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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.
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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,
3Faculty of Health Sciences UiTM
Campus Puncak Alam, Puncak Alam
Selangor, Malaysia
4Department of Human Anatomy,
Faculty of medicine University Utar
Sungai Long Malaysia
Che Norma Mat Taib, Department of
Human Anatomy, Faculty of Medicine
and Health Sciences Universiti Putra
Malaysia, Serdang Selangor, Malaysia
Received: Oct 05, 2018
Accepted: Dec 20, 2018
Published: Jan 04, 2019
© 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
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
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-
ere has been a lot of research conducted on ADs
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
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.
Biomedical Research and Therapy, 6(1):2937- 2944
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
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
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), Downs 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 disease3335.
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, 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
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.
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
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-
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
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
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
e authors declare that they have no conicts of in-
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.
e authors would like to acknowledge Universiti Pu-
tra Malaysia for funding this research project (Grant
number GP-IPS 9535400).
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... 8 Alzheimer's disease is a heterogeneous disorder of multifactorial etiopathogenic factors with divergent clinical 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. 9 It is characterized by neurodegeneration associated with neuroinflammation. 10 Western medicine has revealed many genetic, cellular, and molecular processes that characterize AD such as protein aggregation and inflammation. ...
... 11 During the progression of AD, neurons from different parts of the brain are destroyed, including those areas that enable basic bodily functions like walking and swallowing. 9 Several studies report on the phytochemicals that have been clinically proven with significant anti-AD potentials. 7 ...
... 27,29 Among the better known aspects (Figure 2) of mental and brain functions enhanced by nootropics reported in the literature are: a) attention, b) blood circulation, c) concentration, d) cognition, e) intelligence, f) learning, g) memory, h) motivation, and, i) working memory. 9,27,29,37 ...
... The disease is characterized by selective neuronal loss in the hippocampus, amygdala, basal nucleus of Meynert, locus coeruleus, and neocortex (Connor et al., 1997). Due to a decline in hippocampal functions, the most common AD symptoms include gradual loss of memory, impaired verbal memory, deficiency in orientation and judgment, and behavioral and functional impairment (Alzheimer's Association, 2016;Sajjad et al., 2018;Chiroma et al., 2019). ...
... It is thought that the CNS is vulnerable to damage induced by free radicals because of the high lipid content, high oxygen utilization rate, and lower of antioxidant enzymes in the brain, compared to other tissues. Thus, free radicals appear to play an important role in some neurodegenerative disease such as PD, Down's syndrome (DS), head injury, cerebral ischemia-reperfusion, and AD (Murphy and Park, 2017;Chiroma et al., 2019;Siegel and Chauhan, 2000). ...
Full-text available
Alzheimer’s disease (AD) is a common neurodegenerative disease with a prevalence estimated to reach 115 million by 2050. It is characterized by abnormal extracellular accumulation of amyloid‑beta (Aβ) peptide and intracellular neurofibrillary tangles (NFTs) that result in neuro‑inflammation, synaptic dysfunction, neurotransmitter imbalance, neuronal loss, and dendritic changes. A hypothesis of neurotrophic factor (NTF) involvement in neurodegenerative diseases and their potential as a therapeutic tool has emerged. There are wide information gaps on this topic. However, consistent with this hypothesis, AD may be caused by a deficiency in neurotrophin proteins or receptors expression. In AD brains, an increase in nerve growth factor and a decrease in brain-derived neurotrophic factor in the hippocampus and certain neocortical regions, and a decrease in TrkA in the cortex and nucleus basalis has been observed. Thus, comparative data relating to recent hypotheses addressing NTF content and receptors in experimental animals and human brains, along with their potential roles in the treat ment of AD, are discussed in this review.
... The hypothesis for the cause of Alzheimer's disease consists of the cholinergic hypothesis, amyloid hypothesis, mitochondrial cascade hypothesis, Tau hypothesis [7] . Cholinergic hypothesis showing a dysfunctional cholinergic system that is adequate to produce memory deficit. ...
... Tau hypothesis deals with Tau, a microtubule-related phosphor protein, and the hyperphosphorylation of Tau proteins reduces the biological activity [8] . Mitochondria are quite vulnerable to oxidative stress, which may directly disturb their function which affects energy production, reduction of antioxidant enzymes, and loss of membrane potential and creating a further increase in ROS level that lastly produce cell death by caspase activation and apoptosis [7] . ...
