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Int J Mol Sci. 2020 Aug; 21(16): 5895. PMCID: PMC7460620

Published online 2020 Aug 16. doi: 10.3390/ijms21165895 PMID: 32824367

Possible Neuroprotective Mechanisms of Physical Exercise in Neurodegeneration

B. Mahalakshmi,1 Nancy Maurya,2 Shin-Da Lee,3,4,* and V. Bharath Kumar5,*

Abstract

Physical exercise (PE) improves physical performance, mental status, general health, and well-
being. It does so by affecting many mechanisms at the cellular and molecular level. PE is bene�i-
cial for people suffering from neuro-degenerative diseases because it improves the production of
neurotrophic factors, neurotransmitters, and hormones. PE promotes neuronal survival and
neuroplasticity and also optimizes neuroendocrine and physiological responses to psychosocial
and physical stress. PE sensitizes the parasympathetic nervous system (PNS), Autonomic
Nervous System (ANS) and central nervous system (CNS) by promoting many processes such as
synaptic plasticity, neurogenesis, angiogenesis, and autophagy. Overall, it carries out many pro-
tective and preventive activities such as improvements in memory, cognition, sleep and mood;
growth of new blood vessels in nervous system; and the reduction of stress, anxiety, neuro-
in�lammation, and insulin resistance. In the present work, the protective effects of PE were
overviewed. Suitable examples from the current research work in this context are also given in
the article.

Keywords: Alzheimer’s disease, anti-in�lammation, antioxidant, Irisin, neurodegenerative

diseases, Parkinson’s disease, physical exercise

1. Introduction

Neuroprotection broadly means the prevention of neuronal cell death by intervening and in-
hibiting the pathogenetic process that causes cellular dysfunction and death. The concept of
neuroprotection has attracted signi�icant interest among the scienti�ic world in the search for

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novel therapies that can help preserve brain tissue and improve overall outcome [1]. Aging is the
most important risk factor for the majority of neurodegenerative diseases (like Alzheimer’s and
Parkinson’s disease)in elderly individuals [2,3]. Alzheimer’s disease (AD) prevalence in individu-
als aged ≥95 years in the USA is ~50% [4] and Parkinson’s disease (PD) affects 2–3% of individ-
uals aged ≥65 years [5]. Epidemiological studies have found that physical activity reduces the
risk of AD and dementia by 45% and 28%, respectively [6].

Based on previous studies [7,8], PE has received greater attention as a potential disease-
modifying treatment approach [9]. PE has been described as a non-drug therapy against numer-
ous diseases like neurological diseases, metabolic diseases, psychiatric diseases, and cardiovas-
cular diseases [10]. For example, Lu et al. examined the bene�icial effect of treadmill exercise
upon cognitive function in a streptozotocin (STZ)-induced AD rat model.Treadmill exercise sig-
ni�icantly inhibited neuronal apoptosis in the rat hippocampal CA1 region [11]. Tang et al.
demonstrated treadmill exercise induced angiogenesis possibly by upregulating MT1-MMP ex-
pression, thereby providing protection against cerebral ischemia in rats [12]. Data from in vivo
studies and human patients with neurodegeneration have proved that exercise improves cogni-
tive performance [13,14]. With the major advances in molecular techniques, researchers have
identi�ied various molecules that are induced by PE [15] such as increased superoxide dismutase
(SOD), brain-derived neurotrophic factor (BDNF), endothelial nitric oxide synthase (eNOS),
insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), and nerve growth
factor (NGF) and decreased harmful free radicals production in hippocampus region of brain,
which are mainly involved in memory [16]. Thus, PE brings about many interrelated positive ef-
fects in the brain, which have been summarized in Figure 1.

Figure 1

Effects of exercise on the human brain.

PE is known to slow down the process of such neurodegeneration. Regular physical activities

