Therapeutic approaches of prominent medicinal plants for targetting Alzheimer's disease

Abstract

Alzheimer’s disease is a clinical syndrome that causes progressive cognitive and mental impairment of an individual affected with this condition. Recent epidemiological statistics showed that, more than 5.8 million American population is suffering from Alzheimer’s associated dementia. Therapeutic advancements has been made to avert cognitive and memory problems but so far, there is no definitive treatment for this disease. Several drug therapies approved by Federal Drug Administration, symptomatically treat this condition without impeding the disease progression. However, these drugs despite cognitive amelioration give rise to several adverse effects and disrupts various cellular proteins that are involved in preventing deleterious damage to the nervous system. Therefore, traditional medicinal plants hold promising lead compounds that can be used in Alzheimer’s disease research due to their medieval use in memory deficits. In this review, we highlighted renowned five medicinal plants activity against this disease and also briefly discussed their molecular action on cellular proteins. Thus, it is concluded from our review that several bioactive compounds procured from these medicinal plants could serve as potential agent against this disease, however, further studies and extensive clinical trials are required to confirm their therapeutic efficacy in this disease.

Full text

15
Introduction
Dementia is a chronic mental disorder
that mainly aects elderly populati-
on and this condition is attributed to
Alzheimer’s disease (AD). This disease
is characterized by the appearance of
some characteristic hallmarks such
as deposition and accumulation of
extracellular amyloid plaques, neu-
roinflammation, oxidative stress and
development of intracellular neuro-
brillary tangles, synaptolysis (loss of
synapsis) and neuronal apoptosis ac-
companied with defensive glial system
activation (1–4)frontotemporal lobar
degeneration (FTD. These deleterious
events inside the brain leads to neu-
rodegeneration of cerebral cortex and
hippocampus aecting cognitive and
memory functions. So far, progress
have been made in therapeutic sector
in order to alleviate AD disease sym-
ptoms, but still this disease remains
incurable. Epidemiological studies re-
vealed important risk factor for the on-
set of Alzheimer’s disease is age and
its incidence rate rise exponentially
aer 65 years of age (5). It is estimated
that, prevalence of this is expected to
increase two folds within 20 years as
average life expectancy increases in
developing countries (5).
In Alzheimer’s disease, degeneration of
neurons causes cognitive impairment
along with substantial alterations in
shape and number of dendritic spines
preceding to neuronal loss (6,7). As the
disease progresses, modications in
neurotransmitters expression occurs
(8), synaptotoxicity (9), accretion and
deposition of amyloid plaque extracel-
lularly (10)longitudinal, observational
study that has collected many biomar-
kers since 2004. Recent publications
highlight the multifactorial nature of la-
te-onset AD. We discuss selected topics
that provide insights into AD progres-
sion and outline how this knowledge
may improve clinical trials. Methods
We used standard methods to identify
nearly 600 publications using ADNI
data from 2016 and 2017 (listed in Sup-
plementary Material and searchable at
http://adni.loni.usc.edu/news-publi-
cations/publications/ and intracellular
tau protein accumulation and its corres-
ponding hyperphosphorlation (11) . This
event leads to the production of reacti-
ve oxygen species (4,12) causing neu-
ronal mitochondria dysfunction (13),
and deterioration of blood brain barrier
(14,15) allowing Armageddon of toxins,
pathogens and unnecessary substan-
ces inside the brain, thus exacerbating
neurodegeneration, risk of developing
infection, disruption of glial cells and
demyelination of brain matter.
In the past few decades, attempts
have been made to slow down the
Fahad Hassan Shaha, Syed Turab Ali Shaha, Saad Salmanb, Jawaria Idreesc, Fariha Idreesc, Abid Ali Khana
Therapeutic approaches of
prominent medicinal plants for
targetting Alzheimer's disease
progression of Alzheimer’s disease by
introducing anti-cholinesterase’s, and
N-methyl-D-aspartate (NMDA) receptor
antagonists. These drugs negatively
intervene with the receptors that are
involved in the pathogenesis of this
disease and thus, reviving the cogni-
tive and memory decline. However,
these medications act on its specic
receptor for a brief period alleviating
the disease symptoms whereas igno-
ring other neurotoxic factors (amyloid
plaques, neurobrillary tangles and
oxidative stress) that disrupt neurova-
scular barrier (14,15), aect glial sys-
tem (16) and instigate neuroinflamma-
tion (17). Moreover, these drugs also
give rise to multiple adverse eects
including dysfunctioning of DNA po-
lymerase beta that is responsible for
repairing neural DNA damage induced
by amyloid plaques and other protein
factors (18,19). Therefore, new and al-
ternative drugs or therapies are neces-
sary to be screened and discovered in
Abstract
Alzheimer’s disease is a clinical syndrome that causes progressive cognitive and mental
impairment of an individual aected with this condition. Recent epidemiological statistics
showed that, more than 5.8 million American population is suering from Alzheimer’s asso-
ciated dementia. Therapeutic advancements has been made to avert cognitive and memory
problems but so far, there is no denitive treatment for this disease. Several drug therapies
approved by Federal Drug Administration, symptomatically treat this condition without impe-
ding the disease progression. However, these drugs despite cognitive amelioration give rise
to several adverse eects and disrupts various cellular proteins that are involved in preventing
deleterious damage to the nervous system. Therefore, traditional medicinal plants hold pro-
mising lead compounds that can be used in Alzheimer’s disease research due to their medie-
val use in memory decits. In this review, we highlighted renowned ve medicinal plants acti-
vity against this disease and also briefly discussed their molecular action on cellular proteins.
Thus, it is concluded from our review that several bioactive compounds procured from these
medicinal plants could serve as potenzial agent against this disease, however, further studies
and extensive clinical trials are required to conrm their therapeutic ecacy in this disease.
Keywords
Medicinal Plants, Alzheimer’s disease, cognitive, memory, neural regeneration
Z Arznei- Gewurzpa | 24 (1): 15–18 | ERLING Verlag GmbH & Co. KG | 2020
ReviewF. H. Shah et al. | Therapeutic approaches of prominent medicinal plants for targetting Alzheimer's disease

