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Harnessing Neuroplasticity: Modern Approaches and Clinical Future


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Background and purpose: Neurological diseases and injuries to the nervous system may cause inadvertent damage to neuronal and synaptic structures. Such phenomenon would lead to the development of neurological and neurodegenerative disorders which might affect memory, cognition and motoric functions. The body has various negative feedback systems which can induce beneficial neuroplastic changes in mediating some neuronal damage; however, such efforts are often not enough to ameliorate the derogatory changes. Materials and methods: Articles discussing studies to induce beneficial neuroplastic changes were retrieved from the databases, National Center for Biotechnology Information (NCBI) and MEDLINE, and reviewed. Results: This review highlights the significance of neuroplasticity in restoring neuronal functions and current advances in research to employ this positive cellular event by inducing synaptogenesis, neurogenesis, clearance of toxic amyloid beta (Aβ) and tau protein aggregates, or by providing neuroprotection. Compounds ranging from natural products (e.g. bilobalides, curcumin) to novel vaccines (e.g. AADvac1, RG7345) have been reported to induce long-lasting neuroplasticity in vitro and in vitro. Activity-dependent neuroplasticity is also inducible by regimens of exercises and therapies with instances in human studies proving major successes. Lastly, mechanical stimulation of brain regions through therapeutic hypothermia or deep brain stimulation has given insight on the larger scale of neuroplasticity within the nervous system. Conclusion: Harnessing neuroplasticity may not only offer an arm in the vast arsenal of approaches being taken to tackle neurological disorders, such as neurodegenerative diseases, but from ample evidence, it also has major implications in neuropsychological disorders.
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International Journal of Neuroscience
ISSN: 0020-7454 (Print) 1543-5245 (Online) Journal homepage:
Harnessing neuroplasticity: modern approaches
and clinical future
Andrew Octavian Sasmita, Joshua Kuruvilla & Anna Pick Kiong Ling
To cite this article: Andrew Octavian Sasmita, Joshua Kuruvilla & Anna Pick Kiong Ling (2018):
Harnessing neuroplasticity: modern approaches and clinical future, International Journal of
Neuroscience, DOI: 10.1080/00207454.2018.1466781
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Harnessing neuroplasticity: modern approaches and clinical future
Andrew Octavian Sasmita , Joshua Kuruvilla and Anna Pick Kiong Ling
Division of Applied Biomedical Sciences and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia
Received 9 January 2018
Revised 22 March 2018
Accepted 13 April 2018
Background and purpose: Neurological diseases and injuries to the nervous system may cause
inadvertent damage to neuronal and synaptic structures. Such phenomenon would lead to the
development of neurological and neurodegenerative disorders which might affect memory,
cognition and motoric functions. The body has various negative feedback systems which can
induce benecial neuroplastic changes in mediating some neuronal damage; however, such efforts
are often not enough to ameliorate the derogatory changes.
Materials and methods: Articles discussing studies to induce benecial neuroplastic changes were
retrieved from the databases, National Center for Biotechnology Information (NCBI) and MEDLINE,
and reviewed.
Results: This review highlights the signicance of neuroplasticity in restoring neuronal functions
and current advances in research to employ this positive cellular event by inducing
synaptogenesis, neurogenesis, clearance of toxic amyloid beta (Ab) and tau protein aggregates, or
by providing neuroprotection. Compounds ranging from natural products (e.g. bilobalides,
curcumin) to novel vaccines (e.g. AADvac1, RG7345) have been reported to induce long-lasting
neuroplasticity in vitro and in vitro. Activity-dependent neuroplasticity is also inducible by regimens
of exercises and therapies with instances in human studies proving major successes. Lastly, mechanical
stimulation of brain regions through therapeutic hypothermia or deep brain stimulation has given
insight on the larger scale of neuroplasticity within the nervous system.
Conclusion: Harnessing neuroplasticity may not only offer an arm in the vast arsenal of approaches
being taken to tackle neurological disorders, such as neurodegenerative diseases, but from ample
evidence, it also has major implications in neuropsychological disorders.
neurorestoration; physical
exercise; synaptogenesis
1. Introduction
An outdated dogma that was widely believed stated that
the number of neurons in the brain is xed since birth
[1,2]. Plasticity of the brain can be concisely described as
the brains ability to create adaptive changes in morpho-
logical and network neuronal structure and function of
nervous system, which includes changes in neuronal
connectivity, neurogenesis and neurochemical changes.
Despite such changes being the result of various internal
and external stimuli, strong attention has been given in
the past toward the particular external stimuli stress, or
more specically, repeated or chronic stress, with mod-
ern attention given centering toward its role in trauma
or degenerative illnesses [3].
The most attractive adaptive change is, without a
doubt, neurogenesis, generation of neurons of neural
cell types from neural stem cells or neural progenitor
cells (NPCs) which occurs throughout life [4]. Upon
reaching adulthood, it has also been suggested that the
dentate gyrus and subependymal zone of the adult
hippocampus contain distinct committed NPCs of glial
and neuronal cells [5]. In particular, adult neurogenesis
is often highlighted as the brain is often regarded as
non-renewable [6]andspecic illnesses occur almost
exclusively in adulthood, namely Parkinsonsdisease
(PD) and multiple sclerosis [7]. Furthermore, 3H-thymi-
dine autoradiography [8], thymidine analog 5-bromo-
20-deoxyuridine (BrdU) labeling test [9]and14Ciso-
tope-based tests [10] on animal and human brains have
long disregarded the rst speculation of the brain being
non-renewable, as more evidences are pointing to the
actual presence of neurogenesis in key areas of the adult
brain, including substantia nigra, striatum and hypothal-
amus, although the levels discussed are below those in
non-physiological conditions [11].