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can modulate the potential risk factors of dementia [17] and other neurodegenerative disorders
like AD, PD, and others. Recently, a meta-analysis prepared evidence on the safety and ef�icacy of
physical exercise as an additional therapeutic intervention for the quality of life, cognition, and
depressive symptoms across six chronic brain disorders. These disorders were Huntington’s dis-
ease, AD, PD, multiple sclerosis, unipolar depression, and schizophrenia. This meta-analysis
showed that 69% of the studies reported no complications due to exercise [18]. The study also
suggested that exercising is superior to usual treatment in improving quality of life, depressive
symptoms, attention, working memory, and psychomotor speed [18]. Chang et al. (2010) had
suggested on the basis of their Age Gene/Environment Susceptibility Reykjavik Study in this re-
gard that midlife physical activity may contribute toward the maintenance of cognitive function
and may help delay or reduce the risk of late-life dementia [19]. Modi�iable lifestyle factors such
as physical activity and diet modulate common neuroplasticity substrates (neurogenesis, neu-
rotrophic signaling, in�lammation, antioxidant defense, and stress response) in the brain and
hence these are considered to be important alternative therapeutic options for conditions like
dementia that develop with age [20]. A study done among school children demonstrated a posi-
tive correlation between physical activity and their academic performance [21]. A meta-analysis
of 29 randomized controlled trials (n = 2049) demonstrated that individuals doing aerobic exer-
cise exhibited improvement in memory, attention, processing speed, and executive function [22].

Bene�icial effects of exercise include increased blood �low from brain to the hippocampus and in-
creases in its size in humans [23] and decreased neuro-in�lammation [24]. Silverman and
Deuster (2014) suggested that regular physical activity affects the following biological pathways:
(i) optimization of neuroendocrine and physiological responses to psychosocial and physical
stressors; (ii) acting as buffer against stress and stress-related diseases/chronic diseases; (iii)
promotion of anti-in�lammatory state; and (iv) enhancement of neuroplasticity and growth fac-
tor expression [25]. Not only is the functionality of the brain affected by physical activity, but the
structure is also altered due to it for which there is clinical evidence. For instance, a neu-
roanatomical study of people between 55 to 79 years of age showed that age related reduction in
the cortical tissue density of the temporal, frontal, and parietal cortices was improved signi�i-
cantly as a function of cardiovascular �itness [26]. An animal model-based study also supported
similar �indings where it was demonstrated that long-term voluntary wheel running among rats
changed their spine density and also altered arborization and spine morphology [27]. The study
reported that long-term voluntary running increased the density of dendritic spines in the hip-
pocampus, granule neurons of dentate gyrus, CA1 pyramidal neurons, and in layer III pyramidal
neurons of the entorhinal cortex of adult rats [24]. Upon reviewing the studies related to the
neuroprotective effects of physical activity on the brain in AD using the MEDLINE database
search, it was found that physical activity attenuates AD related neuropathology and brings
about positive effects in hippocampus mediated cognitive function, especially when started early
in the disease process; however, there is a lack of evidence in the literature to support the exact
physical activity guidelines [28]. On the basis of the 38 animal and human studies that met the
desired criteria in this study, it was suggested that incorporating regular physical activity in daily
routines mitigates AD related symptoms, especially if adopted earlier in the disease process [25].
Another meta-analysis showed that physical activity is bene�icial for patients with PD speci�i-
cally in areas such as quality of life, gait, speed, balance, strength, and physical functioning [29].
Exercise effects have also been shown to decrease PD by 33% [30].

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2. Physical Exercise and Neurodegenerative Disease

Lifestyle without suf�icient exercise training may increase the risk of stroke, AD, and PD [31]. In
older adults, aerobic exercise showed improvement in cognitive function [32]. Monteiro et al.
(2015) suggested two hypotheses to explain the underlying mechanism: (a) PE reduces chronic
oxidative stress along with stimulating mitochondria biogenesis and upregulation of autophagy
in PD; and (b) exercise stimulates the synthesis of neuro-transmitters like dopamine and trophic
factors like Glial-derived neurotrophic factor (GDNF), insulin-like growth factor-1 (IGF-1), brain
derived neurotrophic factor (BDNF), and �ibroblast growth factor 2 (FGF-2) [30].

PE affects many neurophysiological aspects and pathways such as autophagy, neuronal plasticity,
neurogenesis, anti-oxidant defense mechanisms, and more. It also decreases neural apoptosis
and neurodegeneration. PE can induce neuro-plastic changes in the human brain but with a wide
inter-individual variability [17]. Regular PE is an effective autophagy inducer [33] and improves
neurological function [12]. It also reduces chronic oxidative stress and promotes mitochondrial
biogenesis. It also promotes the expression of neurotrophic factors like BDNF, GDNF, neurotrans-
mitters like dopamine and hormone irisin, while downregulating Bax and neuro-in�lammatory
cytokines in the hippocampus [34]. Regulation of BDNF through physical exercise is a major key
point as BDNF is a multifunctional molecule that has a role in neuronal plasticity, synaptic trans-
mission and plasticity, neuronal stress resistance, differentiation and maturation of neurons, ac-
tivation of other supporting molecules like NFκB, and dopamine in the neurons [15,35]. Thus, PE
brings about many interrelated positive effects in the brain, which have been summarized in
Figure 1.

