propagating or mitigating properties,
protein family such as the IAPs (inhibitor of apoptosis proteins) have also been reported with similar
functions. These protein family have been extensively identified in bacteria, viruses and humans (Reed,
2000), of which at least one is expressed in neurons (neural apoptosis inhibitory protein). Proteins
belonging to this family inhibit ‘unplanned’ mobilization of effector proteolytic enzymes, however,
negatively regulated by the mitochondrial protein Smac/Diablo. As a result, after suitable stimulation,
the effective operational sequence of the apoptotic cascade is ensured (Hengartner, 2000). In family
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cases of spino-muscular atrophy, inheritable aberrations of neural IAPs are associated with growing
neurodegeneration (Roy et al., 1995).
Furthermore, there are additional signalling mechanisms not directly involved with the programmed
cell death machinery but are capable of interfering with and inhibiting it. These pathways include the
mitogen-activated protein kinase pathway (Fukunaga & Miyamoto, 1998) and the PI3K/Akt signalling
pathway (Franke et al., 1997). Other apoptotic-mitigating indicators are propagated by the mobilization
of specific transcription factors (Reed, 2000; Bozyczko-Coyne et al., 2002).
PROTEIN MISFOLDING AND AGGREGATION IN
NEURODEGENERATIVE DISEASES
The progressive build-up of misfolded protein aggregates in regular patterns commonly known as amyloid
is a pathological feature common to all types of neurodegenerative diseases and it is referred to as the
root cause of these diseases (Goedert, 2015). Evidence derived from neuropathological, genetic, cellular,
and biochemical investigations have showed that the major events that activate pathological abnormalities
associated with neurodegenerative diseases includes cascade of events in which monomeric proteins can
misfold, oligomerized, form aggregates and become accumulated in the brain (Goedert, 2015).
These disease-related proteins though do not demonstrate distinct likenesses in terms of expression
level, sequence, function, structure, or size. However, these proteins from their native states undergo
misfolding to form intermolecular β -sheet-rich structures, ranging from small oligomers to large fibrillar aggregates in the unhealthy brain (Soto, 2003; Goedert, 2015). Amyloid are highly well-organized
aggregates, 100–200 Å in diameter, contained arrangements of intermolecular β -sheets running parallel to the long axis of the fibrils, a structure recognized as cross-β (Fitzpatrick et al., 2013). Staining
with particular dyes such as thioflavin, Congo red, and related dyes is the most common method for
identifying amyloids (Rambaran & Serpell, 2008). Initially, it was thought that these massive protein
deposits in the brain were the harmful species; however, evidence from both experimental and clinical
studies reveal that smaller, soluble misfolded proteins, precursors of fibrillar aggregates, are the major
mediators in ensuing neurodegenerative diseases (Gadad et al., 2011).
Misfolded proteins are diverse group of species ranging from dimeric structures to complex protofibrillar
structures (Breydo & Uversky, 2015). In their oligomeric conformation, these species are characterized
with extreme fluidity in equilibrium relative to their monomeric and fibrillary structures. Furthermore,
some of these oligomeric structures are end-products of rogue pathways which could be highly toxic
while others are on-pathway intermediates for amyloid fibril formation (Figure 1) (Breydo & Uversky,
2015). The diverse nature, spontaneous species interconversion, and characteristics of forming extremely
stable aggregates contributed to the lack of reliable information regarding structural details of misfolded
oligomers as well as the structure associated with disease propagation (Breydo & Uversky, 2015).