16 Z Arznei- Gewurzpa | 24 (1): 15–18 | ERLING Verlag GmbH & Co. KG | 2020
order to prevent disease progression,
neurovascular and DNA damage.
Medicinal plants are famous for their
traditional use in Chinese and Indian
ayurvedic medicine, as these plants
contain wide range of bioactive com-
pounds that have been used to treat
dierent type of illness (20). These
plants are comparatively less toxic and
not only therapeutically intervene with
the disease progression but also invol-
ved in constructing temporary barrier
around delicate organs to prevent any
injury, sequestering reactive oxygen
species whereas capable of activating
various cellular systems to repair the
damage induced due to disease pa-
thology (21–23)dementia has emer-
ged as a serious global health issue.
Alzheimer’s disease (AD. However,
their neurovascular rehabilitation and
therapeutic activity of medicinal plants
in Alzheimer’s disease still remain elu-
sive. Therefore, in this review, we have
selected some famous Chinese and
Indian medicinal herbs to explore and
summarize their peculiar curative acti-
vity in Alzheimer’s disease.
Gingko biloba
Gingko biloba, known to have nu-
merous medicinal applications that
are in practice since medieval times.
This plants is the only extant species
of division Ginkophyta while the rest
haven’t survived due to various envi-
ronmental and evolutionary events.
Phytochemical prole of Gingko bilo-
ba leaves is composed of Terpene tri-
lactones that include bilobalides and
ginkgolides, proanthocyanidins, phe-
nolic acids, and flavonoid glycosides
comprised of myricetin, kaempferol,
isorhamnetin and quercetin (24,25).
But scientists have developed a pe-
culiar approach to utilize these afore-
mentioned phytochemicals by using
Ginkgo’s extracts known as EGb761.
As single phytochemical component
show no probable therapeutic inter-
action (26). EGb761 extract is known
for its versatile broad spectrum phar-
macological activities such as anti-oxi-
dant, antimicrobial, anti-cancer, hepa-
toprotective activity and inflammation
(24,27). However, their medicinal pro-
perties has been greatly explored in
Neurotherapeutics especially in cogni-
tive and memory disorders associated
with Alzheimer’s disease and aging
(28–30). Preliminary studies descri-
bed neuroprotective activity of EGb761
against hypoxia and oxidative stress
induced mouse models (28,31–33). It
was observed that under invitro stress
conditions, this extract preserved the
neuronal integrity by reducing the
intracellular glutathione (GSH) and
glutathione peroxidase (GSH-Px) con-
centration and prevented hippocam-
pal DNA damage by increasing hippo-
campal 8-hydroxy-2'-deoxyguanosine
(8-OHdG) expression (34). Moreover,
it has the property to rejuvenate CAI (A
part of hippocampus responsible for
memory formation) and mitochondri-
al gene expression (35–37). Another
issue associated with AD is the activa-
tion of inflammatory pathway (NF-kB)
due to deposition of amyloid plaques
in the brain and formation of neuro-
brillary tangles causing degeneration
of vital neurons that are responsible
for psychobehavioural and cognitive
functioning (38). Therefore, by utili-
zing the concentrated (~100–120 mg)
extract of EGb761 in induced inflamm-
atory models of mice alleviate inflam-
mation by suppressing the expression
of NF-kB and preventing the cognitive
decline and upregulating doublecortin
(DCX) a neuroblast dierentiation
factor that promotes neurogenesis of
deteriorated neurons (39,40). Further-
more, it reduces amyloid plaques for-
mation by minimizing the expression
of Amyloid precursor protein and blo-
cking all necessary molecular targets
acetylcholinesterase in specic that
exacerbate neurotoxicity of amyloid
aggregates, hence restoring proper
functioning behavioral and cognitive
pathway (41,42). All these activities
carried in mouse models were dose
dependent and detailed literature
review indicated that 100–240 mg
of extract is an optimum dose to ful-
ly exploit its therapeutic potenzial
in this disease. But, according to the
data obtained numerous clinical tri-
als in which EGb761 extract (120–240
mg) was used as principal therapeutic
agent to assess its pharmacological
ecacy in the amelioration of cog-
nitive and memory functionality re-
mained inconclusive as both placebo
and EGb761 nearly showed the same
results (43). Therefore, further studies
are required to study and to improve
its pharmacokinetic properties to fully
enhance its usefulness in age related
dementia and Alzheimer’s disease.
Rosmarinus ocinalis
Another essential medicinal plant
whose aerial parts possess spectrum
of medicinal properties and it is indi-
genous to Mediterranean region and
distributed all over the world due to
its imminent importance in commer-
cial and medicinal uses (44). Variety
of dierent pharmacologically active
constituents have been isolated and
these include essential oils, flavono-
ids, phenolic acids and polyphenolic
diterpenoids (45,46). These active
chemical constituents are renowned
Review