AD is the most common form of dementia and is a major challenge for healthcare in the 21st
century [36]. It is expected that in the U.S., about 15 million people (>65 years) will have AD by
2050 [37]. Since no disease-modifying treatment has been available until now, AD patients are
normally treated with combined pharmacological drugs, counseling, and social care to slow
down the disease progression [9,38]. Exercising is a non-pharmacological strategy that may help
in protecting against cognitive decline and decrease the risk of AD [39]. PE helps stabilize and
improve the cognitive function in AD patients and reduces and delays the onset of severe neuro-
psychiatric symptoms like apathy, confusion, and depression [40]. Exercise has also been shown
to induce anti-in�lammatory effects [41] and neurotrophic factors [42]. An experimental study
done in mice suggests that exercise prevented obesity-induced white matter damage by sup-
pressing neuro-in�lammation and vascular dysfunction despite signi�icant weight gain [43].
Aerobic training signi�icantly increases the mRNA expression of ABCA1, which may improve cog-
nitive function by improving and preventing symptoms of AD [44]. All these �indings provide
treatment options for age-related neurodegenerative disorders like AD.

PD is the second most frequent age related neurodegenerative disease [45]. At the cellular level,
its pathology involves dopaminergic degeneration and accumulation of cytosolic protein
α-synuclein, linked with impaired autophagy-lysosome pathway (ALP) clearance [29].
Considering its therapeutic aspect, many efforts have been made using different approaches, but
even after many advances in its treatment that slow down its progression and minimize locomo-

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tor impairment, its clinical management is still a challenge [46]. Recent clinical �inding data
showed that only high-intensity tread mill exercise training could successfully improve motor
symptoms in PD patients [47]. Aerobic walking in mild to moderate PD patients was safe, well-
accepted, and improved aerobic �itness, fatigue, motor function, mood, and quality of life [48].
Multi-component physical training (for eight weeks) in PD patients improved gait speed and
functional status functional status [49]. In another experiment, voluntary exercise on a running
wheel increased DJ-1, Hsp70, and BDNF concentrations and decreased α-synuclein aggregation
in the brains of exercising mice compared to the control mice [50]. Biochemical analysis done in
the same study showed that running mice had signi�icantly higher concentrations of Hsp70,
BDNF, and DJ-1 [50]. Thus, this in vivo study is strong evidence to support the notion that exer-
cising may slow down PD progression through the prevention of abnormal protein aggregation
in the brain [50]. Physical activities such as horseback riding have also been seen to improve bal-
ance and cognitive impairment in aged adults suffering PD, as described in a recent simulation
study [51]. Many studies have indicated that exercise can enhance brain function and also atten-
uate neurodegeneration [52]. Neuroplasticity is improved by changing the synaptic structure
and function in different regions of brain and also modulates multiple systems that regulate glial
activation and neuro-in�lammation [52]. Furthermore, exercising, in addition to carvacrol (a food
additive), is also helpful in reducing rotational behavior and improves aversive memory de�icit
and decreases lipid peroxidation levels, along with increasing total thiol concentration in the
hippocampus and/or hemi-Parkinson rats [53]. This indicates that this combination of carvacrol
and treadmill exercise can be an effective therapeutic tool to treat neuro-behavioral de�icits in
PD patients [53]. Regular exercise also contributes to health in PD patients as it improves the
ability of the patient to adapt to barriers encountered during gait, regardless of the medication
state [54].

A preliminary study done on 36 PD patients reported the effects of coordination and manipula-
tion therapy in which patients performed various activities like dry land swimming and para-
spinal muscle stretching for 30 min every day for one year, while the control group did not exer-
cise regularly. It was found that the treated group exhibited improved balance, mobility disorder,
and cardiac function in PD patients [55]. Aaseth et al. (2018) have also suggested that by making
appropriate lifestyle changes such as PE and intake of natural anti-oxidants help reduce deterio-
ration of dopaminergic neurons, however, many other strategies are to be followed or com-
pounds like iron binding agents and oxygen radical scavengers are also required [56]. Minakaki
et al. (2019) reported improvement of gait activity, postural stability, and promotion of
dopaminergic and α-synuclein homeostasis due to treadmill exercise in their study based on
mice models of PD; however, no signi�icant induction of cerebral ALP occurred due to it [57].