Physalis minima L. belong to the family of Solanaceae has been traditionally used to prevent neurodegenerative disorders. The scientific values of the traditional claim haven't been explored yet. The present study aims to investigate the role of ethanol extract of Physalis minima L. fruit in learning, memory, and neurodegeneration in D- galactose induced Alzheimer' s model.The total phenolic and flavonoid content of the ethanol extracts of P. minima fruit was executed by Folin Ciocalteu and aluminium chloride colorimetric method respectively. It was further evaluated for nitric oxide scavenging assay and acetylcholinesterase inhibitory activity. The in vivo studies were performed by D- galactose induced Alzheimer' s model and the behavioural observations were executed using Y maze, Morris water maze, Elevated plus maze, Radial arm maze, and open field apparatus. Data were analysed by two-way ANOVA followed by Tukey' s multiple comparison test.The phytochemical analysis of the extract explored the presence of carbohydrates, glycosides, phenolics, flavonoids, proteins, terpenoids, steroids. The present study revealed the presence of 0.96 and 0.974 milli equivalence of flavonoids and phenolics. In vitro studies confirmed the role of antioxidant and acetylcholinesterase enzyme. The in vivo study revealed the reduced transfer latency, high corrected score in spontaneous alteration, low working and reference memory error, reduced escape latency, and normal locomotory activity. The histopathological analysis further confirmed the neuroprotective effect. The neuroprotective effect of P. minima provides new insight into the possible therapeutic use for treating Alzheimer' s disease and acetylcholinesterase inhibition may be a probable mechanism.Keywords: Physalis minima L; Alzheimer' s disease; D- galactose induced Alzheimer' s model; Acetylcholinesterase enzyme
... Based on the available literature searched, both on pre-clinical and clinical effects 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, further studied in AD patients [112]. According to the BCC publishing group, the global market of nutraceuticals should reach $336.1 billion by 2023 from $230.9 billion in 2018 at a compound annual growth rate (CAGR) of 7.8%, from 2018 to 2023. ...
Ageing comes with degeneration in many biological activities like impairment of cognition, intelligence, attention, and memory. The decline in all those mental capabilities would be due to the abnormal changes in neuronal architecture with increasing age, chronic oxidative stress and inflammatory state of the tissue, nutritional deficiency. Nootropics or smart drugs enhance memory, attention, creativity, and cognitive performance by affecting the synthesis and receptor binding of neurotransmitters in the brain, especially dopamine, serotonin, gamma-aminobutyric acid, glutamate, and acetylcholine. Nootropics have shown their positive effects in parkinson's, autism, alzheimer's, huntington's disorders, where impaired memory is the primary concern. Synthetic class of nootropics has limitations and reported exacerbation of other brain disorders (off label effects) or therapeutic failure in some instances. Nutraceuticals are dietary derived vitamins, minerals, herbal products, proteins, marine products, and probiotics. The health benefits derived from Nutraceuticals are increasing brain blood flow, reducing inflammation in nervous tissues, detoxifying toxins from the brain, balancing neurotransmitter turnover rate, correcting neuronal and receptor damages and facilitating synaptic transmission, good antioxidant properties and power of improving neuroplasticity of the brain that combat neurodegeneration. The demands for effective nootropics will remain high as the number of cases are increased tremendously.
... It was shown that ACh can likewise be generated by the catalyst carnitine acetyltransferase (CarAT) in few non-neuronal cells, for example, skeletal muscle cells and the urothelium [52]. Craig proposed a changed cholinergic theory by recommending that the diminution of the ACh neurotransmitter decreases the capacity of the brain to make up for secondary outcomes that accompany the aging cycle [53] Acetylcholinesterase[AChE] is a serine hydrolase basically found at neuromuscular intersections and synapses of the cholinergic brain. Its vital biological function is end of transmission of impulse at cholinergic neural connections by fast hydrolysis of the neurotransmitter ACh to acetate and choline [54]. ...