Studying of neurogenesis in humans directly pos-
sesses various obstacles, with a large portion of studies
stemming from in vivo rodent experiments, which pos-
sess the advantage of similarities in location and regula-
tion with a key example being that of adult hippocampal
CONTACT Anna Pick Kiong Ling
© 2018 Informa UK Limited, trading as Taylor & Francis Group
neurogenesis [12]. However, due to scaling up, concerns
do exist of signicant difference in number [13], turnover
rate [14] and maturation [15] of neuronal cells such as
new adult born dentate granule cells (DGCs), between
rodents and humans [1].
The present-day ability to elucidate biological mecha-
nisms, however, such as knocking in or down specic
genes, and studying the corresponding effects in geneti-
cally modied rodents provides invaluable information
on neuroplasticity. In addition, modern improvements in
identifying functional, structural and metabolic-based
data and metadata analysis of the brain following imple-
mentation of various molecular, physiological, psycho-
logical and surgical treatments continue, which has
been accelerating rapidly in the last decade on account
of increased interest in neuroplasticity [1,16]. This review,
thus, considers modern approaches of inducing neuro-
plasticity in patients or models of neurological disorders
whereby neuroplasticity is known to be impaired, albeit
in ranging degrees, which span from neurodegeneration
to traumatic brain injury and learning disability.
2. Overview and components of neuroplasticity
There exists an immense spectrum of neurogenic regu-
latorsas Kempermann concisely noted which reect
the sensitivity of adult neurogenesis to many different
types of stimuli[17]. Individual molecules and environ-
mental conditions may contribute to neurogenesis and
subsequently neuroplasticity as well; thus, presence of
such compounds form knowledge regarding neurogene-
sis regulation which is a pivotal priority in the hope to
achieve therapeutic interventions utilizing the concept
of neuroplasticity [3,17]. These interventions may utilize
molecules including natural products, sex steroids such
as estrogen, alongside growth factors including brain-
derived neurotrophic factor (BDNF) and vascular endo-
thelial growth factor (VEGF), all of which are elaborated
in this review. Modulation of neuroplasticity, however,
requires the presence of neuronal proteins and recep-
tors, more of which have been elucidated through the
As a prime example of an internal stimuli for neuro-
plasticity, disrupted in schizophrenia 1 (DISC1), a multi-
functional scaffolding protein regulates many aspects of
neuroplasticity throughout the development and adult-
hood phase, with a variety of its molecular interactions
noted to correlate to neuroplasticity activity, includes
centrosomal interaction with phosphodiesterase 4B
(PDE4B), sequestering and preventing cyclic adenosine
monophosphate (cAMP) conversion, which is key as
cAMP plays a key role in neuronal plasticity [18]. DISC1
additionally interacts with Kalirin-7 (Kal-7), a GDP/GTP
exchange factor, which is a notable regulator of spine
morphology and plasticity [19]. Following inux of Ca2+
through the N-methyl-D-aspartate receptor (NMDA)
receptor, neuroplasticity may be regulated by the
cascade of intracellular events such as long-term poten-
tiation (LTP), synaptogenesis and dendritic patterning
[1921]. Dysbindin, a putative schizophrenia risk gene,
has been found to be crucial for adaptive neuroplasticity
as it serves a function for retrograde, homeostatic modu-
lation of neurotransmission [22]. Neurotransmitters such
as glutamate [23] and astroglia [24] are speculated to
generate a particular microenvironment favoring gener-
ation or differentiation of neuroblasts.
As an external stimulus, chronic social stress has been
found to lessen hippocampal neurogenesis [25,26].
Evidence of its reversibility has been seen in a study by
Tauber et al., where newborn marmoset monkeys
exposed to synthetic glucocorticoid dexamethasone saw
decreased proliferation rate of putative precursor cells
which was no longer detectable in their two-year-old sib-
lings suggesting stress effects were not long-lasting and
possibly reversible [27]. Stress also makes its molecular
mark within our genome, whereby patterns of conserved
transcriptional response to adversity (CTRA) are present
in individuals who had experienced adversities in their
lifetime [28,29]. CTRA has further implications in activa-
tion of pro-inammatory components which may pro-
mote neuroinammation and disruption of neuronal
structures [30]. Chronic stress was also reported to
induce dendritic arborization in the bed nucleus of stria
terminalis of amygdala, which further suggests the
degree of structural changes stress might impose on
dendritic structures [31]. This is supported by another
study which reported dendritic hypertrophy and amyg-
dala hyperexcitability upon receiving stress stimuli in
rodent models [32]. However, in the hippocampus and
prefrontal cortex regions, chronic stress was observed to
induce a general sense of dendritic atrophy [33,34].
To assess the varying degrees of neuroplasticity, novel
methods were invented, such as BrdU labeling tech-
nique, which was the rst evidence of identifying neuro-
plasticity in hippocampus in 1998 [2,9]. Due to safety
reasons, however, alternative methods are used to study
neurogenesis include ex vivo measurements; postmor-
tem brain tissues undergoing immunostaining with
endogenous markers (such as NeuN, calbindin, double-
cortin, Ki67 and nestin) [2] as well as its genomic DNAs
14C abundance utilized to identify neuronal age (which
incorporates bioinformatics-based mathematical mod-
els). [10] Yet these methods do not identify the role of
adult neurogenesis. Examples of in vivo alternatives
include magnetic resonance spectroscopy (MRS) which
identies NPC-specic metabolic biomarker and
magnetic resonance imaging (MRI) which identied posi-
tive correlation of cerebral blood volume and neurogene-
sisbasedontheircoupling[35,36]. It should be noted
that most of our understanding regarding neuroplasticity
pathways and markers stems from neurodegenerative
research, with much of the mechanism details, remains
highly debated among the scientic community.