3. The Role of Exercise in Neurological Diseases and Involved Mechanisms

3.1. Neuroendocrine Regulation by Physical Exercise

PE is a stressor for the human body and acts as an activator of the neuro-endocrine system if the
exercise is of suf�icient intensity and/or duration [58]. Chronic exposure to exercise training
leads to neuroendocrine system adaptations such as a decrease in hormonal stress response to

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sub-maximal exercise [58]. PE provokes many major changes in concentration of hormones like
vasopressin, cortisol, β-endorphin, adreno-corticotropic hormone, and some others from resting
levels. The greater the exercise volume (intensity and/or duration of exercise), the greater the
neuroendocrine response [59]. PE begins a coordinated series of physiological responses that in-
clude the hypothalamic–pituitary–adrenal axis and sympathetic nervous system activation. This
combination leads to the appropriate selection and use of metabolic substrates. It acts as a pow-
erful stimulus for the hypothalamic–pituitary axis, but the nature of this stimulus depends on
many factors like the kind of exercise (intensity, aerobic, duration, strength), time of the day,
meal ingestion, and subject characteristics (previous training, gender) [60].

3.2. Neurotransmitter Regulation by PE

PE in�luences the central dopaminergic, seratonergic, and noradrenergic systems [61].

Peripheral physiological adaptations toward exercise occur to adjust to the disturbance in rest-
ing homeostasis, which is induced by exercise stimulus. Many experimental studies in which ho-
mogenized tissues have been used to check the level of different neurotransmitters indicate that
changes in the synthesis and metabolism of monoamines and neurotransmitters occurs during
exercise [61]. Application of micro-dialysis and voltammetry for measuring in vivo release neu-
rotransmitters have indicated that then release of most neurotransmitters is in�luenced by exer-
cise [61]. According to Lin and Kuo (2013), dopamine (DA), noradrenaline (NA), and serotonin
or hydroxytryptamine(5-HT) are the three main monoamine neurotransmitters modulated by
exercise [62] and their release is increased during exercise. The extracellular levels of dopamine,
noradrenaline, serotonin,γ-amino butyric acid (GABA), and glutamate (GLU) are in�luenced by
exercise training. Upregulation of DA in the brain is associated with exercise induced higher lev-
els of serum calcium that is transported in the brain and effects calcium/calmodulin-dependent
DA synthesis by activating the tyrosine hydroxylase enzyme [63]. In addition, the binding af�inity
between DA and its receptor, which is determined by [3H]spiroperidol binding, is enhanced by
exercise training [64,65]. Furthermore, exercise provokes neuronal adaptation in response to
uncontrollable stress [66]. This protective mechanism of PE against stress is due to the expres-
sion of galanin in the locus coeruleus [67], which hyperpolarizes noradrenergic neurons and in-
hibits neuronal �iring by locus coeruleus, causing suppression of norepinephrine (NE) release
[68]. NE, which targets the amygdala and frontal cortex, prohibits anxiety behavior upon de-
creased release [67]. NE also participates in the consolidation and retrieval of memory [69].
Chronic and wheel exercise both increase the levels of NE in spinal cord pons-medulla in com-
parison to sedentary controls [70] and the endogenous activity of NE is enhanced by exercise,
showing a potential link between NE and exercise-enhanced cognitive function [62].

The HT system is modulated by exercise, but this modulation is dependent on the brain region
and is also determined by the duration and intensity of exercise. For instance, four weeks of
moderate treadmill exercise decreased the 5-HT levels with no effect on the metabolism of 5-HT
in the hippocampus [71]. On the other hand, seven days of high-intensity treadmill exercise in-
creased the levels of hippocampal 5-HT signi�icantly [72].

3.3. Exercise-Enhanced Neural Insulin Signaling

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Brain insulin signaling is required for neuronal survival and maintenance of crucial brain func-
tions, and can both prevent and reverse the defects in the BDNF transport [73]. Insulin deregula-
tion are connected with diabetes, obesity, cardiovascular disease, and hypertension and abnor-
mal neural insulin signaling pathways are linked with various neurodegenerative diseases and
learning memory de�icits [74]. The insulin receptor (IR) is densely expressed in pyramidal cell
axons in the hippocampal-CAl region and is mainly distributed in the dominant learning, mem-
ory, and cognitive function regions of the brain [75]. IR was found in different parts of the brain,
however, it was mainly seen in the hypothalamus, hippocampus, and cerebral cortex at high con-
centrations [76]. Among these regions, the hippocampus plays an important role in storing new
memories [77]. During normal physiological conditions, insulin and growth factors like BDNF,
insulin like growth factors 1 and 2 (IGF-1 and 2) and VEGF transmit intracellular signals in the
hippocampal neurons for their integrity and to keep hippocampus functional [78]. However,
when the functionality of these growth factors is inhibited, the possibility of AD becomes high
[78].

