The use of nootropics in Alzheimer’s disease: is there light at the end of the tunnel?

Abstract

Background: The nootropic or simply known as smart drug is a common term given to any compound that is responsible for enhancing mental capability or performance. Alzheimer's disease is characterized clinically by lose of cognitive abilities and pathologically by two hallmark lesions, neurofibrillary tangles and senile plaques. It is unfortunate that AD has no cure yet. In this review attempt has been made to elucidate the general views on AD pathogenic hypotheses and common nootropics being used in AD research. Methods: Articles from credible scientific data bases such as Sciencdirect, Scopus Pubmed, and Google scholar were searched and retrieved using keywords nootropics', Alzheimer's disease', amyloid beta hypotheses', tau hypotheses', cholinergic hypotheses', oxidative stress' and cognitive impairments'. Results: The nootropics act as Ca-channel blockers, AChE inhibitors, glysine antagonists, antioxidants, serotonergic, dopaminergic and glutamic acid receptors antagonists. Conclusion: Based on the available literature searched, there is no doubts the nootropics are attenuating cognitive deficits in both preclinical and clinical studies on AD.

Full text

Review Article
1Department of Human Anatomy,
Faculty of Medicine and Health Sciences
Universiti Putra Malaysia, Serdang
Selangor, Malaysia
2Department of Human Anatomy,
Faculty of Basic Medical Sciences
University of Maiduguri, Borno state,
Nigeria
3Faculty of Health Sciences UiTM
Campus Puncak Alam, Puncak Alam
Selangor, Malaysia
4Department of Human Anatomy,
Faculty of medicine University Utar
Sungai Long Malaysia
Correspondence
Che Norma Mat Taib, Department of
Human Anatomy, Faculty of Medicine
and Health Sciences Universiti Putra
Malaysia, Serdang Selangor, Malaysia
Email: chenorma@upm.edu.my
History
•Received: Oct 05, 2018
•Accepted: Dec 20, 2018
•Published: Jan 04, 2019
DOI :
https://doi.org/10.15419/bmrat.v6i1.513
Copyright
© Biomedpress. This is an open-
access article distributed under the
terms of the Creative Commons
Attribution 4.0 International license.
The use of nootropics in Alzheimer’s disease: is there light at the
end of the tunnel?
Samaila Musa Chiroma1,2, Che Norma Mat Taib1,∗, Mohamad Aris Mohd Moklas1, Mohamad Tauk Hidayat
Baharuldin1, Zulkhairi Amom3, Saravanan Jagadeesan1,4
ABSTRACT
Background: The nootropic or simply known as smart drug is a common term given to any com-
pound that is responsible for enhancing mental capability or performance. Alzheimer's disease
is characterized clinically by lose of cognitive abilities and pathologically by two hallmark lesions,
neurobrillary tangles and senile plaques. It is unfortunate that AD has no cure yet. In this review
attempt has been made to elucidate the general views on AD pathogenic hypotheses and com-
mon nootropics being used in AD research. Methods: Articles from credible scientic data bases
such as Sciencdirect, Scopus Pubmed, and Google scholar were searched and retrieved using key-
words nootropics', Alzheimer's disease', amyloid beta hypotheses', tau hypotheses', cholinergic hy-
potheses', oxidative stress' and cognitive impairments'. Results: The nootropics act as Ca-channel
blockers, AChE inhibitors, glysine antagonists, antioxidants, serotonergic, dopaminergic and glu-
tamic acid receptors antagonists. Conclusion: Based on the available literature searched, there is
no doubts the nootropics are attenuating cognitive decits in both preclinical and clinical studies
on AD.
Key words: Alzheimer's disease, Amyloid beta hypotheses, Cholinergic hypotheses, Nootropics,
Oxidative stress and cognitive impairments, tau hypotheses
INTRODUCTION
Alzheimer’s disease (AD) is the most common type
of age-related dementia, characterized by a progres-
sive decline in hippocampal-dependent functions, in-
cluding cognitive deterioration, memory loss, behav-
ioral and functional disturbances, and functional im-
pairment1,2. Clinically, AD is diagnosed by dementia,
while pathologically it is diagnosed by two cardinal
lesions including senile plaques caused by the extra-
cellular deposits of amyloid beta brils and neurob-
rillary tangles formed by the abnormal intracellular
aggregation of tau protein 3. e etiopathogenesis of
AD is multifactorial. Oxidative stress and cholinergic
dysfunction have been suggested to play a vital role
in the onset and progression of the disease4,5. During
the progression of AD, neurons from dierent parts of
the brain are destroyed, including those areas that en-
able basic bodily functions like swallowing and walk-
ing. Hence, AD patients in the nal stage usually be-
come bedridden and eventually dies6. Advances in
science and technology, as well as good healthcare de-
livery, have increased life expectancy. Unfortunately,
it is accompanied by a cost of a higher frequency of
age-related diseases such as AD.
e “nootropic” or simply known as “smart drug”,
“memory-enhancing drug” or “brain booster” is a
common terminology given to compounds with the
ability to enhance mental performance7, although
people with a history of mental disorder may be sus-
ceptible to its adverse eects8. By denition, nootrop-
ics are compounds that increase mental abilities in-
cluding attention, concentration, memory, and moti-
vation7.
ere has been a lot of research conducted on AD’s
prevention and treatment strategies. Although dif-
ferent approaches were implemented to lessen the
progression of the disease, there is no cure for AD.