3. Neurological disorders and impact on
Hallmarks of neurodegeneration are known to impair
synaptic and non-synaptic neuroplasticity, while neuro-
logical disorders posit theories on neuronal loss-induced
neuroplasticity, thus studying long-term neuroplastic
changes of neurodegeneration and neurological disor-
ders, which may give insight on molecular events to tar-
get to potentially restore neuronal functions.
As a primary example, impaired neuroplasticity has
been observed in Alzheimers disease (AD) cases. Amy-
loid beta (Ab) plaques, known not only to degenerate
neuronal structures but also to impair neuroplasticity in
AD, appear at higher levels in early-onset AD (EOAD)
patients as compared to late-onset AD (LOAD) cases
[37]. Pathological effects of Abmay be due to excess
amyloid precursor protein (APP) production through
modulation of a-secretase [38,39]. Abdeposits can pose
long-lasting cholinergic damage which may be revers-
ible based on load of Abdeposits in in vivo models [40],
underlining the long-term reduction of NMDA receptors
at synapses which in turn affects LTP and long-term
depression (LTD) [41]. Aside from Ab, accumulation of
hyperphosphorylated tau protein has been associated
with neuronal losses in the cortical regions of AD brain
[42,43] aside from tau mutations [44,45]. Given other fac-
tors such as apolipoprotein E4 (APOE4) which serves as
the strongest LOAD genetic risk factor in increased Ab
levels [46], the malicious effects brought about by toxic
Aband tau are not limited to just impairing synaptic
plasticity, but also mitochondrial functions of neurons
[47], which underline the severity of plasticity impairment
within AD and other types of dementia.
PD is another major neurodegenerative disease with
motoric decits being its most prominent chronic symp-
tom. Chronic accumulation of a-synuclein (SNCA) which
forms Lewy bodies in neurons would lead to neuronal
death, specically, in substantia nigra [48], and this has
been identied as a hallmark of PD [49,50]. Lewy bodies
and Lewy neurites may be hallmark in a-synucleinopa-
thies[51], but PD patients specically undergo extensive
motoric function impairment due to disruption of dopa-
minergic neurons essential in motoric signal relay. This
motoric decit alongside synaptic integrity is actively
affected by oxidative stress [52,53] and genetic muta-
tions of SNCA or PINK1 genes [54] in PD mice models.
Moreover, demented PD patients display higher tau pro-
tein concentration in serum samples as opposed to non-
demented PD patients, suggesting a common mecha-
nism of how tau aggregates mediate synaptic, cognitive
and memory losses in AD, PD and other neurological dis-
orders [55,56].
Upon surviving extensive neuronal losses, the ner-
vous system could still adapt and reorganize itself in
cases of epileptic seizures [57], stroke [58] and traumatic
brain injuries (TBI) [59], although the degree of restora-
tion may differ based on how progressive the neuronal
losses are and age [60]. By understanding the ways that
neuroplasticity is impaired in neurodegeneration and
natural ways that the nervous system reorganizes itself
in events of neuronal losses, we could better target
the various molecular or physiological components to
enhance neuroplasticity in the hope of restoring neu-
ronal functions.
4. Approaches in harnessing neuroplasticity
against neurological disorders
4.1. Molecular compounds and targets
Various categories could be considered in neuroplasticity
induction (i.e. synaptogenesis, neurogenesis, neuropro-
tection, reduction of molecular etiologies of neurode-
generation). This subsection will discuss on the available
preclinical and clinical data of molecular compounds
which impact neuroplasticity in translational neuronal
restoration. Given the various outlets of harnessing neu-
roplasticity by administration of molecular compounds,
studies have shown that there is often cross-talk
between each benecial function, which would lead to a
greater synergism in restoring neuroplasticity. Clear limi-
tations exist with administration of molecular com-
pounds to treat any neurological problems, including
the persisting bloodbrain barrier predicament and
retention of drugs within the system to reach the desired
targets. Table 1 summarizes the promising molecular
compounds, whereby some will be elaborated further in
this section.
4.1.1. Promotion of synaptogenesis, neurogenesis
and repair
Synaptic impairment is implicated not only in neurode-
generation, but also in depression and other forms of
dementia [56]. Compounds that induce synaptogenesis
upon excessive neuronal losses offer great potential in
bridging the gaps destroyed by hallmarks of neurode-
generation. Naturally derived compounds such as
quercetin and bilobalide extracted from Ginkgo biloba
were shown to be capable in inducing hippocampal syn-
aptogenesis and neurogenesis alongside the production
of brain-derived neurotrophic factor in vivo and in vivo
via a possibly common modulation of the cyclic-AMP
response element binding protein (CREB) pathway [62].
Phosphorylation of CREB via mitogen-activated protein
kinase (MAPK)/ERK pathway inhibitors, U0126 and
PD169316, has been shown to improve cognitive and
memory impairments in Ab-injected rats [108], suggest-
ing a synergistic relationship between neuroprotection
and synaptogenesis. The relationship between neuro-
protective effects and synapse regeneration was further
supported by a study conducted in 5XFAD mice model
for increased expression of the RNA binding protein,
RBM3 [109], whereby synapse regeneration has been
reported to be diminished in RBM3-knockdown model.