Aged rats showed decreased aversive memory as well as increased in�lammatory markers such
as TNFα, IL1-β, and NF-kβ, and decreased anti-in�lammatory cytokine IL-4 and global histone H4
acetylation levels. However, forced exercise(running daily for 20 min for two weeks)reversed
this effect in 20 month-old rats [79]. PE has been shown to exert anti-in�lammatory effects and
enhances insulin signaling in the hippocampal neurons [78]. PE also elicits an insulin sensitizing
effect in the peripheral nervous system [80] and hence the possibility of it to bring about the
same effect in the central nervous system and play a neuroprotective role is quite possible [81].
There have been many other experimental evidences to show that PE helps in neuroprotection
through its effect on the peripheral nervous system as well as central nervous system. In the pe-
ripheral tissues, PE promotes uptake of glucose in an insulin independent way by activating pro-
tein kinase that is itself activated by AMP (AMPK) and mammalian target of rapamycin (mTOR)
[82]. On the other hand, the central nervous system is affected by PE in quite different ways. For
instance, it improves cognition and synaptic plasticity [83,84], along with increasing neurogene-
sis [85] and angiogenesis [86]. It is also shown to regulate the production and degradation of
various neurotransmitters [87,88]. However, the complete understanding of the molecular
mechanisms involved is still lacking.

3.4. Exercise-Enhanced Brain-Derived Neurotrophic Factor BDNF-Signaling

BDNF is a neurotrophin expressed in the hippocampus and is involved in processes related to

memory and learning and is thought to play a crucial role in major depression [89]. BDNF is thus
a central regulator of neuronal plasticity inside the post-natal hippocampus [89]. It plays an im-
portant role in synaptic plasticity and neuronal stress resistance [90]. It has an established role
to play in promoting differentiation and maturation of developing neurons [91], while in mature
neurons, it positively regulates the synaptic transmission and plasticity [92] and thus contrib-
utes to memory formation and learning [93]. Raichlen and Gordon (2011) reported a positive
correlation between the size of the human brain and endurance exercise capacity, suggesting a
co-evolution between locomotion and cognition in human [94]. Mattson et al. (2012) suggested
that since endurance exercise clearly increases BDNF expression in the brain, improvement in

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exercise capacity may positively enforce brain growth, especially in hippocampus [95].
Considering the cases of peripheral nerve injury where transected �ibers distal to the lesion are
disconnected from the neuronal body, activity dependent therapy like early treadmill running
decreases the synaptic stripping and disorganization of peri-neuronal nets on axotomized motor
neurons. The underlying mechanisms that bring about such effects are not known, but the bene-
�its of exercise are attributed to increase in BDNF [96]. Exercise training is known to enhance
amygdala- and hippocampus-associated neuronal function [97]. Lin et al. (2015) also suggested
that PE may serve as a way to delay the onset of Alzheimer’s disease on the basis of their
APP/PS1 transgenic mice based study. It was reported that 10 weeks of treadmill training (from
the age of 1.5 to four months) of the transgenic mice increased their dendritic arbor of CA1 and
CA3 neurons, hippocampus-associated memory, restored the amygdala-associated memory, and
dendritic arbor of amygdalar basolateral neurons [97]. Furthermore, they reported that PE in-
creased the levels of BDNF/TrkB signaling molecules (p-AKT, p-PKC, and p-TrkB) in the hip-
pocampus and amygdala, in addition to reducing the levels of soluble amyloid-β in both regions
[97]. Fahimi et al. (2017) reported that around four weeks of treadmill and running wheel exer-
cises in mice brought about many changes such as (1) signi�icant increase in BDNF mRNA and
protein levels; (2) signi�icantly increased synaptic load in dentate gyrus; (3) changes in the mor-
phology of astrocytes; and (4) orientation of astrocytic projections toward dentate gyrus cells
[98]. These changes were possibly linked to an increase in TrkB receptor levels in the astrocytes
[98]. Zsuga et al. (2016) suggested that BDNF modulates neuronal dopamine content and its re-
lease, which are essential for neuronal plasticity, neuronal survival, and learning and memory
[99]. BDNF signaling is summarized in Figure 2.

Figure 2

Effect of physical exercise (PE) on neurons involving brain-derived neurotrophic factor BDNF and irisin.