Hence, nootropics have been explored for this pur-
pose and have been yielding some promising results.
is review aimed to elucidate the general view on
AD pathogenic hypotheses and common nootrop-
ics being used in AD research. All the vital in-
formation required for this review was gathered by
searching the relevant keywords including, nootrop-
ics, Alzheimer’s disease, amyloid beta hypotheses, tau
hypotheses, cholinergic hypotheses, oxidative stress,
and cognitive impairments from published articles.
e search on nootropics is basically from 2011 to
2018, and reliable scientic databases were searched
namely ScienceDirect, Scopus, PubMed, and Google
Scholar.
Cite this article : Chiroma S M, Taib C N M, Moklas M A M, Baharuldin M T H, Amom Z, Jagadeesan S. The
use of nootropics in Alzheimer’s disease: is there light at the end of the tunnel?. Biomed. Res.
Ther.; 6(1):2937-2944.
2937
Biomedical Research and Therapy, 6(1):2937- 2944

ALZHEIMER’S DISEASE
PATHOGENESIS: GENERAL VIEWS
AD is a heterogeneous disorder with divergent clini-
cal symptomatology, various ages of onset, presence
or absence of germline mutations, degree and spread
of pathological changes, existence or non-existence of
risk factors and manifestation or non-appearance of
polymorphic susceptibility alleles. erefore, it is not
surprising that several hypotheses with “treatment in-
sinuations” have been proposed. However, it is unfor-
tunate that none of these hypotheses have led to tan-
gible treatment benets or a cure for AD 9. e most
widely acclaimed hypotheses in the scientic com-
munity include amyloid cascade hypotheses, tau hy-
potheses, cholinergic hypotheses, and oxidative stress
among others.
Amyloid cascade hypothesis
e vast majority of research in the eld of AD have
focused on amyloid cascade hypotheses since the
early 90s when AD research began to gain momen-
tum. e amyloid cascade hypothesis states that “the
pathogenic cascade of AD initiates upon accumula-
tion, oligomerization, and aggregation of the amyloid
beta peptide (Aβ) in extracellular deposits termed se-
nile plaques”10 . is aggregation of senile plaques
consequently stimulate the hyperphosphorylation of
tau protein, leading to the formation of neurobril-
lary tangles and neurodegeneration. e creeds of
the amyloid beta hypotheses are generally founded on
the existence of rare autosomal, early-onset forms of
AD, all of which involved mutations that aect the
processing of APP and resulted into increased pro-
duction and accumulation of Aβ. Based on these
explanations, the hypothesis assumes that reversing,
halting or preventing this process will cure the dis-
ease 10. is current evidence based on amyloid cas-
cade hypotheses does not support the pathogenesis
of sporadic form of AD which is 95% of AD cases
diagnosed 11. erefore, this view envisages that all
amyloid-beta-centered therapies for AD will continue
to be unsuccessful12. It is also unfortunate that devel-
oping alternative therapies could not be possible un-
less the etiology of AD is well understood.
Tau hypothesis
As senile plaque and neuronal loss does not com-
pletely correlate in AD, research have turned towards
other characteristics well known to AD, backing-
up the idea known as the “tau hypothesis”13. e
tau hypothesis of the pathogenesis of AD suggests
that tau abnormality facilitates neurotoxicity and neu-
rodegeneration and these are important contributors
to the development of AD14 . Tau is a microtubule-
associated protein (MAP) with amino acids ranging
from 352-441 in length. Six Tau isoforms in the adult
human brain are all derived from a single gene called
MAPT gene through alternative RNA splicing. e
primary role of tau is to regulate the stability of mi-
crotubules. Another physiological function of tau is
to allow signaling molecules, neurotransmitters, and
trophic factors to travel along axons15. Under nor-
mal physiological conditions, tau is in a continuous
dynamic equilibrium of short biding and detachment
to microtubules through phosphorylation by kinases
and dephosphorylation by phosphatases respectively.
ese cycles ensue an eective axonal transport16 .
Phosphorylation and dephosphorylation of tau hap-
pen under regular physiological conditions, with sup-
posed hyperphosphorylation happening in diseased
brains17 . e imbalance of phosphorylation causes
phosphorylated tau to detach from microtubules and
aggregate into dense paired-helical laments within
the cell, which eventually kills the neuron13. Anti-
bodies were developed to remove toxic tau with the
hope that by doing so, it will stop or slow the pro-
gression of AD18 . However, none of the antibodies
has been shown to be eective. ough the impact
of tau in distracting the functions of neurons is clear,
it has been shown that tau aggregation occurs at the
late stage of AD pathogenesis where intervention is
likely ineective. For tau hypotheses to be accepted,
there must be evidence that tau dysregulation is both
the main initiator and occurs very early in the disease
onset12.
The Cholinergic hypotheses of AD
e cholinergic hypothesis was the pioneer theory
suggested to explain the etiology of AD and had led
to the development of the only drug that is approved
by US food and drugs authority for the treatment of
mild to moderate AD19,20. e theory was based on
the fact that a loss of cholinergic activity is regularly
observed in AD patients brains21 . And, results from
multiple studies in human and animal have suggested
a role of acetylcholine in cognitive functions. ese
studies reported that blocking the central choliner-
gic activity with scopolamine could induce memory
decits in young subjects to behave like old individu-
als. On the other hand, administration of cholinergic
agonist physostigmine could reverse the cognitive im-
pairment22. Based on the cholinergic theory, another
2938
Biomedical Research and Therapy, 6(1):2937- 2944

type of cholinergic agonist, acetylcholinesterase in-
hibitors (AChEIs) were developed and have shown ef-
fectiveness in reversing cognitive impairments in AD
patients. Small improvements in cognitive abilities
have been reported in some clinical trials with AChEIs
as compared to placebo. However, the eects are not
permanent as patients showed cognitive deterioration
over time23,24. In addition, some AD patients are not
responding to AChEIs treatments, and the dierence
between responders and non-responders hasnot been
discovered25,26. Others have reported a decrease in
acetylcholine (ACh) level does not cause severe mem-
ory impairments in rats27,28 . Some researchers have
used this nding together with the failure of AChEIs
to cure AD as a reason to invalidate the cholinergic
hypotheses and shied their attention towards muta-
tions of APP genes, tau protein production, and Aβ
depositions as the more likely causative factors29,30.