The mechanism underlying protein misfolding/aggregation can be better defined using the seeding–nucleation model, first proposed by Lansbury and colleagues (Jarrett & Lansbury, 1993), which
has been modelled kinetically in great detail (Meisl et al., 2017). During this process, a slow and
thermodynamically unfavourable nucleation stage is preceded by a fast elongation phase (Soto et al.,
2006). In the nucleation phase, the rate-determining step is the formation of a stable seed or nucleus of
polymerized protein. Once the seeds are formed, they rapidly grow by incorporating monomeric protein
into the polymer (Soto et al., 2006). Bulky polymeric aggregates can break in a procedure not yet fully
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Figure 1. Mechanism of Protein Misfolding and Aggregate Formation in Neurodegenerative diseases
elucidated internally to produce more nuclei to continue the process. A distinctive characteristic of the
seeding–nucleation model is the capability of preformed seeds to significantly enhance the aggregation
process by engaging the soluble normal protein into the growing aggregate (Soto et al., 2006). Using
biophysical mode of analysis, the procedure by which protein misfold and aggregates includes the rearrangement of the protein structures into a series of highly stabilized β -strands. These structures possess
open up ‘sticky’ ends for attracting folded or partially unfolded proteins, forcing its misfolding to fit into
the cross-β polymeric structure. Although the primary scaffold of the misfolded aggregates is similar,
the individual molecules can adopt many quite varied structures, which give rise to the possibility of
conformational strains.
Even with the unities in the disease mechanisms of neurodegenerative disorders, vital significant
differences exist between the key diseases: genes implicated, cellular types injured, areas of the brain
affected, clinical symptoms, risk factors, and prevalence. Furthermore, the pathogenesis of each of the
well-studied neurodegenerative disease is linked with the misfolding and aggregation of a specific protein that forms deposits that accumulate in diverse cellular locations. Conclusively, although there are
immense structural similarities among these protein aggregates, their individual structures are likely
to be a distinguishing factor depending on the affected protein and ensuing disease, which most likely
contribute to their mechanism of cellular toxicities.
OXIDATIVE STRESS IN PATHOGENESIS OF NEURODEGENERATIVE DISEASES
Oxidative Stress in Pathogenesis of Parkinson’s Disease (PD)
Parkinson’s disease is the second major neurodegenerative diseases, characterized by the disintegration of dopaminergic nerve cells in the brain (McCormack et al., 2002). About 1-2 percent of the total
population of persons above the age of 65 suffer Parkinson’s disease, and the occurrence increases to
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4% in individuals over the age of 85 (Farrer, 2006; Oladele et al., 2020a). The pathological mechanism
underlying dopaminergic neuron degeneration has been linked to an excess of reactive oxygen/nitrogen
species and other free radicals. Excessive ROS production can be caused by either mitochondrial dysfunction or inflammation (Dias et al., 2013). Redox homeostasis is required for the biological functions
of redox-sensitive signaling proteins in brain cells and neuronal survival (Chinta & Anderson, 2008).
The nerve cell and glia mitochondria are the primary source of reactive oxygen/nitrogen species in the
brain (Figure 23.2). (Dias et al., 2013). The production of ROS is increased in Parkinson’s disease due
2+
to high levels of iron or Ca
, GSH depletion, aging, mitochondrial dysfunction, dopamine degradation,
and neuroinflammation (Dias et al., 2013).
Figure 2. Molecular Pathogenesis of Neurodegenerative Diseases
Therefore, when individuals suffering Parkinson’s disease have contact with triggering factors or
chemicals including dopamine, neurotoxins, and pesticides, ROS secretion may be aggravated (Gangemi
et al., 2016). This confirmed that there is a connection between chemicals exposure and Parkinson’s
disease (Gangemi et al., 2016). ROS have been implicated in the loss of dopaminergic neurons (Dias et
al., 2013). Several research findings suggest that the presence of neuromelanin is connected to distinguishing damage associated with dopaminergic neurons, because neurons showing high pigmentation
are even more susceptible to damage (Perfeito et al., 2012). The formation of neuromelanin appears to
be linked to dopamine auto-oxidation, a ROS-mediated pathway that takes precedence over secretion
(Perfeito et al., 2012).
ROS are produced during neurodegeneration, which can damage vital cellular proteins and alter
membrane integrity, causing oxidative stress. Dysfunction of the mitochondria raises the level of free
radicals in the respiratory chain (Dias et al., 2013). There exists established connection between PD and
mitochondrial complex I deficiencies in particular (Zuo & Motherwell, 2013). This impairment is linked
to a mutation in the PTEN-induced putative kinase 1 gene (PINK1), an enzyme ubiquitous in human and
function in reducing oxidative stress (Zuo & Motherwell, 2013). The PINK1 mutation has been connected
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to the development of Parkinson’s disease (Zuo & Motherwell, 2013). Mutations in leucine-rich repeat
kinase 2 (LRRK2), parkin, alpha-synuclein (α-syn), and DJ-1 have been related to PD development.