Other constituents of Ginkgo biloba such as ginkgolide J
have also been researched to repair Ab-induced LTP
impairment but not modulate neurogenesis, suggesting
different pathways in LTP restoration [72].
Modulation of neuronal migratory and guiding pro-
teins such as doublecortin (DCX) [95,110]hasbeen
repeatedly shown to successfully promote synaptogen-
esis and neurogenesis upon their overexpression in
cases of TBI. BDNF is another majorly studied molecule
implicated in modulation of neurogenesis at a dose-
dependent manner [89] via tropomyosin-related kinase
B coupled with phospholipase Cg(PLCg), phosphatidyli-
nositol 3-kinase (PI3K), Akt, Ras and Etv1 pathways
[9092]. With regards to ion channels involved in signal
relay, the existing antidepressant, spadin, targets the
potassium channel protein TREK-1, effectively blocking
its activity and inducing neurogenesis via the CREB
pathway [82]. The utilization of other antidepressants
has been studied to induce neurogenesis in applica-
tions which go beyond depression and psychological
problems, such as sertraline which increased neuro-
blasts and mature neurons, indicating neuronal differ-
entiation through glucocorticoid receptor mechanisms
[83]. Fluoxetine, a type of selective serotonin reuptake
inhibitors, was also reported to accelerate maturation of
Table 1. Molecular compounds with their respective mechanisms of actions in harnessing neuroplasticity.
Compounds Mechanism of action and effects Related studies
Natural products
Azaphilone In vitro inhibition of tau polymer assembly via microtubule destabilization. [61]
Bilobalide Increase of CREB phosphorylation, BDNF, neurogenesis, synaptogenesis and prevented Ab-induced synaptic loss. [62]
Reduction of APP and Abburden by modulation of PI3K pathway [63]
Curcumin Direct binding to Abto prevent formation in vitro and in vivo, while increasing IL-4 and IL-2 aside from reducing tau. [64,65]
Signicant reduction of LTD, lipid peroxide, lipofuscin and COX-2, while increasing BDNF, SOD and GPxin vivo. [66,67]
EGCG Reduced b- and g-secretases alongside APP and Abwhich enhanced memory function in vivo. [68]
Suppresses production of soluble and insoluble toxic Abalongside sarkosyl-soluble phosphorylated tau in vivo [69]
Signicantly reduced pro-inammatory cytokines and dampen LPS-induced neurotoxicity by neuroprotection. [70,71]
Ginkgolide J Promotes LTP rescue in CA1 hippocampal region and protects culture from Ab-induced neuronal loss/death. [72]
Ginsenoside Reduced toxic Abvia modulation of BACE1, b-CTF, PPARgtranslocation and inhibits a-synuclein [73,74]
Increased Abclearance by autophagy via inhibition of mTOR phosphorylation in astrocytes. [75]
Resveratrol Anti-neuroinammatory by increasing IL-4 and FGF-2 aside from CSF toxic Ablevels. [76]
Marked reduction of Abcytotoxicity but no change in rate of Aboligomeric formation. [77,78]
Squalamine Competitively displaces a-synuclein within carrier vesicles in vitro and reduces paralysis in vivo. [79]
Edaravone SOD salvage and activation of Nrf2 in vivo to reduce tau burden and ameliorate cognitive decit. [80,81]
Spadin Blockage of K
channel protein TREK-1 and increasing CREB pathway for neurogenesis and synaptogenesis. [82]
Sertraline Glucocorticoid-dependent increased expression of CDKi genes, DCX+ neuroblasts and neurogenesis. [83]
Fluoxetine Increased arborization of dendrites of DCX+ neuroblasts and LTP in chronic uoxetine treatment. [84]
Epigenetic modulation
HDAC2 Deciency of this gene allowed restoration of BDNF, GLUR1, and related pro-synaptic genes and proteins. [85]
lin-4 Inhibits LIN-14 which results in increased synaptogenesis as compared to branch formation. [86]
miR-181c Reduction of this miRNA modulates expression of genes and cascades which promote neurite and synapse growth. [87]
miR-214 Overexpression of this miRNA promotes dendritic growth and synaptogenesis by targeting the gene Qki. [88]
Biochemical mediators and precursor compounds
BDNF Dose-dependent induction of neurogenesis via PLCg, PI3K, Akt, Ras and Etv1 pathways. [8992]
DHA Increased synapsin in neurite, upregulation of p-Akt, downregulation of PTEN and synaptic plasticity. [93,94]
DCX Neural progenitor cells expressing this compound are required for injury-induced remodeling in hippocampus. [95]
IGF-II Neuroprotection against long-term oxidative stress via IGFII/M6P receptor in neuronal cultures [96]
AAV8-induced overexpression resulted in mEPSC rescue and signicant Abclearance. [97]
TGF-bIncreased another NMDA receptor ligand, D-serine and induced synaptogenesis in cerebral cortical neurons. [98]
Uridine Compensation of P2Y receptor deciency common in AD, increased neurite outgrowth and synaptogenesis. [94,99]
VEGF Stimulation of neural stem cells expressing VEGFR-3 and neurogenesis within subventricular zone in vivo. [100]
Wnt Neurogenesis in the dentate gyrus of a neuroinammatory in vivo model via various cytokines. [101]
Lentiviral vector expressing Wnt3a-HA enhanced recovery from focal ischemic injury in in vivo model. [102]
AADvac1 95% reduction of pathological and not physiological tau in vivo, while Phase I trial (n= 30) showed safety. [103,104]
ACI-35 Reduction of tauopathy indices and bodyweight loss in vivo with good safety prole of long-term vaccination. [105]
RG7345 Chronic immunization detectable in lysosomes via lipid rafts reduces tau/pS422 pathology. [106]
43D; 7739 Reduced total tau (2 doses) and hyperphosphorylated tau (6 doses) with spatial and short-term memory rescue. [107]
neurons and promote synaptic plasticity in hippocam-
pal granule cells [84]. The effect of uoxetine is also
more pronounced in the chronic corticosterone in mice
models [111].