Notwithstanding, other researchers continued to ex-
plore the role of ACh in the development of AD with
the hopes that one day they could explain the dysfunc-
tion of ACh in AD brains. Craig proposed a modied
cholinergic hypothesis by suggesting that the deple-
tion of the neurotransmitter ACh reduces the ability
of the brain to compensate for secondary insults that
come with the aging process31 . With the plethora of
AD risk factors, there are many questions needed to be
addressed relating to this hypothesis such as if aging
the only risk factor to be considered, how the mod-
ied cholinergic hypothesis explains the early onset
form of AD, and what causes of the ACh depletion?
ese questions will open discussion for more specic
causative factors and theories.
Oxidative stress hypotheses of AD
Recent studies have developed a keen interest in the
role of oxidative stress in neurologic disorders. ere
are indications that free radicals have a role in Parkin-
son’s disease (PD), Down’s syndrome (DS), head in-
jury, cerebral ischemia-reperfusion, and AD32 . e
CNS is particularly sensitive to damages induced by
free radical because of the high lipid content, high
oxygen utilization rate, and less presence of antiox-
idant enzymes in the brain compared to other tis-
sues33. e most interesting part of the oxidative
stress hypothesis for neurodegenerative diseases is
that accumulative oxidative injury over a long time
could lead to a late onset and progression of neurode-
generative disease33–35.
Studies on transgenic animal models, biological uids
from DS, mild cognitive impairment (MCI) and AD
patients, cell culture models, and postmortem brains
have demonstrated the involvement of oxidativestress
in the early stage of these disorders. Apart from an
increase of several oxidative stress markers in AD,
there is also evidence of lower antioxidant power in
the blood, CSF, and brain of AD patients36 . GSH
is the most predominant antioxidant in brain cells.
GSH can react with oxidized products and ROS to
create glutathione disulde (GSSG), either catalyzed
independently or by Glutathione Peroxidase (GPx).
e GSSG can be further reconverted back to GSH by
Glutathione Reductase (GR). Studies of lymphocytes
from AD patients have shown that the ratio between
reduced and oxidized glutathione (GSH/GSSG) is de-
creased37, this is also observed in the brain of AD pa-
tients38, and in the hippocampus of MCI patients39 .
In spite of several studies indicating the strong eects
of oxidative stress in the pathogenesis of neurodegen-
erative diseases and the use of antioxidants in reduc-
tion or prevention of damage caused by free radicals,
the ecacy in clinical trials is still controversial. Re-
sults from clinical trials using antioxidantsfor preven-
tion or treatment of AD have been so far disappoint-
ing, and there are several reasons for these failures36 .
e possible reasons for the failed clinical trials with
antioxidants could be; (i) small sample size enrolled
for the trials which are not good enough for statistical
analysis; (ii) short-term duration of antioxidant inter-
ventions which could not give enough time for the
desired outcomes to surface; (iii) dosages used dur-
ing the trials as high dose may produce adverse eect
while low dose could not be enough to produce good
results; (iv) poor choice of antioxidant for specic ef-
fects in most cases several antioxidants are needed in-
stead of one; (v) clinical conditions of the AD patients
enrolled for the trials since there are multiple signal-
ing pathways that can generate oxidative stress36,40 .
e arguments are still open-ended; should antioxi-
dant therapy be continued or discontinued, what are
the other possible options for preventing, slowing or
stopping AD progression and which of the hypotheses
should be adopted for more eective treatments?
NOOTROPICS
Nootropics, also known as “smart drugs”, are com-
pounds that have been developed over the past 35
years and perhaps the rst to be used for the treatment
of cognitive decits41 . e word nootropic coin from
Greek word (“noos” means “to mind” and “tropein”
means “to monitor”) is used to dene in a wide range,
any substance that is accredited with the ability to
enhance cognition and support healthy brain func-
tion42. e nootropics can be broadly classied into
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Biomedical Research and Therapy, 6(1):2937- 2944

Figure 1:Schematic representation of mechanism of action of nootropics: The nootropics improve learning
and memory through the blockage of Ca channels, inhibition of AChE activities, increases the level of antioxidants
and the increase in synaptic and mitochondrial response genes. They also provide neuroprotective potentials by
reducing the burdens of Aβaccumulation, synaptic dysfunctions, inammation, apoptosis, and oxidative stress.
two categories: the naturally occurring, such as Cen-
tella asiatica,Ginkgo biloba, and Panax quinquefolius
among others and synthetic nootropic, a laboratory
created compounds such as Piracetam, modanil, and
racetams41. ese types of substances include a num-
ber of agents like cholinergic, serotonergic, dopamin-
ergic, and antioxidants drugs. However, for this work,
we analyze nootropics that are specically used to tar-
get AD and few brain injuries, the reason for this
choice is to shed light on these promising agents in the
ght against AD. Below are highlights of some stud-
ies on nootropics and the major ndings, both ani-
mal and human studies were reviewed. To gain more
insight into the pharmacodynamics of nootropics, re-
cent studies on cell lines as well as review papers were
also considered.