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Dementia is defined by the debilitation of cognition and behavior of individuals more than 65 y. Alzheimer's disease (AD) is the most pervasive pervasive form of dementia, afflicting around 47 million individuals worldwide. Oxidative damage is a significant component in the pathophysiology of Alzheimer's disease (AD). Assessment of Alzheimer's disease mind has shown a lot of oxidative harm, related with both trademark pathologies (senile plaques and neurofibrillary tangles) just as in typical seeming pyramidal neurons. By the by, the process that eventually causes disruption of redox balance and furthermore the origin of the free radicals are as yet hazy. There is likewise the accessibility of proof that oxidative stress may enhance the conglomeration and production of Aβ and furthermore help the polymerization just as phosphorylation of tau, subsequently making a pernicious cycle that invigorates the development and even commencement of Alzheimer's. These neurotic trademarks have complex proportional collaborations with cholinergic abrasions. This review may give complemental data for understanding the relationship between oxidative stress, amyloid plaques, tau proteins and cholinergic system in processing of AD.
... Transient and progressive cognitive impairment is due to deficiency of acetylcholine levels in the basal forebrain is one of the chief causes of AD 5 . Alzheimer's disease etiopathogenesis may also include extracellular deposits of senile plaques of beta-amyloid, intracellular aggregation of neurofibrillary tau protein tangles and increased oxidative stress 6 . Cholinergic neurodegeneration in Alzheimer's disease results in deficiency of acetylcholine at the areas of brain that causes impairment in cognitive functions like learning, thinking and memory 7 . ...
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Cocculus hirsutus, a tropical South Asian creeper,traditionally used as a diuretic, laxative, cardiotonic, anti-microbial, antidiabetic, anti-inflammatory and spermatogenic. However, the neuroprotective role was less explored; therefore, this researchwas conducted to investigate neuroprotective potentials of Cocculus hirsutus leaf hydroalcoholic extract in 6,7-Epoxytropine tropate (Scopolamine) induced cognitive impairment and oxidative lipid peroxidation in the brain of wistar albino rat. Scopolamine (1 mg/kg body weight, i.p.) was given in rats for 14 days to induce transient cognitive impairment. Donepezil (2 mg/kg body weight, orally) has been used for this research as a positive control. Behavioral studies were done using Morris water maze and elevated plus maze and neurobiochemical parameters such as acetylcholinesterase activity, reduced glutathione levels and activity of catalase were assessed in rats brain homogenate. Cocculus hirsutus leaf hydroalcoholic extract(200 mg/kg and 400 mg/kg) exhibited an improvement in spatial, exteroceptive learning and memory. The extract showed significant decline in the activity of acetylcholinesterase, enhancement of reduced glutathione levels and catalase activity (p<0.001). All the outcomes were assessed by Bonferroni post hoc tests with ANOVA for multiple comparison studies. This study reveals that hydroalcoholic extract of Cocculus hirsutusleaf acts as neuroprotective against scopolamine induced behavioral and neurobiochemical changes.
... Nootropics may also have neuroprotective effects reducing Aβ accumulation, synaptic dysfunctions, inflammation, apoptosis, and oxidative stress 69 . Nootropics have been demonstrated to protect against experimentally induced disruption of acquisition, retention or retrieval in animal models in either passive avoidance or similar procedures 70 . ...
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Objective: The objectives of this review are to explore the neuronal pathways and cellular and molecular mechanisms involved in both healthy and impaired cognitive function and to discuss the role of nootropics, in particular, those with cholinergic activity, as promising interventions to preserve and/or improve cognitive performance in patients in the symptomatic pre-dementia stage, known as mild cognitive impairment (MCI). Materials and methods: Papers were retrieved by a PubMed search, using different combinations of keywords (e.g., cognitive function AND aging AND nootropics), without limitations in terms of publication date or language. Results: Nootropics modulate the activities of specific brain pathways involving neurotransmitters and neuromodulators that have distinct roles in the cognitive processes. The nootropic L-a-glyceryl-phosphoryl-ethanolamine (L-a GPE), by virtue of its action as a phospholipid (PL) precursor and acetylcholine (Ach) donor, targets neural stem cell aging, cholinergic depletion, oxidative stress and microglia activation, loss of entorhinal cortex neurons, and reduced hippocampal volume. Cognitive reserve levels may be linked to the resilience and adaptability of the brain to cope with age-related cognitive decline. L-a GPE may contribute to cognitive reserve preservation via its neuronal well-being promoting action. Conclusions: The substantial burden of age-related cognitive decline demands effective long-term and well-tolerated interventions aimed at maximizing the span of effective functioning. The use of inappropriate medication may lower cognitive reserve, thus hastening the onset of symptomatic AD, while the use of nootropics, such as L-a GPE may contribute to cognitive reserve preservation via its neuronal well-being promoting action.