3.5. Irisin Production and Secretion

Irisin is basically a myokine that is secreted from the muscles in response to exercise [100] in
mice and human. FNDC5 is a muscle protein that is induced in exercise and is cleaved and se-

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creted as irisin [101]. Irisin serves as a circulating myokine that increases thermogenesis and
improves glucose homeostasis and obesity [102]. Wrann et al. (2013) found that forced expres-
sion of FNDC5 in primary cortical neurons increased expression of BDNF [101]. In addition, the
peripheral delivery of FNDC5 to the liver through adenoviral vectors resulted in increased blood
irisin, induced expression of BDNF, and other neuroprotective genes in the hippocampus [101].
Thus, through their study, Wrann et al. (2013) linked endurance exercise and metabolic media-
tors PGC-1α (regulator of neuronal Fndc5 gene expression) and FNDC5 (exercise induced) with
BDNF expression in the brain [101]. Zsuga et al. (2016) also suggested on the basis of their study
that irisin may be a link between physical activity and motivation and reward related processes
[99] that are in turn related to the neurotransmitter dopamine, which itself gets activated
through BDNF’s activity. Furthermore, Li et al. (2017) suggested that irisin decreases ischemia
induced neuronal injury by activating Akt and ERK1/2 signaling pathways and thus contributes
toward neuroprotective effects of exercise against cerebral ischemia [103]. This further indicates
that irisin may be a factor that links metabolism and cardio-cerebrovascular disorders [103].
Another recent study by Peng et al. (2017) showed that irisin mitigates oxygen-glucose
deprivation-induced neuronal injury in part by inhibiting the ROS-NLRP-3 (reactive oxygen
species-Nod like receptor pyrin-3) in�lammatory signaling pathway, indicating a possible mecha-
nism for irisin induced therapeutic effects in ischemic stroke [104]. Another aspect of the bene�i-
cial effects of exercise is a reduction in neuropathic pain. Dameni et al. (2018) carried out their
study in a chronic constriction injury model in male rats and found that acute administration of
irisin increased pain threshold; however, irisin could not prevent the decline in the number of
neurons [105]. Wang et al. (2018) reported on the basis of their study in primary cell cultures of
astrocytes and neurons that a pretreatment of astrocyte-conditioned medium with irisin for
about 12 h protected neurons from the toxicity of amyloid-β [106]. Irisin could also attenuate
the release of IL-6 and IL-1β from cultured astrocytes and reduced expression of COX-2 and
phosphorylation of AKT [106]. In addition, irisin could decrease NFκB activation of astrocytes
exposed to amyloid-β by preventing phosphorylation and loss of IκBα [106]. Thus, irisin is sup-
posed to be have a novel application in the treatment of AD and memory dysfunction in diabetes
mellitus in the future [106].

3.6. Anti-Neural-Inflammatory and Anti-Neural-Oxidative Responses of PE

In response to PE, the autonomic nervous system and the hypothalamic–pituitary–adrenal axis
come into action to maintain homeostasis. As a result, there is elevation in the level of cortisol
and cathecholamines in plasma [107]. Exercise stimulates the secretion of growth hormone and
prolactin and may in�luence the type of immunity by stimulating the TH2 response pro�ile [107].
There have been attempts to identify potential biomarkers to characterize the response to exer-
cise and to understand the molecular mechanisms leading to health bene�its or mal adaptation
due to physical activity, and such a study was conducted recently using 2D-gel electrophoresis
followed by protein identi�ication using liquid chromatography-tandem mass spectroscopy
[108]. In this study done on six human subjects, it was found that 20 resolved serum proteo-
forms were signi�icantly altered at 5 min and 1 h after high-intensity interval exercise, which in-
cluded serpins (protease inhibitors), apolipoproteins, and immune system proteins that have
broad antioxidant and anti-in�lammatory effects and are involved in cardio-protective, neuro-