Dichrocephala integrifolia improved cogni-
tive decits and attenuated neuronal death on
scopolamine-induced mouse model of AD43 , while
Pharmaceutical substance (PhS) based on amide
form Human leukemia dierential factor -6 (AF
HLDF-6) restores cognitive dysfunction in C57B1/6
transgenic mouse model of AD44 . Further, setin
reverses synaptic dysfunction, prevented neuro-
inammation, and improves memory in C57BL/6N
transgenic mouse model of cognitive dysfunction45 ,
and Cerebrolysin showed its neuroprotective poten-
tial by protecting graed Neural stem cells (NSCs)
in an APP Transgenic mice model of AD, hence it
could be a potential adjuvant therapy for AD when
combined with graing46 . Treatment of rat model of
AD with “2-(2-benzofuranyl)-2-imidazoline (2-BFI)
restored cognitive impairments, attenuated oxidative
stress, and protects against inammation and apop-
tosis in a dose-dependent manner47. Simvastatin
ameliorated cognitive impairment and inammation
in both rat model of AD and clinical patients of AD by
modulating the expression of MicroRNA106b (miR-
106b) as reported by Huang48 . Similarly, Centella
asiatica (CA) an Ayurvedic herb attenuated cognitive
impairments in d-galactose and aluminum chloride
induced rats through the prevention of apoptosis and
ultrastructural alterations of hippocampal neurons49.
CA was also reported to attenuate Aβinduced
oxidative stress and mitochondrial dysfunction in
vitro50,51 and improve spatial memory in animals52.
2940
Biomedical Research and Therapy, 6(1):2937- 2944

Increased in synaptic density and improvement in
executive functions was also observed in healthy
aged mice aer treatment with CA53 . Similarly, short
treatment with CA has increased the expression of
synaptic, mitochondrial, and antioxidant response
genes and improved dierent domains of cognitive
performance (executive function, memory, and
learning) in 5xFAD animals as well as reduced the
burden of Aβplaque burden in the hippocampus54.
Lipopolysaccharide (LPS) induced oxidative
stress, cell death and inammatory response in
Sprague Dawley rats were reversed by piracetam
through attenuation against mitochondria-mediated
caspase-independent pathway55 . A new Tacrine-
Hydroxyphenylbenzimidazole (TAC-BIM) hybrid
compound with excellent multifunctional activity
was developed and tested on Human neuroblastoma
SH-SY5Y Cell lines. e chemical inhibits AChE
activity better than drug tacrine by preventing self-
induced or Copper-induced Aβaggregation, having
antioxidant activity, and showing neuroprotective
capacity against Aβ56. Another nootropic com-
pound “L-theamine” protects SH-SY5Y cells against
glutamate-induced toxicity through inhibition of N-
methyl-D-aspartate (NMDA) glutamate subtype of
receptors and related pathways. Hence, L-theamine
may serve as prophylaxis and treatment for AD57.
Further, Piracetam exerts its neuroprotective eects
on PC12 cells, SH-SY5Y cells, and SH-SY5Y APPwt
cells by improving synaptic plasticity, maintaining
mitochondrial dynamic and neuritogenesis58 . In
addition, Noopept protects PC12 cells against
Aβ25-35 induced toxicity by inhibiting of oxidative
damage, preventing of calcium overload, suppressing
apoptosis, attenuating hyperphosphorylation of tau,
and ameliorating the neural outgrowth induced by
Aβ25-3559.
In addition to the preclinical studies, several clini-
cal trials were also conducted on nootropics in AD
patients and related dementias with impressive re-
sults. Galantamine was tested on 50 aggressive AD
patients and had a signicant improvement in Zarit
burden interview (ZBI) scores aer 12 weeks of treat-
ment60. Similarly, a historical cohort study was
conducted on 33 patients with severe disability af-
ter traumatic brain injury (TBI), administration of
cerebrolysin decreased mortality rate and improved
the functional recovery in TBI patients though it had
seizure as an adverse sideeect61. In another develop-
ment, huperzine A and curcumin were given as sup-
plements to AD, MCI, and other dementia patients.
e patients showed improvements in their cogni-
tive functions as measured by AD assessment scale-
cognitive subscale Japanese version (ADAS-Jcog)62.
Conversely, in three randomized clinical trials on
2525 AD patients addition of idalopirdine as an ad-
junct to cholinesterase inhibitors did not improve
cognitive decits over a period of 24 weeks63 . Fur-
ther, a retrospective observational study was con-
ducted on 189 AD patients, no signicant dierence
in cognitive decline was observed between donepezil
and Ginkgo biloba extract in over 12 months as mea-
sured with Mini mental state examination (MMSE)
score although more adverse side eects were seen
in donepezil64. Another retrospective study was con-
ducted on 2570 AD patients. e study suggested that
using of statins might be benecial to all AD patients
especially those with homozygous for Apolipoprotein
E4 (ApoE4)65 .
Because of the numerous preclinical and clinical stud-
ies on nootropics, several reviews were also conducted
to harness the impressive outcomes. e neurocog-
nitive eects of brahmi on cognitive impaired exper-
imental animals was reviewed, the authors opined
that brahmi could be a good candidate against AD
in human patients66 . Similarly, the use of galan-
tamie, donepezil, and rivastigmine in mild to mod-
erate AD provide modest cognitive function and be-
havior as reviewed by Mohammad 67 . Furthermore,
proling donepezil template into multipotent hybrids
through molecular docking has shown that it has anti-
cholinesterase activity with escalating antioxidant po-
tential68.