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Background: Alzheimer’s disease (AD) is a neurodegenerative disorder and the commonest cause of dementia among the aged people. D-galactose (D-gal) is a senescence agent, while aluminium is a known neurotoxin linked to pathogenesis of AD. The combined administration of rats with d-gal and aluminium chloride (AlCl3) is considered to be an easy and a cheap method to obtain an animal model of AD. The plant Centella asiatica (CA) is reported to exert neuroprotective effects both in vitro and in vivo. Therefore, this study explored the protective effects of CA on cognition and brain ultrastructure in d-gal and AlCl3 induced rats. Materials and methods: Rats were exposed to d-gal 60 mg/kg/b.wt/day + AlCl3 200 mg/kg/b.wt/day and CA (200, 400 and 800 mg/kg/b.wt/day) and 1 mg/kg/b.wt/day of donepezil for 70 days. Different cognitive paradigms viz. T maze spontaneous alternation, modified elevated plus maze and novel object recognition test, were used to evaluate full lesions of the hippocampus, spatial learning and memory and non-spatial learning and memory respectively. Nissl’s staining was used to determine the survival of hippocampus CA1 pyramidal cells, while transmission electron microscopy was used to check the ultrastructural changes. Results: The results revealed that d-gal and AlCl3 could significantly impair behavior and cognitive functions, besides causing damage to the hippocampal CA1 pyramidal neurons in rats. In addition, it also caused ultrastructural morphological alterations in rat hippocampus. Conversely, co-administration o;f CA, irrespective of the dosage used, alleviated the cognitive impairments and pathological changes in the rats comparable to donepezil. Conclusion: In conclusion the results suggest that CA could protect cognitive impairments and morphological alterations caused by d-gal and AlCl3 toxicity in rats. Biochemical and molecular studies are ongoing to elucidate the probable pharmacodynamics of CA.
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Introduction Centella asiatica is a plant used for centuries to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuates age‐related spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its mechanism of improving age‐related cognitive impairment. This study investigates the effects of CAW on a variety of cognitive tasks as well as on synaptic density and mitochondrial and antioxidant pathways. Methods Twenty‐month‐old CB6F1 mice were treated with CAW (2 mg/ml) in their drinking water for 2 weeks prior to behavioral testing. Learning, memory, and executive function were assessed using the novel object recognition task (NORT), object location memory task (OLM), and odor discrimination reversal learning (ODRL) test. Tissue was collected for Golgi analysis of spine density as well as assessment of mitochondrial, antioxidant, and synaptic proteins. Results CAW improved performance in all behavioral tests suggesting effects on hippocampal and cortical dependent memory as well as on prefrontal cortex mediated executive function. There was also an increase in synaptic density in the treated animals, which was accompanied by increased expression of the antioxidant response gene NRF2 as well as the mitochondrial marker porin. Conclusions These data show that CAW can increase synaptic density as well as antioxidant and mitochondrial proteins and improve multiple facets of age‐related cognitive impairment. Because mitochondrial dysfunction and oxidative stress also accompany cognitive impairment in many pathological conditions this suggests a broad therapeutic utility of CAW.
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Piracetam, a nootropic drug that has been clinically used for decades but remains enigmatic due to no distinct understanding of its mechanism of action. The present study aimed to investigate the role of caspase independent pathway in piracetam mediated neuroprotection. LPS administration caused significant alterations in oxidative stress related parameters like glutathione, glutathione reductase and increased lipid peroxidation. LPS administration also caused augmented expression of inflammatory cytokines and astrocytes activation. Piracetam treatment offered significant protection against LPS induced oxidative and inflammatory parameters and inhibited astrocytes activation. LPS administration caused augmented level of reactive oxygen species and depleted mitochondrial membrane potential which were attenuated with piracetam treatment. This study for the first time demonstrates the role of caspase independent death factors in piracetam induced neuroprotective effects in rat brain. Translocation of mitochondrial resident apoptosis inducing factor and endonuclease G to nucleus through cytosol after LPS administration was significantly blocked with piracetam treatment. Further, LPS induced DNA fragmentation along with up regulated Poly [ADP-ribose] polymerase 1 (PARP1) levels were also inhibited with piracetam treatment. Apoptotic death was confirmed by the cleavage of caspase 3 as well as histological alteration in rat brain regions. LPS administration caused significantly increased level of cleaved caspase 3, altered neuronal morphology and decreased neuronal density which were restored with piracetam treatment. Collectively our findings indicate that piracetam offered protection against LPS induced inflammatory responses and cellular death including its antioxidative antiapoptotic activity with its attenuation against mitochondria mediated caspase independent pathway. Download Link-
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Alzheimer’s disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer’s disease.