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protective effects, and lipid clearance [108]. There have been relevant studies to elucidate the
synergistic effects of physical activity and anti-oxidants on neurons to act as a neuro-protective
strategy in conditions like PD. One such study with a mice model of PD was recently done by Gil-
Martinez et al. (2018), which involved the study of a combination of physical activity and an anti-
oxidant named NAC (N-Acetyl-L-cysteine) as a neuro-protective strategy; however, this study re-
ported that physical activity is bene�icial, but in the long-term only and the combination of the
NAC with physical activity brought about therapeutic bene�its due to NAC only [109]. Another
aspect of the effect of PE with reference to neuronal physiology is that PE produces intracellular
as well as extracellular-heat shock proteins (iHSP70 and eHSP70, respectively) [110]. The activa-
tion of iHSP70 is an absolute requirement for promoting tissue repair, cyto-protection, and anti-
in�lammatory effect [110]. PE induces the appearance of HSP70 in extra cellular medium
(eHSP70), which is involved in the activation of the immune system.Since, iHSP70 is unable to
respond to stress in the motor neurons, the eHSP70 can be internalized by them to act as an in-
tracellular chaperon, protecting the cell against protein denaturation and oxidative damage
[110]. A lowered iHSP70 expression capacity is associated with neurodegenerative diseases like
AD, PD, ALS, Huntington’s disease, and hence the elucidation of the role of eHSP70 can be helpful
in treating these neurodegenerative disorders along with an understanding of the bene�icial ef-
fects of PE in the neuronal cells [110]. Anti-oxidant enzymes like SOD (superoxide dismutase)
become more active in response to exercise [30]. All these effects promote neuroplasticity, de-
crease neural apoptosis, and delay the neurodegeneration process, thus decreasing or prevent-
ing PD development [31].

3.7. Neural Pro-Survival and Anti-Apoptotsis Effects of PE

PE not only affects the activity of different brain cells, but also determines their survival and
death. Recent evidence in a Long Evans rat model based study showed that voluntary exercise, in
addition to enriched environment improves cognitive function, promoted neurogenesis and
brain microvasculature in these rats exposed to hypobaric hypoxia at high altitudes by mediating
VEGF signaling [111]. In a Wistar rat model, it was demonstrated that early PE in childhood and
adolescence induces long term morphological alterations in hippocampal and cortical neurons
even during the sedentary period of rats [112]. It is supposed that PE enhances the expression of
neurotrophic factors and promotes neuronal growth, leading to usage of a neuronal reserve in
later stages of life [112]. Furthermore, the study showed that exercise during juvenile stages in-
creased and maintained the number of hippocampal and cortical neuronal cells and dendritic ar-
borization [112]. In addition, the expression of survival proteins like cortical mTOR and hip-
pocampal BDNF was found to be enhanced at P60, but were restored to control levels at P90 and
P120 [112]. BDNF has been considered to be likely to also elicit the bene�icial effects of exercise
with regard to protection against dementia and type-II diabetes [113]. Another study done in rat
models showed that changes in the expression of in�lammatory and cell survival proteins in the
brain region of aged rats depended on the type of PE training [114]. The aerobic training in-
creased expression of proteins such as p38, Akt, ERK, and p70S6k in the cortex of the brain
[114]. Another recent study based on middle aged APP/PS1 transgenic mice with AD showed the
protection of neurons and adult neurogenesis in the dentate gyrus and thus showed improved
memory and spatial learning due to running exercise [115].

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In aged PS2 mutant mice, treadmill exercise prevented PS2 mutation-induced memory impair-
ment and decreased Aβ-42 deposition by inhibiting β-secretase (BACE-1) and its product C-99 in
the hippocampus and/or cortex of these mice [116]. In the same study, it was found that tread-
mill exercise downregulated expression of GRP78/Bip and PDI proteins along with inhibiting the
activation of PERK, ATF6α, eIF2α, sXBP1, and JNK-p38 MAPK [116]. Furthermore, it activates
caspase-3, -12, and CHOP; upregulates expression of Bcl-2; and downregulates Bax expression in
the hippocampus of aged PS2 mutant mice [116]. Varying intensities of PE have different effects
on the nervous system, for example, instead of high intensity exercise, moderate intensity tread-
mill exercise has a neuroprotective effect in rats suffering from cerebral ischemia. Thus, it is
speculated that due to high intensity treadmill exercise, the neurotrophic factors were downreg-
ulated, further affecting the expressions of cell cycle-related proteins [117].

Voluntary running is considered a powerful neurogenic stimulus that triggers proliferation of

progenitor cells in the dentate gyrus, which is the site for adult neurogenesis occurring through-
out life [118]. The retinal ganglion cells that become increasingly vulnerable to injury with aging
also become protected through exercise, which is because PE prevents the loss of BDNF in retina
post-injury, along with preserving neuronal function and survival by the prevention of comple-
ment mediated elimination of the synapses [119]. The examination of the effects of different in-
tensities of aerobic exercise on resting serum BDNF, IGF-1 concentration, and cortisol, the hor-
mone released in response to stress and memory of adolescent human, has been done in order
to understand how PE brings changes in their expression [120]. For this, 40 adolescent males
were recruited who performed aerobic exercise of moderate to high intensity, and it was found
that PE also had a positive effect on the serum levels of BDNF at rest and on cognitive function
[120].