Docosahexaenoic acid (DHA) [93], uridine [94] and
choline [112], amongst the synaptic membrane precur-
sors, were reported to improve synaptogenesis and neu-
rogenesis in neurodegenerative and mechanical injury
cases, even in combinatorial administration of the health
food, Souvenaid [113]. Out of these precursors, DHA was
reported to induce synapsin production in neurite out-
growth while upregulate p-Akt and downregulate phos-
phatase and tensin homolog (PTEN) which are essential
in synaptic plasticity [93]. Uridine has also been identi-
ed to compensate for P2Y receptor deciency often
observed in AD patients by increasing neurite outgrowth
aside from neuronal differentiation [99].
Lastly, promising synaptogenesis molecular targets
may be modulated epigenetically, such as knockdown of
histone deacytelase 2 (HDAC2), an enzyme which func-
tions to suppress gene expression within synapses by
implicating proteins such as Sp3 [85]. Activation of genes
not only promotes synaptogenesis upon HDAC2 inhibi-
tion in mice models, but also restoration of long-term
memory formation. A randomized double-blind trial
with placebo of valproate (VPA), an inhibitor of HDAC,
resulted in test subjects receiving VPA obtaining better
perfect pitch control as opposed to the control group
[114], further signifying the fundamental and transla-
tional role of HDAC in synaptogenesis. Other epigenetic
attempts by modulation of microRNA include lin-4 [86]
and miR-181c [87], alongside microRNA applications in
schizophrenia cases [88,115].
The various compounds discussed have shown ample
preclinical data with the potential of each one to pro-
mote neuroplasticity, and with the advent of high-
throughput analysis techniques, the pipeline could
hopefully be signicantly shortened [116], especially
because there are only limited options to assess local-
ized neuronal responses for drug screening. Aside from
the limited options, commonly used in vitro models of
neuronal settings, often only consider survivability of the
models as a positive measure of studies, while counting
out important factors related to the successful growth,
migration or activation of markers of neurogenesis. The
high-throughput techniques, which include the utiliza-
tion of microuidics and microfabrication to create
micro-compartmentalized neurobiology tools, such as
microarray chips that analyze synaptic or axonal
responses, may circumvent these basic limitations
[117,118]. Aside from microarray-based technology,
novel single-cell transcriptomic approaches have also
been developed to study the development of neuronal
circuits and assembly [119,120], whereby the utility of
such tools may also be explored for drug-screening pur-
poses. Single-cell approaches have also been shown to
be benecial as they elaborate on neuronal and non-
neuronal diversities of models which work dynamically
hand-in-hand to provide spatiotemporal changes in the
face of drug molecules [120]. Aside from just focusing
on drug target representation, current neuroscience
research also utilizes computational and mathematical
representation of neuropsychiatric and neurological dis-
orders which allow scientists to further visualize such dis-
orders as dynamical entities as opposed to diseases
comprising static etiologies [121]. Given that mathemati-
cal models are required to be in concordance with their
biological counterparts, computational neuroscience
research has progressed massively in the past few deca-
des, able to recapitulate key neurogenesis steps in drug-
screening simulations, which does not only include syn-
aptogenesis but also the long-term maintenance of syn-
apses [122]. Together with high-throughput analysis
discussed, computational neuroscience may provide a
broader insight in the current status quo of drug discov-
ery for neuroplasticity which would quicken the process
of effective agent discovery as treatment for neurologi-
cal disorders whereby neuroplasticity is impaired.
4.1.2. Reduction and inhibition of toxic protein
Destruction of neurons and synapses may be mediated
strongly by accumulation of toxic protein aggregates
which were reported to target neural cell adhesion mole-
cule 2 (NCAM2) in AD models [123]; thus, another strat-
egy to be considered in gaining neuroplasticity involves
the depletion of toxic proteins which disrupt synaptic
signal relay. Despite not being its natural etiology, accu-
mulation of protein aggregates may be triggered in
cases of TBI [124,125] or be gained overtime in cases of
epilepsy [126] or ataxia [127], albeit not at the same cali-
ber found in neurodegenerative disorders. Alas, these
ndings display prospects of ameliorating toxic protein
aggregates beyond just healing AD or PD.
Natural products have tremendous clinical potential
portrayed in extensive reviews due to their antioxidative
nature, providing clearance of Ab[128] and tau protein
aggregates [129]. Squalamine, which has been known to
induce neuroprotective effects on Caenorhabditis elegans
model of PD [130], was studied in vitro and in vivo to sig-
nicantly reduce both the presence and toxicity of tau
protein aggregates in models of PD by competitive inhi-
bition of the toxic aggregates on neuronal structures
[79]. Previously mentioned bilobalide obtainable from
Ginkgo biloba was also shown to modulate PI3K pathway
and subsequently reducing APP and Ab[63]. Oral
administration of epigallocatechin-3-gallate (EGCG)
extractable from Camellia sinensis and Ceratonia siliqua
was reported to inhibit ERK and NF-kB pathways, reduc-
ing Aband tau prole in AD mice models [68,69], which
improved cognitive functions. Curcumin, the active
agent of Curcuma longa, was observed to not only cause
amelioration of Abaggregates at IC
as low as 1 mM
with better inhibitory effects compared to naproxen and
ibuprofen [64], but it also promotes reduction of phos-
phorylated tau burden within in vivo models [65]. Other
widely studied natural compounds in neurodegenerative
cases include ginsenosides [7375], azaphilones [61] and
resveratrol [7678], all of which pose incredible preclini-
cal potentials.