CONCLUSION
Scientists in the eld of AD research has been work-
ing vigorously on nootropics, which has expanded
the understanding of the mechanism of action of
both synthetic and natural nootropics for the past 35
years. e nootropics improve memory and learn-
ing by acting as Ca-channel blockers, AChEI, glycine
antagonists, antioxidants, serotonergic, dopaminer-
gic, and glutamic acid receptors antagonists. Fur-
ther, nootropics exhibit neuroprotective potentials by
decreasing the burden of Aβaccumulation, apopto-
sis, synaptic dysfunction, inammation and oxidative
stress (Figure 1). Based on the available literature
searched, both on pre-clinical and clinical eects of
the nootropics in AD, there is no doubt some of the
obtained results are encouraging. Some animal AD
models and cell lines responded well to the treatments
with nootropics, which was further studied in AD pa-
tients. However, clinical trials with a small number of
patients cannot serve as a basis for a meaningful as-
sessment of clinical ecacy. In addition, the data ob-
tained on the ecacy or inecacy of the nootropics
could be impractical because of the intrinsic problems
2941
Biomedical Research and Therapy, 6(1):2937- 2944

with clinical trials. For example, can patients who
responded well to Ca-channel blockers do the same
to AChE inhibitors or what pathological or physio-
logical dierence t hat s eparates r esponders t o non-
responders? Therefore, there is still a need to study
further on nootropics with multimodal targets, with
the hope it could nally bring light at the end of the
tunnel.
ABBREVIATIONS
2-BFI: 2-(2-benzofuranyl)-2-imidazoline
AChE: Acetylcholinesterase
AD: Alzheimer’s disease
ADAS-Jcog: AD assessment scale cognitive sub-scale
Japanese version
ApoE4: Apolipoprotein E4
Aβ: Beta amyloid
Cu: Copper
HLDF-6: Human leukemia dierential factor -6
LPS: Lipopolysacchride
MCI: Mild cognitive impairment
miR-106b: MicroRNA106b
MMSE: Mini mental state examination
NMDA: N-methyl-D-aspartate
NSCs: Neural stem cells
PhS: Pharmaceutical substance:
TAC-BIM: Tacrine-Hydroxyphenylbenzimidazole
TBI: Traumatic brain injury
ZBLPS: Zarit caregiver burden interview
COMPETING INTERESTS
e authors declare that they have no conicts of in-
terest.
AUTHORS’ CONTRIBUTIONS
All authors contributed to the design of the research.
MSC and SJ extracted the data and summarized it.
MTBH, CNMT, ZA and MAMM edited the rst dra.
All authors reviewed, commented and approved the
nal dra.
ACKNOWLEDGMENTS
e authors would like to acknowledge Universiti Pu-
tra Malaysia for funding this research project (Grant
number GP-IPS 9535400).
REFERENCES
1. Cooper EL, Ma MJ. Alzheimer Disease: clues from tradi-
tional and complementary medicine. Journal of Traditional
and Complementary Medicine. 2017;7:380–5. Available from:
DOI:10.1016/j.jtcme.2016.12.003.
2. Deshmukh R, Sharma V, Mehan S, Sharma N, Bedi KL. Ame-
lioration of intracerebroventricular streptozotocin induced
cognitive dysfunction and oxidative stress by vinpocetine–
a PDE1 inhibitor. European Journal of Pharmacology.
2009;620:49–56. Available from: DOI:10.1016/j.ejphar.2009.
08.027.
3. Firuzi O, Pratico D. Coxibs and Alzheimer’s disease: should
they stay or should they go? Annals of Neurology.
2006;59:219–28. Available from: DOI:10.1002/ana.20774.
4. Weinreb O, Amit T, Bar-Am O, Youdim MB. Ladostigil: a
novel multimodal neuroprotective drug with cholinesterase
and brain-selective monoamine oxidase inhibitory activ-
ities for Alzheimerś disease treatment. Current Drug
Targets. 2012;13:483–94. Available from: Doi:10.2174/
138945012799499794.
5. Santos DB, Peres KC, Ribeiro RP, Colle D, dos Santos AA, Mor-
eira EL. Probucol, a lipid-lowering drug, prevents cognitive
and hippocampal synaptic impairments induced by amyloid
? peptide in mice. Experimental Neurology. 2012;233:767–75.
Available from: DOI:10.1016/j.expneurol.2011.11.036.
6. Association A. 2018 Alzheimer”s disease facts and gures.
Alzheimerś & Dementia. 2018;14:367–429. Available from:
DOI:10.1016/j.jalz.2018.02.001.
7. Lanni C, Lenzken SC, Pascale A, Vecchio ID, Racchi M, Pistoia F.
Cognition enhancers between treating and doping the mind.
Pharmacological Research. 2008;57:196–213. Available from:
DOI:10.1016/j.phrs.2008.02.004.
8. Garcia HS, Reula LM, Fernandez AP, Sanchez VP, Lopez NO,
Heredero EM. Nootropics: emergents drugs associated with
new clinical challenges. European Psychiatry. 2017;41:S877–
8. Available from: DOI:10.1016/j.eurpsy.2017.01.1769.
9. Castellani RJ, Zhu X, Lee HG, Smith MA, Perry G. Molecu-
lar pathogenesis of Alzheimer’s disease: reductionist versus
expansionist approaches. International Journal of Molecu-
lar Sciences. 2009;10:1386–406. Available from: DOI:10.3390/
ijms10031386.
10. Karran E, Mercken M, Strooper BD. The amyloid cascade hy-
pothesis for Alzheimer’s disease: an appraisal for the devel-
opment of therapeutics. Nature Reviews Drug Discovery.
2011;10:698–712. Available from: DOI:10.1038/nrd3505.
11. Thonberg H, Chiang HH, Lilius L, Forsell C, Lindstrom AK,
Johansson C. Identication and description of three fami-
lies with familial Alzheimer disease that segregate variants in
the SORL1 gene. Acta Neuropathologica Communications.
2017;5:43. Available from: DOI:10.1186/s40478-017-0441- 9.
12. Castello MA, Soriano S. On the origin of Alzheimer’s disease.
Trials and tribulations of the amyloid hypothesis. Ageing Re -
search Reviews. 2014;13:10–2. Available from: DOI:10.1016/j.
arr.2013.10.001.