3.8. Autophagy

Evolution favored organisms with superior physical and cognitive abilities under stressful condi-
tions like limited food sources, and hence the brain function can be optimized by intermittent di-
etary energy restriction and exercise [31]. These energy challenges engage various cellular
stress-response signaling pathways in the neurons involving protein chaperones, neurotrophic
factors, DNA-repair proteins, mitochondrial biogenesis, and autophagy [31]. Lack of physical ac-
tivity, overeating, and suppressing adaptive cellular stress responses thus may increase the risk
of AD, PD, depression, and stroke [31]. Mattson (2014) suggested that interventions like exercise
intermittent energy restriction can counteract neurodegenerative processes and improve brain
function in animal models. This is because these interventions may support neuronal adaptive
stress response pathways that enhance DNA repair, neurotrophic signaling, mitochondrial bio-
genesis, and proteostasis [121]. Pathways involving Ca2+, CREB, NFκB, and PGC-1α are activated
in neurons upon physical activity (aerobic exercise) and food deprivation and these stimulate
cellular stress response and mitochondrial biogenesis [122].

Autophagy ensures lysosome mediated breakdown and self-material recycling as it degrades

damaged intracellular components and provides building blocks for biosynthetic and energy
production [123]. Many animal model based studies, along with those involving drosophila, have

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shown that defects in the autophagic process cause a rapid decline in neuro-muscular function,
sensitivity to stress conditions like starvation or oxidative damage, neurodegeneration, and stem
cell loss [123]. Impairment of the autophagic pathway is known to play a role in β-amyloid pro-
duction and AD progression following a complex mechanism. In the Alzheimer’s disease mice
model based study, it was found that when autophagy is genetically hyperactivated by knocking-
ina gene-point mutation (Becn1F121A) in the autophagy essential gene (Beclin 1/Becn 1), a sig-
ni�icant decrease in amyloid accumulation is observed and there is a prevention of cognitive de-
cline along with restoring the survival of AD mice.This happens because the F121A point muta-
tion induced in Becn 1 signi�icantly decreases the interaction of BECN 1 with its inhibitor BCL2,
leading to constitutively active autophagy even in non-autophagy inducing conditions [124]. It
was observed that biochemically, amyloid-β-oligomers are autophagic substrates and se-
questered inside autophagosomes in the brain of autophagy hyperactive AD mice [124]. The
same study suggested that voluntary exercise is a physiological autophagy inducer and exerts
similar Becn1-dependent protective effects on amyloidβ removal and memory in these AD mice
[124].

4. Conclusions

Physical activities have been proven to have bene�icial effects on the general health and well-
being of the people who exercise on a regular basis. Each and every part of the body is bene�itted
in one way or another among regular exercisers. Talking speci�ically about their effects on neu-
ronal cells and brain function, there are many research-based evidences that prove that PE has
neuroprotective effects. Physical activities elicit their bene�its through some signaling mecha-
nisms that have, however, not been completely elucidated to date, but neurotrophins like BDNF,
hormones like irisin, and neurotransmitters like dopamine are direct participants in these mech-
anisms. Considering its effect among PD patients, it improves gait, balance, cognition, along with
a slowing down progression of the disease by avoiding protein aggregation in the brain. In AD
patients, it also slows down the progression of the disease, along with improvement in cognition,
memory, and delays the onset of neuro-psychiatric symptoms like depression, apathy, and oth-
ers. The different physiological aspects affected by PE are:hippocampal insulin signaling, au-
tophagy, anti-oxidant and anti-in�lammatory responses, cell survival and death pathways.
Physical activities enhance the expression of BDNF, which is an essential mechanistic step in-
volved in the bene�icial process occurring due to them. Molecules like dopamine, irisin, GABA,
and Aktare also involved in these mechanisms. Still, PE cannot be applied as a stand-alone way
to handle neuro-pathologies. As an add-on therapy; however, it has great potential in this regard.

Acknowledgments

Our gratitude goes to Michael Burton at Asia University for proofreading.

Author Contributions

V.B.K., B.M., and N.M. contributed to the conception of this manuscript and wrote the draft; V.B.K.,

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B.M., N.M., and S.-D.L. contributed to the literature collection, preparation and MS revision. All
authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no con�lict of interest.

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