Immunotherapeutic approaches have also been
researched to promote clearance of both Aband tau
proteins, such as with ACI-35, a liposome-based system
delivering phosphorylated portions of tau acting as a
vaccine promising safety and efcacy both preclinically
and clinically [105]. In vivo studies of an active vaccine of
tau called AADvac1 has also been shown to induce
reduction of pathological tau proteins but not normal
physiological tau by 95% whilst showing commendable
safety prole [103]. Phase I clinical trial of AADvac1 (n=
30) has also generated favorable safety and efcacy pro-
les with two of the subjects withdrawing due to serious
adverse injection site reaction effects [104]. Passive
immunization approach of 77E9 and 43D has suggested
a potential in ameliorating not only tauopathies but also
amyloid burden in 3xTg-AD mice models [107]. Another
notable passive vaccination trial of RG7345 conducted
by Roche showed clearance of tau pathology by target-
ing phosphorylated tau (pS422) in TauPS2APP mice
models [106], which could be theoretically induced inter-
nalization via Fcgreceptor interaction with the antibody
epitope [131,132]. Much like conventional drug discov-
ery, development of immunotherapy to induce neuro-
plasticity is often met with safety or toxicity problems in
clinical settings, as in vivo effects do not always recapitu-
late human responses.
4.1.3. Neuroprotection and anti-neuroinammation
Degeneration of synapses and neuronal structures may
be mediated by prolonged inammation [133] and oxi-
dative stress [134]. Compounds capable in inducing neu-
roprotection or anti-neuroinammation may offer
another avenue in salvaging neuroplasticity. Antioxida-
tive natural products are popular in inducing protective
and anti-inammatory effects which are not necessarily
bound within neuronal settings, but have implications in
combating neurodegeneration and neuropsychological
disorders, such as depressive disorders [135] and autism
[136,137]. Previously stated natural products, including
curcumin [66,67], ginsenosides [138,139] and EGCG
[70,71], have been shown to yield intercalating effects in
promoting neuroplasticity, whereby one is to promote
neuroprotection. Edaravone, an intravenous medication
with well-known antioxidant properties, was approved
for stroke and amyotrophic lateral sclerosis [140], by
restoring superoxide dismutase and signicantly reduc-
ing tau hyperphosphorylation [80], as well as working
alongside the antioxidative Nrf2 signaling pathway [81]
to induce neuroprotective effects in various animal
Within models of oxidative damage induced by glu-
cocorticoids, insulin-like growth factor II (IGF-II) was
reported to display long-lasting antioxidative properties
accompanied by recovery of neuronal damage upon
assessment of postsynaptic density protein 95 (PSD-95)
and synaptophysin [96]. One strategy utilized IGF-II over-
expression by an adeno-associated virus 8 (AAV8) vec-
tors which reversed impairments in dendritic spine,
miniature excitatory postsynaptic currents (mEPSC) and
memory in Tg2576 AD mice models [97]. IGF-II also
seemed to be lowered within AD patients, whereby the
tau protein burden was also shown to be associated
with increasing level of IGF-II [141]. Related growth fac-
tors, namely Wnt [101,102,142], VEGF [100] and trans-
forming growth factor b(TGF-b)[98,143] have also been
reported in literature to directly impact synaptogenesis
via distinctive pathways stated further in Table 1.
Long-term estrogen therapy in post-menopausal
women has also been reported to induce synaptic plas-
ticity aside from neuroprotection via anti-inammatory
component modulation in senescent female brains of
animal models and patients [144] via B-cell lymphocyte
2 (Bcl-2) or Bcl-2-associated X (BAX) proteins [145].
Collectively, neuroprotective agents might be indicated
for TBI, stroke and depression, aside from neurodegener-
ative diseases to induce neuroplasticity. Anti-neuroin-
ammatory and neuroprotective components of these
compounds often present intercalating effects men-
tioned in previous subsection, thus calling for a more
thorough research to be conducted to create a
robust molecular approach in inducing long-lasting
4.2. Activity-dependent psychological stimuli and
Physical exercise, popular for its myriad of health-related
benets, is a key treatment option to induce neurogene-
sis, correlating strongly with improved memory and
attention as can be seen in rodents [146,147]. High-
intensity exercise has been shown to empirically increase
hippocampal neurogenesis [148] and medium
low-intensity exercise improves newborn neuronal sur-
vival [149,150], maturation and spatial memory [1,149]. A
study by van Praag et al. noted through running mice
that measurable electrophysiological changes occurred
in same regions where neurogenesis was stimulated,
pointing to a correlation of exercise-induced neurogene-
sis with learning and memory [151]. One study utilized
focal irradiation to inhibit hippocampal neurogenesis
that led to cognitive impairment, with IEG labeling prov-
ing that three weeks of wheel running amend this defect
[152]. Variations in exercise inuence different phases of
development, heightened hippocampal neurogenesis
found in Morris water maze, but only the addition of
platform triggered subsequent young neuron activation
[153,154]. The mechanism of physical exercise inducing
hippocampal neurogenesis in the sub-granular zone
niche sees functional unit and local neurons, as well as
cortical/subcortical areas outside of the niche, upregulat-
ing energy supplies and releasing regulation factors,
thereby enhancing hippocampal neurogenesis [155,156].