13. Iqbal K, Liu F, Gong CX, Alonso AC, Grundke-Iqbal I. Mecha-
nisms of tau-induced neurodegeneration. Acta Neuropatho-
logica. 2009;118:53–69. Available from: DOI:10.1007/s00401-
009-0486- 3.
14. Desai AK, Chand P. Tau-based Therapies for Alzheimer’ s Dis-
ease : wave of the Future? Primary Psychiatry. 2009;16:40–6.
15. Dixit R, Ross JL, Goldman YE, Holzbaur EL. Dierential reg-
ulation of dynein and kinesin motor proteins by tau. Sci-
ence. 2008;319:1086–9. Available from: DOI:10.1126/science.
1152993.
16. Kosik KS. Traveling the tau pathway: a personal account.
Journal of Alzheimer’s Disease. 2006;9:251–6. Available from:
Doi:10.3233/jad-2006- 9s327.
17. Lace GL, Wharton SB, Ince PG. A brief history of tau:
the evolving view of the microtubule-associated protein tau
in neurodegenerative diseases. Clinical Neuropathology.
2007;26:43–58. Available from: Doi:10.5414/npp26043.
18. Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney
SE. Anti-tau antibodies that block tau aggregate seeding in
vitro markedly decrease pathology and improve cognition in
vivo. Neuron. 2013;80:402–14. Available from: DOI:10.1016/j.
neuron.2013.07.046.
19. Bartus RT, Dean RL, Beer B, Lippa AS. The cholinergic hypoth-
esis of geriatric memory dysfunction. Science. 1982;217:408–
14. Available from: DOI:10.1126/science.7046051.
2942
Biomedical Research and Therapy, 6(1):2937- 2944

20. Bartus RT. On neurodegenerative diseases, models, and treat-
ment strategies: lessons learned and lessons forgotten a gen-
eration following the cholinergic hypothesis. Experimental
Neurology. 2000;163:495–529. Available from: DOI:10.1006/
exnr.2000.7397.
21. Davies P, Maloney AJ. Selective loss of central cholinergic neu-
rons in Alzheimer’s disease. Lancet. 1976;2:1403. Available
from: Doi:10.1016/s0140-6736(76)91936- x.
22. Bartus RT. Evidence for a direct cholinergic involvement in the
scopolamine-induced amnesia in monkeys: eects of concur-
rent administration of physostigmine and methylphenidate
with scopolamine. Pharmacology, Biochemistry, and Behav-
ior. 1978;9:833–6. Available from: Doi:10.1016/0091- 3057(78)
90364-7.
23. Doody RS, Dunn JK, Clark CM, Farlow M, Foster NL, Liao T.
Chronic donepezil treatment is associated with slowed cog-
nitive decline in Alzheimerś disease. Dementia and Geriatric
Cognitive Disorders. 2001;12:295–300. Available from: Doi:
10.1159/000051272.
24. Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E,
et al. Long-term donepezil treatment in 565 patients with
Alzheimerś disease (AD2000): randomised double-blind trial.
Lancet. 2004;363:2105–15. Available from: Doi:10.1016/
s0140-6736(04)16499- 4.
25. Connelly PJ, Prentice NP, Fowler KG. Predicting the out-
come of cholinesterase inhibitor treatment in Alzheimerś dis-
ease. Journal of Neurology, Neurosurgery, and Psychia-
try. 2005;76:320–4. Available from: DOI:10.1136/jnnp.2004.
043539.
26. Lemstra AW, Richard E, van Gool WA. Cholinesterase in-
hibitors in dementia: yes, no, or maybe? Age and Ageing.
2007;36:625–7. Available from: DOI:10.1093/ageing/afm117.
27. Parent MB, Baxter MG. Septohippocampal acetylcholine: in-
volved in but not necessary for learning and memory? Learn-
ing & Memory (Cold Spring Harbor, NY). 2004;11:9–20. Avail-
able from: DOI:10.1101/lm.69104.
28. Mesulam M. The cholinergic lesion of Alzheimer’s disease: piv-
otal factor or side show? Learning & Memory (Cold Spring
Harbor, NY). 2004;11:43–9. Available from: DOI:10.1101/lm.
69204.
29. Bartus RT. On neurodegenerative diseases, models, and treat-
ment strategies: lessons learned and lessons forgotten a gen-
eration following the cholinergic hypothesis. Experimental
Neurology. 2000;163:495–529. Available from: DOI:10.1006/
exnr.2000.7397.
30. Mesulam MM. Neuroplasticity failure in Alzheimer’s disease:
bridging the gap between plaques and tangles. Neuron.
1999;24:521–9. Available from: Doi:10.1016/s0896-6273(00)
81109-5.
31. Craig LA, Hong NS, McDonald RJ. Revisiting the cholinergic
hypothesis in the development of Alzheimerś disease. Neuro-
science and Biobehavioral Reviews. 2011;35:1397–409. Avail-
able from: DOI:10.1016/j.neubiorev.2011.03.001.
32. Markesbery WR. Oxidative stress hypothesis in Alzheimer’s
disease. Free Radic Biol Med. 1997;23:134–47.
33. Coyle JT, Puttfarcken P. Oxidative stress, glutamate, and neu-
rodegenerative disorders. Science. 1993;262:689–95. Avail-
able from: DOI:10.1126/science.7901908.
34. Dexter D, Carter C, Agid F, Agid Y, Lees AJ, Jenner P. Lipid
peroxidation as cause of nigral cell death in Parkinsonś dis-
ease. Lancet. 1986;2:639–40. Available from: Doi:10.1016/
s0140-6736(86)92471- 2.
