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Harnessing Neuroplasticity: Modern Approaches and Clinical Future

April 2018
The International journal of neuroscience 128(11):1061-1077

DOI:10.1080/00207454.2018.1466781

Authors:

Andrew Octavian Sasmita

Max Planck Institute for Multidisciplinary Sciences

Joshua Kuruvilla

Universiti Sains Malaysia

Anna Pick Kiong Ling

International Medical University (IMU)

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.

Molecular compounds with their respective mechanisms of actions in harnessing neuroplasticity.

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Activity-dependent psychological stimuli and therapies with potential in harnessing neuroplasticity.

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Mechanical and surgical procedures with potential in harnessing neuroplasticity.

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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

ARTICLE HISTORY

Received 9 January 2018

Revised 22 March 2018

Accepted 13 April 2018

ABSTRACT

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 (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.

KEYWORDS

Neuroplasticity;

neurogenesis;

neurorestoration; physical

exercise; synaptogenesis

1. Introduction

An outdated dogma that was widely believed stated that

the number of neurons in the brain is ﬁxed since birth

[1,2]. Plasticity of the brain can be concisely described as

the brain’s 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 speciﬁcally, 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]andspeciﬁc illnesses occur almost

exclusively in adulthood, namely Parkinson’sdisease

(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 ﬁrst 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 anna_ling@imu.edu.my

INTERNATIONAL JOURNAL OF NEUROSCIENCE, 2018

https://doi.org/10.1080/00207454.2018.1466781

neurogenesis [12]. However, due to scaling up, concerns

do exist of signiﬁcant 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 speciﬁc

genes, and studying the corresponding effects in geneti-

cally modiﬁed 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-

lators’as Kempermann concisely noted which reﬂect

‘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

years.

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 inﬂux 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

[19–21]. 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-inﬂammatory components which may pro-

mote neuroinﬂammation 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 ﬁrst 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 DNA’s

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

identiﬁes NPC-speciﬁc metabolic biomarker and

2 A. O. SASMITA ET AL.

magnetic resonance imaging (MRI) which identiﬁed ‘posi-

tive correlation of cerebral blood volume and neurogene-

sis’basedontheircoupling[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 scientiﬁc community.

3. Neurological disorders and impact on

neuroplasticity

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 Alzheimer’s 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 deﬁcits being its most prominent chronic symp-

tom. Chronic accumulation of a-synuclein (SNCA) which

forms Lewy bodies in neurons would lead to neuronal

death, speciﬁcally, in substantia nigra [48], and this has

been identiﬁed as a hallmark of PD [49,50]. Lewy bodies

and Lewy neurites may be hallmark in a-synucleinopa-

thies[51], but PD patients speciﬁcally undergo extensive

motoric function impairment due to disruption of dopa-

minergic neurons essential in motoric signal relay. This

motoric deﬁcit 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 beneﬁcial 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 blood–brain 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

INTERNATIONAL JOURNAL OF NEUROSCIENCE 3

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

[90–92]. 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]

Signiﬁcant 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]

Signiﬁcantly reduced pro-inﬂammatory 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-neuroinﬂammatory 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]

Drugs

Edaravone SOD salvage and activation of Nrf2 in vivo to reduce tau burden and ameliorate cognitive deﬁcit. [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 ﬂuoxetine treatment. [84]

Epigenetic modulation

HDAC2 Deﬁciency 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. [89–92]

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 signiﬁcant Abclearance. [97]

TGF-bIncreased another NMDA receptor ligand, D-serine and induced synaptogenesis in cerebral cortical neurons. [98]

Uridine Compensation of P2Y receptor deﬁciency 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 neuroinﬂammatory in vivo model via various cytokines. [101]

Lentiviral vector expressing Wnt3a-HA enhanced recovery from focal ischemic injury in in vivo model. [102]

Immunization

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 proﬁle 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]

4 A. O. SASMITA ET AL.

neurons and promote synaptic plasticity in hippocam-

pal granule cells [84]. The effect of ﬂuoxetine 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-

ﬁed to compensate for P2Y receptor deﬁciency 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 signiﬁcantly 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 microﬂuidics 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 beneﬁcial 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

aggregates

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

ﬁndings 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-

niﬁcantly 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

INTERNATIONAL JOURNAL OF NEUROSCIENCE 5

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 proﬁle 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 [73–75], azaphilones [61] and

resveratrol [76–78], 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 efﬁcacy 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 proﬁle [103]. Phase I clinical trial of AADvac1 (n=

30) has also generated favorable safety and efﬁcacy pro-

ﬁles 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-neuroinﬂammation

Degeneration of synapses and neuronal structures may

be mediated by prolonged inﬂammation [133] and oxi-

dative stress [134]. Compounds capable in inducing neu-

roprotection or anti-neuroinﬂammation may offer

another avenue in salvaging neuroplasticity. Antioxida-

tive natural products are popular in inducing protective

and anti-inﬂammatory 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 signiﬁcantly reduc-

ing tau hyperphosphorylation [80], as well as working

alongside the antioxidative Nrf2 signaling pathway [81]

to induce neuroprotective effects in various animal

models.