Physical exercise is a potential therapeutic option for
neurodegenerative diseases, as neurodegenerative dis-
eases AD and PD are age-dependent and hippocampal
neurogenesis decreases with age [157]. With age-related
reduction of neurogenesis and cognitive function linked
with reduced blood ow and decreased numbers of
exercise, exercise contradicts these dynamics by revital-
izing the aforementioned neurogenic niche with
increased blood ow directed to the brain and enhanced
hippocampal neurogenesis [155,158]. Deep breathing
exercises such as Tai Chi markedly reduced levels of
stress and inammation quantied through TNF-aand
IL-6 reduction in patients suffering from insomnia in a
randomized controlled trial [159].
It was noted that there is a critical time window of
»46 weeks for DGC maturation in rodents and slightly
longer in humans, whereby novel neurons experienced
heightened sensitivity toward physical exercise and
exhibited stronger synaptic plasticity relative to mature
DGCs. This and further detailed studies are needed to
pave the way for utilizing it to exercise intervention for
reducing brain aging, achieving the best effect as either
a direct intervention to reduce brain aging or as an
adjunctive therapeutic option for neurodegenerative dis-
eases [160]. In addition to being effective, its potential as
a marketable option of therapy has rooted the fact that
it is additionally low-cost, non-invasive, low-tech and a
Mental training through long-term meditation and
mindfulness practice regimens have been observed to
increase grey matter density within brain stems of
human subjects [161,162], which correlates with learning
and memory improvements. The anterior cingulate cor-
tex (ACC), a region often associated with meditation, has
been reported to play a role in an increased size of white
matter in meditation practitioners and not in control par-
ticipants, which further support the functionality of men-
tal training as a way to rewire neural connections for the
better [163]. Meditation also displays anti-inammatory
properties by signicantly reducing TNF-aas shown by
Epel et al.[164],while another study showed effects of
yogic meditation in reducing the level of pro-inamma-
tory NF-kB from caregivers of demented patients as a
stress model [165]. Effects of meditation which include
HDAC2 silencing [166] have also been suggested to
depend on the time that individuals have spent meditat-
ing [167]. Exercises also often include components of
concentration and focus which are commonly found in
meditation, and thus these activities may synergistically
promote activity-dependent neuroplasticity.
Effects of enrichment, both learning and exercise, are
noted strongly on neurogenesis (four weeks after BrdU
exposure) in dentate gyrus in a study conducted on
mice by van Praag et al. [151]. Table 2 further summa-
rizes the approaches of utilizing activities and therapies
to induce neuroplastic changes to the nervous system.
4.3. Mechanical and surgical procedures
Aside cellular responses elicited upon molecular or activ-
ity-dependent treatments, experimental mechanical
methods are available to be utilized in physically
Table 2. Activity-dependent psychological stimuli and therapies with potential in harnessing neuroplasticity.
Methods Mechanism of action and effects Related studies
Physical exercise High-intensity exercise increased hippocampal neurogenesis. [145]
Mediumlow-intensity exercise increased newborn neuronal survival, maturation and spatial memory. [1,146,147]
Running increased electrophysiological changes in the same area where neurogenesis is detectable in vivo.[148]
Wheel running of in vivo mice models for 3 weeks ameliorated previously detected cognitive impairment. [149]
Increased blood ow directed to brain with implications in enhanced hippocampal neurogenesis. [152,155]
Tai Chi practitioners have marked reduction of TNF-aand IL-6 as compared to control patients. [159]
Mental training Meditation increased grey matter density in brain stems of humans which correlate to learning and memory. [161,162]
Increase in white matter and ACC size in meditation practitioners. [163]
Insomnia patients undergoing long-term meditation have marked reductions of NF-kB and TNF-a.[164,165]
Meditation regimens promoted silencing of HDAC2. [166]
Effects of meditation may be dependent on the time spent by individuals in meditating. [167]
inducing electrical currents with the hope of inducing
long-lasting neuroplasticity in various neurological disor-
ders. Table 3 highlights the current mechanical and sur-
gical approaches to induce neuroplasticity.
A classic example of neuroplasticity-inducing proce-
dure is therapeutic hypothermia in cases of stroke. As
much as 80% of spinal cord injury (SCI) patients (n= 20)
were also reported to experience motoric restorations
upon undergoing localized extradural cord hypothermia
[168]. Such responses were also improved with the use
of steroids concomitantly [184]. Mild reductions of tem-
perature carried out in moderate epidural hypothermia
have been shown to be restorative, neuroprotective and
anti-neuroinammatory [169]. The molecular mecha-
nisms behind this phenomenon have been studied
throughout the years, with ndings in ischemic rat mod-
els such as reduction of heat shock protein 70 (Hsp70)
[170], intercellular adhesion molecule-1 (ICAM-1) [171]
and macrophage inammatory protein-3a(MIP-3a)
[172] have been identied. Therapeutic hypothermia has
also been shown to induce neurogenesis in brains of
neonatal rats [173] and global ischemic rats [174],
although contradictory ndings were reported by Lasar-
zik et al.whereby no long-term neurogenesis was
reported in post-ischemic SpragueDawley rat models
Despite the controversies, deep brain stimulation
(DBS) has been reported to promote beneciary neuro-
plastic, anti-anxiety and antidepressant properties in rats
[175178] and human subjects [179,180,186188].