35. Olanow CW. A radical hypothesis for neurodegeneration.
Trends in Neurosciences. 1993;16:439–44. Available from:
Doi:10.1016/0166-2236(93)90070- 3.
36. Persson T, Popescu BO, Cedazo-Minguez A. Oxidative stress
in Alzheimer’s disease: why did antioxidant therapy fail? Ox-
idative Medicine and Cellular Longevity. 2014;2014.
37. Calabrese V, Sultana R, Scapagnini G, Guagliano E, Sapienza
M, Bella R. Nitrosative stress, cellular stress response, and
thiol homeostasis in patients with Alzheimerś disease. Antiox-
idants & Redox Signalling. 2006;8:1975–86. Available from:
DOI:10.1089/ars.2006.8.1975.
38. Benzi G, Moretti A. Age - and peroxidative stress-related mod-
ications of the cerebral enzymatic activities linked to mito-
chondria and the glutathione system. Free Radical Biology &
Medicine. 1995;19:77–101. Available from: Doi:10.1016/0891-
5849(94)00244-e.
39. Sultana R, Piroddi M, Galli F, Buttereld DA. Protein levels
and activity of some antioxidant enzymes in hippocampus
of subjects with amnestic mild cognitive impairment. Neu-
rochemical Research. 2008;33:2540–6. Available from: DOI:
10.1007/s11064-008- 9593-0.
40. Feng Y, Wang X. Antioxidant therapies for Alzheimer’s
disease. Oxidative Medicine and Cellular Longevity.
2012;2012:472932. Available from: Doi:10.1155/2012/472932.
41. Suliman NA, Taib CNM, Moklas MAM, Adenan MI, Baharuldin
MTH, Basir R. Establishing Natural Nootropics: Recent
Molecular Enhancement Inuenced by Natural Nootropic.
Evidence-Based Complementary and Alternative Medicine.
2016;2016:4391375. Available from: 10.1155/2016/4391375.
42. Malykh AG, Sadaie MR. Piracetam and piracetam-like drugs:
from basic science to novel clinical applications to CNS disor-
ders. Drugs. 2010;70:287–312. Available from: Doi:10.2165/
11319230-000000000- 00000.
43. Kouemou NE, Taiwe GS, Moto FC, Pale S, Ngoupaye GT,
Njapdounke JS. Nootropic and neuroprotective eects of
Dichrocephala integrifolia on scopolamine mouse model of
Alzheimerś disease. Frontiers in Pharmacology. 2017;8:847.
Available from: DOI:10.3389/fphar.2017.00847.
44. Bogachouk AP, Storozheva ZI, TeleginGB, Chernov AS, Proshin
AT, Sherstnev VV, et al. Studying the Specic Activity of the
Amide Form of HLDF-6 Peptide using the Transgenic Model
of Alzheimer’s Disease. Acta Naturae (aoa epc). 2017;9.
45. Ahmad A, Ali T, Park HY, Badshah H, Rehman SU, Kim
MO. Neuroprotective Eect of Fisetin Against Amyloid-
Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinam-
mation, and Neurodegeneration in Adult Mice. Molecular
Neurobiology. 2017;54:2269–85. Available from: DOI:10.
1007/s12035-016- 9795-4.
46. Rockenstein E, Desplats P, Ubhi K, Mante M, Florio J, Adame
A. Neuro-peptide treatment with Cerebrolysin improves
the survival of neural stem cell grafts in an APP transgenic
model of Alzheimer disease. Stem Cell Research (Amsterdam).
2015;15:54–67. Available from: DOI:10.1016/j.scr.2015.04.008.
47. Tian JS, Zhai QJ, Zhao Y, Chen R, Zhao LD. 2-(2-benzofuranyl)-
2-imidazoline (2-BFI) improved the impairments in AD rat
models by inhibiting oxidative stress, inammationand apop-
tosis. Journal of Integrative Neuroscience. 2017;16:385–400.
Available from: Doi:10.3233/jin-170032.
48. Huang W, Li Z, Zhao L, Zhao W. Simvastatin ameliorate mem-
ory decits and inammation in clinical and mouse model
of Alzheimerś disease via modulating the expression of miR-
106b. Biomedicine and Pharmacotherapy. 2017;92:46–57.
Available from: DOI:10.1016/j.biopha.2017.05.060.
49. Chiroma SM, Baharuldin MTH, Taib CNM, Amom Z, Ja-
gadeesan S, Adenan MI. Protective eect of Centella asiat-
ica against D-galactose and aluminium chloride induced rats:
behavioral and ultrastructural approaches. Biomedicine and
Pharmacotherapy. 2019;109:853–64. Available from: DOI:
10.1016/j.biopha.2018.10.111.
50. Gray NE, Sampath H, Zweig JA, Quinn JF, Soumyanath A. Cen-
tella asiatica Attenuates Amyloid-?-Induced Oxidative Stress
and Mitochondrial Dysfunction. Journal of Alzheimerś Dis-
ease. 2015;45:933–46. Available from: Doi:10.3233/jad-
142217.
51. Gray NE, Zweig JA, Murchison C, Caruso M, Matthews DG,
Kawamoto C. Centella asiatica attenuates A?-induced neu-
rodegenerative spine loss and dendritic simplication. Neuro-
science Letters. 2017;646:24–9. Available from: DOI:10.1016/
j.neulet.2017.02.072.
52. Soumyanath A, Zhong YP, Henson E, Wadsworth T, Bishop J,
Gold BG, et al. Centella asiatica extract improves behavioral
2943
Biomedical Research and Therapy, 6(1):2937- 2944

decits in a mouse model of Alzheimerś disease: investigation
of a possible mechanism of action. International Journal of
Alzheimer’s Disease. 2012;2012.