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Objective: To provide pilot data for the safety and efficacy of EGb 761 in the oldest-old patients (aged 80 or older). Materials and methods: In a retrospective analysis, we compared treatment outcomes with EGb 761 or donepezil over 12 months in 189 patients aged 80 years or older suffering from Alzheimer's disease (AD). Results: Over 12 months, there was no significant difference in cognitive decline, measured with the mini-mental state examination (MMSE) score, between donepezil and EGb 761 (p = 0.31). We found more adverse events in the donepezil group. Conclusion: Results suggest similar effects on cognitive symptoms from the use of EGb 761 in the treatment of dementia in AD together with favorable safety compared to donepezil. .
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Importance New therapeutic approaches for Alzheimer disease (AD) are needed. Objective To assess whether idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, is effective for symptomatic treatment of mild to moderate AD. Design, Setting, and Participants Three randomized clinical trials that included 2525 patients aged 50 years or older with mild to moderate AD (study 1: n = 933 patients at 119 sites; study 2: n = 858 at 158 sites; and study 3: n = 734 at 126 sites). The 24-week studies were conducted from October 2013 to January 2017; final follow-up on January 12, 2017. Interventions Idalopirdine (10, 30, or 60 mg/d) or placebo added to cholinesterase inhibitor treatment (donepezil in studies 1 and 2; donepezil, rivastigmine, or galantamine in study 3). Main Outcomes and Measures Primary end point in all 3 studies: change in cognition total score (range, 0-70; a lower score indicates less impairment) from baseline to 24 weeks measured by the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog); key secondary end points: Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change Scale and 23-item Activities of Daily Living Inventory scores. Dose group efficacy required a significant benefit over placebo for the primary end point and 1 or more key secondary end points. Safety data and adverse event profiles were recorded. Results Among 2525 patients randomized in the 3 trials (mean age, 74 years; mean baseline ADAS-Cog total score, 26; between 62% and 65% of participants were women), 2254 (89%) completed the studies. In study 1, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs placebo, 0.05 [95% CI, −0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, −0.59 to 1.26] for the 30-mg dose group). In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs placebo, 0.63 [95% CI, −0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs placebo, −0.55 [95% CI, −1.45 to 0.36]). Treatment-emergent adverse events occurred in between 55.4% and 69.7% of participants in the idalopirdine groups vs between 56.7% and 61.4% of participants in the placebo groups. Conclusions and Relevance In patients with mild to moderate AD, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment. These findings do not support the use of idalopirdine for the treatment of AD. Trial Registration Identifiers: NCT01955161, NCT02006641, and NCT02006654
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Alzheimer’s disease the most common form of dementia in the elderly is a neurodegenerative disease that affects 44 millions of people worldwide. The first treatments against Alzheimer’s disease are acetylcholinesterase inhibitors; however, these medications are associated with many side effects. Dichrocephala integrifolia is a traditional herb widely used by indigenous population of Cameroon to treat and prevent Alzheimer’s disease and for memory improvement. In this study, we evaluated the effect of the decoction prepared from leaves of D. integrifolia, on scopolamine-induced memory impairment in mice. Seven groups of six animals were used. The first two groups received distilled water for the distilled water and scopolamine groups. The four test groups received one of the four doses of the decoction of the plant (35, 87.5, 175 or 350 mg/kg p.o.) and the positive control group received tacrine (10 mg/kg), a cholinesterase inhibitor used in the treatment of Alzheimer’s disease, during 10 consecutive days. Scopolamine (1 mg/kg), a cholinergic receptor blocker, administered 30 min after treatments, was used to induce memory impairment to all groups except the distilled water group on day 10 of drug treatment. The behavioral paradigms used to evaluate the effects of the treatment were the elevated plus maze for learning and memory, Y maze for spatial short-term memory, the novel object recognition for recognition memory and Morris water maze for the evaluation of spatial long-term memory. After behavioral tests, animals were sacrificed and brains of a subset were used for the assessment of some biomarkers of oxidative stress (malondialdehyde and reduced glutathione levels) and for the evaluation of the acetylcholinesterase activity. From the remaining subset brains, histopathological analysis was performed. The results of this study showed that, D. integrifolia at the doses of 87.5 and 350 mg/kg significantly (p < 0.01) improved spatial short-term and long-term memory, by increasing the percentage of spontaneous alternation in the Y maze and reducing the escape latency in the Morris water maze. Furthermore, the results of histopathological evaluation showed that D. integrifolia attenuated the neuronal death in the hippocampus induced by scopolamine. The main finding of this work is that D. integrifolia improves learning capacities and counteracts the memory impairment induced by scopolamine. Thus, D. integrifolia can be a promising plant resource for the management of Alzheimer’s disease and memory loss.