Although ndings vary, DBS has been shown to induce
neurogenesis in prefrontal cortex of stress-induced rat
models [176] alongside nucleus accumbens of depres-
sive rat models [178]. Bambico et al.observed hippocam-
pal but not prefrontal cortex increase of BDNF upon DBS,
which might mediate neurogenesis [176]. These results
contradict ndings by Isabella [177], which stated that
there was a 21% reduction of BDNF in hippocampal
pyramidal cells, although p-CREB and DCX levels were
increased although not as signicantly as the positive
control. Biochemical reductions by DBS implants in tyro-
sine hydroxylase (TH) expression and neurotransmitters
norepinephrine (NE) and dopamine (DA) were also
reported, albeit not achieving statistical signicance
[178]. Several studies have highlighted memory salvage
and cognitive function improvement in dementia cases
[179,186]. DBS has also been utilized in Huntingtons dis-
ease (HD) whereby chorea was reduced as much as 60%
in six months [180], while other studies only observed
transient motoric benets due to disease aggressiveness
Finally, transcranial magnetic stimulation (TMS) in sin-
gle [189] or repetitive signals [181,190] has various appli-
cations in restoring motoric functions in TBI or SCI cases
when paired with peripheral nerve [182] and functional
electrical stimulation [183], measurable through electro-
myogram (EMG) and electroencephalogram (EEG). Limi-
tations may arise with TMS techniques if patients or
subjects have abnormal motor functions or are incapable
of voluntarily contracting their muscles. Despite the
Table 3. Mechanical and surgical procedures with potential in harnessing neuroplasticity.
Methods Mechanism of action and effects Related
Cord cooling alongside steroid administration and decompression restored some motoric functions in 80% of SCI
patients (n= 20) whereby two patients recovered the ability to walk.
Moderate epidural hypothermia signicantly reduced neuronal, glial and oligodendrocyte apoptosis which are
hallmarks of SCI and promoted functional recovery in vivo.
Hypothermia and ketoprofen as single and combinatorial agents were neuroprotective and reduced Hsp70 receptor
rampantly found in ischemic areas of in vivo models of the disease.
Signicantly reduced ICAM-1, monocytes, and microglia in in vivo models of experimental stroke. [171]
Suppressed MIP-3aand its receptor in astrocytes of focal cerebral ischemia in vivo models. [172]
Conferred neuroprotection to hypoxic-ischemia in vivo models by increasing Bcl-2 expression and signicantly
increasing amount of newborn immature and mature neurons.
Promoted salvage of CA1 neurons in global ischemic injury in vivo model and survivability of neurons that are newly
generated within the dentate gyrus. Functional performance of rats was improved chronically.
DBS Chronic ventromedial prefrontal cortex high-frequency DBS promoted robust memory enhancement in vivo via
upregulation of neurogenesis-related genes, DCX, Nes and Angpt2.
Signicant increase of hippocampal neurogenesis possibly mediated by increase in BDNF. [176]
Signicant increase of BrdU and DCX levels which mediate and/or signify neuronal differentiation and survival. [177]
In vivo nucleus accumbens DBS displayed lesser anxiety and reduced dopamine and norepinephrine levels in the
prefrontal cortex as well as modulation of dendritic lengths.
Bilateral low-frequency DBS treatment on AD patients (n= 6) showed improvement in cerebral glucose consumption
for 50% of study population accompanied by an increase in memory and cognition scores.
Reduced chorea scores and improved quality-of-life scores of HD patients (n= 6) in a pallidal DBS pilot trial. [180]
TMS Repetitive TMS (rTMS) at duration of 15 days signicantly improved visuospatial performance in patients (n=3)
suggesting induction of neuroplastic changes.
rTMS administered at 0.05 Hz for 30 minutes induced rapid and reversible plasticity in patients (n= 22) [182]
Spinal lesion recovery and creation of articial neuronal connection to bridge injured musculospinal and corticospinal
connections within in vivo monkey model.
seemingly viable potential of mechanical methods to
harness neuroplasticity, this phenomenon is still medi-
ated by molecular signals which may not be specically
targeted, and thus leading to a haphazard response.
5. Future directions
Given the nature of some methods in harnessing neuro-
plasticity being physical and some others psychological,
it is also essential for future studies to see the synergistic
effect of both when administered concomitantly or at
different stages of neuronal restoration. It is important to
tread cautiously through data as most are preclinical and
may eventually not be clinically suitable. Moreover,
some approaches only measured the markers of neuro-
plasticity and not evident physiological and psychologi-
cal effects, which may create a huge gap in certain
preclinical and translational studies of neuroplasticity.
More studies should rule out preclinical and clinical
data which are symptom-curative and not curative
6. Conclusion
Induction of neuroplasticity has been a longstanding
concept in neurorestoration. From molecular approaches
to activity-dependent neuroplasticity and, nally, surgi-
cal interventions, neuroplasticity has great potential as
an arsenal in combating various neurological and neuro-
degenerative diseases. However, there needs to be a
careful consideration upon viewing neuroplasticity
research as some are only symptom-curative. Neuroplas-
ticity has a long way to go before achieving a commer-
cial success, but with higher throughput technology,
novel techniques or molecules, and more collaborative
efforts; translational harnessing of neuroplasticity is not
at all impossible.
Disclosure statement
No potential conict of interest was reported by the authors.
Andrew Octavian Sasmita
Anna Pick Kiong Ling
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