53. Gray NE, Zweig JA, Caruso M, Martin MD, Zhu JY, Quinn JF.
Centella asiatica increases hippocampal synaptic density and
improves memory and executive function in aged mice. Brain
and Behavior. 2018;8:e01024. Available from: DOI:10.1002/
brb3.1024.
54. Gray NE, Zweig JA, Caruso M, Zhu JY, Wright KM, Quinn JF.
Centella asiatica attenuates hippocampal mitochondrial dys-
function and improves memory and executive function in ?-
amyloid overexpressing mice. Molecular and Cellular Neu-
rosciences. 2018;93:1–9. Available from: DOI:10.1016/j.mcn.
2018.09.002.
55. Verma DK, Gupta S, Biswas J, Joshi N, Singh A, Gupta P, et al.
New therapeutic activity of metabolic enhancer piracetam in
treatment of neurodegenerative disease: Participation of cas-
pase independent death factors, oxidative stress, inamma-
tory responses and apoptosis. Biochimica et Biophysica Acta
(BBA)-Molecular Basis of Disease. 2018;1864:2078–2096.
56. Hiremathad A, Keri RS, Esteves AR, Cardoso SM, Chaves S,
Santos MA. Novel Tacrine-Hydroxyphenylbenzimidazole
hybrids as potential multitarget drug candidates for
Alzheimerś disease. European Journal of Medic-
inal Chemistry. 2018;148:255–67. Available from:
DOI:10.1016/j.ejmech.2018.02.023.
57. Di X, YanJ, Zhao Y, Zhang J, Shi Z, Chang Y. L-theanine protects
the APP (Swedish mutation) transgenic SH-SY5Y cell against
glutamate-induced excitotoxicity via inhibition of the NMDA
receptor pathway. Neuroscience. 2010;168:778–86. Available
from: DOI:10.1016/j.neuroscience.2010.04.019.
58. Stockburger C, Miano D, Pallas T, Friedland K, Muller WE. En-
hanced Neuroplasticity by the Metabolic Enhancer Piracetam
Associated with Improved Mitochondrial Dynamics and Al-
tered Permeability Transition Pore Function. Neural Plastic-
ity. 2016;2016:8075903. Available from: Doi:10.1155/2016/
8075903.
59. Ostrovskaya RU, Vakhitova YV,Kuzmina US, Salimgareeva MK,
Zainullina LF, Gudasheva TA. Neuroprotective eect of novel
cognitive enhancer noopept on AD-related cellular model in-
volves the attenuation of apoptosis and tau hyperphospho-
rylation. Journal of Biomedical Science. 2014;21:74. Available
from: DOI:10.1186/s12929-014- 0074-2.
60. Nakayama S, Suda A, Nakanishi A, Motoi Y, Hattori N. Galan-
tamine Response Associates with Agitation and the Prefrontal
Cortex in Patients with Alzheimerś Disease. Journal of
Alzheimer’s Disease. 2017;57:267–73. Available from: Doi:
10.3233/jad-160902.
61. Khalili H, Niakan A, Ghaarpasand F. Eects of cerebrolysin
on functional recovery in patients with severe disability af-
ter traumatic brain injury: A historical cohort study. Clinical
Neurology and Neurosurgery. 2017;152:34–8. Available from:
DOI:10.1016/j.clineuro.2016.11.011.
62. TabiraT, Kawamura N. A study of a supplement containing hu-
perzine A and curcumin in dementia patients and individuals
with mild cognitive impairment. Journal of Alzheimerś Dis-
ease. 2018;63:75–8. Available from: Doi:10.3233/jad-171154.
63. Atri A, Frolich L, Ballard C, Tariot PN, Molinuevo JL, Boneva N.
Eect of idalopirdine as adjunct to cholinesterase inhibitors
on change in cognition in patients with alzheimer disease:
three randomized clinical trials. Journal of the American Med-
ical Association. 2018;319:130–42. Available from: DOI:10.
1001/jama.2017.20373.
64. Rapp M, Burkart M, Kohlmann T, Bohlken J. Similar treatment
outcomes with Ginkgo biloba extract EGb 761 and donepezil
in Alzheimerś dementia in very old age: A retrospective ob-
servational study. International Journal of Clinical Pharmacol-
ogy and Therapeutics. 2018;56:130–3. Available from: Doi:
10.5414/cp203103.
65. Geifman N, Brinton RD, Kennedy RE, Schneider LS, Butte AJ.
Evidence for benet of statins to modify cognitive decline and
risk in Alzheimer’s disease. Alzheimer’s Research & Therapy.
2017;9:10. Available from: DOI:10.1186/s13195-017-0237- y.
66. Chaudhari KS, Tiwari NR, Tiwari RR, Sharma RS. Neurocog-
nitive eect of nootropic drug Brahmi (Bacopa monnieri) in
Alzheimerś disease. Annals of Neurosciences. 2017;24:111–
22. Available from: Doi:10.1159/000475900.
67. Mohammad D, Chan P, Bradley J, Lanctot K , Herrmann N.
Acetylcholinesterase inhibitors for treating dementia symp-
toms - a safety evaluation. Exper t Opinion on Drug Safety.
2017;16:1009–19. Available from: Doi:10.1080/14740338.2017.
1351540.
68. Mezeiova E, Spilovska K, Nepovimova E, Gorecki L, Soukup O,
Dolezal R. Proling donepezil template into multipotent hy-
brids with antioxidant properties. Journal of Enzyme Inhi-
bition and Medicinal Chemistry. 2018;33:583–606. Available
from: Doi:10.1080/14756366.2018.1443326.
2944
Biomedical Research and Therapy, 6(1):2937- 2944