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-inﬂammatory

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-

ﬂammatory 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

neuroplasticity.

4.2. Activity-dependent psychological stimuli and

therapies

Physical exercise, popular for its myriad of health-related

beneﬁts, 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–

6 A. O. SASMITA ET AL.

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 inﬂuence 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 ﬂow and decreased numbers of

exercise, exercise contradicts these dynamics by revital-

izing the aforementioned neurogenic niche with

increased blood ﬂow directed to the brain and enhanced

hippocampal neurogenesis [155,158]. Deep breathing

exercises such as Tai Chi markedly reduced levels of

stress and inﬂammation quantiﬁed 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

»4–6 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

non-drug.

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-inﬂammatory

properties by signiﬁcantly reducing TNF-aas shown by

Epel et al.[164],while another study showed effects of

yogic meditation in reducing the level of pro-inﬂamma-

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]

Medium–low-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 ﬂow 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]

INTERNATIONAL JOURNAL OF NEUROSCIENCE 7

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-neuroinﬂammatory [169]. The molecular mecha-

nisms behind this phenomenon have been studied

throughout the years, with ﬁndings in ischemic rat mod-

els such as reduction of heat shock protein 70 (Hsp70)

[170], intercellular adhesion molecule-1 (ICAM-1) [171]

and macrophage inﬂammatory protein-3a(MIP-3a)

[172] have been identiﬁed. Therapeutic hypothermia has

also been shown to induce neurogenesis in brains of

neonatal rats [173] and global ischemic rats [174],

although contradictory ﬁndings were reported by Lasar-

zik et al.whereby no long-term neurogenesis was

reported in post-ischemic Sprague–Dawley rat models

[185].

Despite the controversies, deep brain stimulation

(DBS) has been reported to promote beneﬁciary neuro-

plastic, anti-anxiety and antidepressant properties in rats

[175–178] and human subjects [179,180,186–188].

Although ﬁndings 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 ﬁndings 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 signiﬁcantly 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 signiﬁcance

[178]. Several studies have highlighted memory salvage

and cognitive function improvement in dementia cases

[179,186]. DBS has also been utilized in Huntington’s dis-

ease (HD) whereby chorea was reduced as much as 60%

in six months [180], while other studies only observed

transient motoric beneﬁts due to disease aggressiveness

[187,188].

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

studies

Therapeutic

hypothermia

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.

[168]

Moderate epidural hypothermia signiﬁcantly reduced neuronal, glial and oligodendrocyte apoptosis which are

hallmarks of SCI and promoted functional recovery in vivo.

[169]

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.

[170]

Signiﬁcantly 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 signiﬁcantly

increasing amount of newborn immature and mature neurons.

[173]

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.

[174]

DBS Chronic ventromedial prefrontal cortex high-frequency DBS promoted robust memory enhancement in vivo via

upregulation of neurogenesis-related genes, DCX, Nes and Angpt2.

[175]

Signiﬁcant increase of hippocampal neurogenesis possibly mediated by increase in BDNF. [176]

Signiﬁcant 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.

[178]

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.

[179]

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 signiﬁcantly improved visuospatial performance in patients (n=3)

suggesting induction of neuroplastic changes.

[181]

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 artiﬁcial neuronal connection to bridge injured musculospinal and corticospinal

connections within in vivo monkey model.

[183]

8 A. O. SASMITA ET AL.

seemingly viable potential of mechanical methods to

harness neuroplasticity, this phenomenon is still medi-

ated by molecular signals which may not be speciﬁcally

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

pathophysiologically.

6. Conclusion

Induction of neuroplasticity has been a longstanding

concept in neurorestoration. From molecular approaches

to activity-dependent neuroplasticity and, ﬁnally, 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 conﬂict of interest was reported by the authors.

ORCID

Andrew Octavian Sasmita http://orcid.org/0000-0001-7379-

6749

Anna Pick Kiong Ling http://orcid.org/0000-0003-0930-0619

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INTERNATIONAL JOURNAL OF NEUROSCIENCE 17

Harnessing Neuroplasticity: Modern Approaches and Clinical Future

Abstract and Figures