Centella asiatica is a medicinal plant used to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuates β-amyloid (Aβ)-induced spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its in vivo mechanism of improving Aβ-related cognitive impairment. This study investigates the effects of CAW on learning, memory and executive function as well as mitochondrial function and antioxidant response in the 5xFAD model of Aβ accumulation. Seven month old 5xFAD female mice were treated with CAW (2 mg/mL) in their drinking water for two weeks prior to behavioral testing. Learning, memory and executive function were assessed using the object location memory task (OLM), conditioned fear response (CFR) and odor discrimination reversal learning (ODRL) test. Mitochondrial function was profiled using the Seahorse XF platform in hippocampal mitochondria isolated from these animals and tissue was harvested for assessment of mitochondrial, antioxidant and synaptic proteins. CAW improved performance in all behavioral tests in the 5xFAD but had no effect on WT animals. Hippocampal mitochondrial function was improved and hippocampal and cortical expression of mitochondrial genes was increased in CAW-treated 5xFAD mice. Gene expression of the transcription factor NRF2, as well as its antioxidant target enzymes, was also increased with CAW treatment in both WT and 5xFAD mice. CAW treatment also decreased Aβ-plaque burden in the hippocampus of treated 5xFAD mice but had no effect on plaques in the cortex. These data show that CAW can improve many facets of Aβ-related cognitive impairment in 5xFAD mice. Oral treatment with CAW also attenuates hippocampal mitochondrial dysfunction in these animals. Because mitochondrial dysfunction and oxidative stress accompany cognitive impairment in many pathological conditions beyond Alzheimer's disease, this suggests potentially broad therapeutic utility of CAW.
Extracts from Huperzia serrata (HS) function as a cholinesterase inhibitor and a glutamic acid receptor antagonist. We tested a supplement containing HS extracts, curcumin, and others in dementia patients and individuals with mild cognitive impairment (MCI) in an open label study. Most patients with Alzheimer's disease, dementia with Lewy bodies, and MCI individuals exhibited improvements in cognitive functions, as assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale Japanese version. The scores were significantly improved at 6-12 weeks compared with baseline scores (p = 0.007) and at 22-28 weeks (p = 0.004). Thus, this supplement may be administered to dementia patients as well as MCI individuals.
Alzheimer's disease (AD) is a severe age-dependent neurodegenerative disorder affecting millions of people, with no cure so far. The current treatments only achieve some temporary amelioration of the cognition symptoms. The main characteristics of the patient brains include the accumulation of amyloid plaques and neurofibrillary tangles (outside and inside the neurons) but also cholinergic deficit, increased oxidative stress and dyshomeostasis of transition metal ions. Considering the multi-factorial nature of AD, we report herein the development of a novel series of potential multi-target directed drugs which, besides the capacity to recover the cholinergic neurons, can also target other AD hallmarks. The novel series of tacrine-hydroxyphenylbenzimidazole (TAC-BIM) hybrid molecules has been designed, synthesized and studied for their multiple biological activities. These agents showed improved AChE inhibitory activity (IC50in nanomolar range), as compared with the single drug tacrine (TAC), and also a high inhibition of self-induced- and Cu-induced-Aβ aggregation (up to 75%). They also present moderate radical scavenging activity and metal chelating ability. In addition, neuroprotective studies revealed that all these tested compounds are able to inhibit the neurotoxicity induced by Aβ and Fe/AscH(-) in neuronal cells. Hence, for this set of hybrids, structure-activity relationships are discussed and finally it is highlighted their real promising interest as potential anti-AD drugs.