These genetic alterations may affect function of the mitochondria, increasing reactive oxygen species
(ROS) generation and sensitivity to oxidative stress. Because of its participation in decreasing reactive
species and regulating the generation of nerve cell-toxic proteins generated by targeted degradation,
mutant parkin may participate in important roles in the occurrence of autosomal recessive Parkinson’s
disease (Zuo & Motherwell, 2013). Furthermore, α-syn accumulation affect mitochondrial complex I
functions, resulting in decreased energy generation and mitochondrial malfunction. Malfunction of the
proteasome system, mostly aggravated by dopamine-associated reactive species, is also a contributing
factor in PD onset (Ganguly et al., 2017).
Role of Oxidative Stress in Pathogenesis of Alzheimer’s Disease (AD)
Of all known NDs, Alzheimer’s disease (AD) is quite common, characterized with progressive decreases
in behaviour, memory, and functioning that severely impair daily activities (Zuo et al., 2015). AD patho-
genesis is principally connected to the production of amyloid beta (Aꞵ) and extracellular intracellular tau
neurofibrillary tangles (NFT) (Figure 23.2) (Butterfield, 2014). Endoplasmic reticulum (ER) plaques can
2+
limit Ca
tion in the cytosol depletes the level of antioxidant enzymes, and reactive oxygen species accumulates
within the cells (Ferreiro et al., 2008). ROS-induced ROS over-secretion also leads to Aꞵ accumulation
and production in AD, causing oxidative stress to emerge as a major component in the AD occurrence
(Bonda et al., 2010). Malfunction of the mitochondria can lead to increased ROS generation, reduced
ATP synthesis, altered Ca
the development of Alzheimer’s disease (Huang et al., 2016).
tients can result in severe oxidative damage. This receptor sensitization has been shown to cause severe
2+
Ca
nitrogen species (RNS) (Nakamura & Lipton, 2010; 2011). Reactive oxygen species can mediate JNK/
stress-activated protein kinase pathways (ROS). Both tau protein hyperphosphorylation and Aꞵ-mediated
apoptosis have been connected to the activation of these cascades (Patten et al., 2010). Additionally, by
activating NADPH oxidase, Aꞵ proteins can instantly mediate the generation of free radicals (Shelat et
al., 2008). The stimulation of p38 mitogen activated protein kinase (p38 MAPK) by Aꞵ-mediated ROS
overproduction changes cellular signalling pathways and causes tau over phosphorylation. The creation of
intracellular NFTs may be induced by an uneven aggregation of over phosphorylated tau proteins (Bulat
& Widmann, 2009; Giraldo et al., 2014). As a result, Aꞵ has been shown to play an important role in
the triggering of cellular apoptosis (Agostinho et al., 2008). Aꞵ may increase calcineurin activity, which
subsequently stimulates the Bcl-2-associated death promoter, resulting in mitochondrial cytochrome c
release (Awasthi et al., 2005). Aꞵ may also interact with caspases directly, resulting in neuron apoptosis
(Awasthi et al., 2005).
tal stress can all cause a rise in Aꞵ production by producing extra oxidative stress (Smith et al., 2010;
Hamilton & Holscher, 2012). The aged persons are more prone to oxidative stress, illuminating their
susceptibility to this disease (Hamilton & Holscher, 2012). Inflammation causes elevated amounts of
cytokines, ROS, and cellular damage, all of which hasten AD emergence (Holmes et al., 2009). Fol-
storage, causing Ca2+ overproduction in the cytosol. Similarly, an increase in Ca2+ concentra-
2+
homeostasis, and excitotoxicity. All of these changes might have a role in
Oversensitization of N-methyl-D-aspartate-type glutamate receptors (NMDARs) in Alzheimer’s pa-
invasion by increasing cell permeability and producing neurotoxic amounts of reactive oxygen and
Certain dietary variables (for example, redox-active metals), inflammation, aging, and environmen-
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