17
Z Arznei- Gewurzpa | 24 (1): 15–18 | ERLING Verlag GmbH & Co. KG | 2020
for their broad biological activity such
as anti-microbial, anti-oxidant, anti-
inflammatory, anti-cancer and cogni-
tive amelioration activity (44,47). But
among these constituents, polypheno-
lic diterpens (mainly Carnosic acid and
Carnosol) are of prime importance due
to their wide array of inhibitory activi-
ty in the various steps involved in the
Alzheimer’s disease progression (48).
It has been observed that rosemary
diterpens are chemically involved in
the activation of NRF2/KEAP1 pathway
that is responsible for regulating anti-
oxidant response element (ARE) that
produces dierent anti-oxidant enzy-
mes helping in the removal oxidative
stress induced by amyloid proteins
(49). Apart from that, these extracts
also render anti-inflammatory res-
ponse by inhibiting the expression of
Nuclear Factor Kappa B, Tumor Necro-
sis Factor-a, intercellular and vascu-
lar cell adhesion molecule (ICAM-1,
VCAM-1) and other proinflammatory
cytokines (50,51). They also upregulate
the expression of NRF2 (Nuclear factor
erythroid 2-related factor 2) and HO-1
(Heme-oxygenase-1) an anti-oxidant
activator protein to control the respon-
se of microglia inflammatory activity
in AD (52). Moreover, these diterpe-
noids can inhibit one of the secretase
enzymes (alpha-secretase) which are
involved in cleavage and processing
of Amyloid precursor protein (53,54).
Metal chelation is another characteris-
tic property of these diterpens (55) as
they sequester copper, Zinc and Iron
ions (56) that causes insoluble precipi-
tates of amyloid proteins and promote
inflammation, nitric oxide and reactive
oxygen production and deterioration of
blood brain barrier (57). All these stu-
dies demonstrated that rosemary po-
lyphenolic terpenoids are capable of
reversing memory and cognitive de-
cits. However, there is no clinical trials
or human studies conducted to eva-
luate these diterpens in Alzheimer’s
disease. Therefore, these essential
compounds could be a promising can-
didate and should be subjected for cli-
nical trials to determine its benecial
activity against AD.
Panax Ginseng
This plant is well known for its tradi-
tional use for longevity among Asian
countries. Phytochemical investigati-
on revealed high concentration of ac-
tive tripenoids dammarane glycosides,
(Ginsenosides) and polysaccharides
and polyacetylenes in low amounts
(58). More than 30 dierent Ginsenosi-
des have been procured from ginseng
utilizing various processing methods
and it is frequently used for many me-
dicinal and scientic purposes (59).
These Ginsenosides exhibits wide
array of neuroprotective and curative
psychosomatic eects i.e. anti-cancer,
anti-inflammation, anti-microbial, he-
patoprotective and anti-anxiety and
depression (60,61). In the beginning,
roots of ginseng was utilized to alle-
viate stress and amplify memory and
cognitive functioning and also to revi-
talize metabolic and bodily functions.
All this knowledge paved way to eva-
luate its pharmaco-signicance in neu-
rodegenerative disorders especially in
Alzheimer’s disease. Numerous stu-
dies indicated that ginseng not only
reduces the concentration and accu-
mulation of beta Amyloid plaques in
cortical regions of the rat-brain (62,63).
This also rejuvenates synaptophysin
and choline acetyltransferases activity
to restore normal synaptic functioning
and suppresses acetylcholinesterase
and secretase enzyme to prevent the
progression of AD pathology (64). In
this disease, amyloid plaques promo-
te neuroinflammation and oxidative
stress which in turn activate brain de-
fensive glial system (microglia) that is
key factor of degeneration of neurons
(65). This event causes the onset of
AD and promotes neurodegenerati-
on. To address this problem, Li and
their colleagues exploited the anti-
inflammatory activity of Ginsenosides
on AD mouse models. These bioactive
molecules suppressed the activity of
neurotoxic interleukins (IL-1b, IL-8) and
tumor necrosis factor alpha that was
activation in response to Amyloid beta
(1–40) and deterred neuronal apopto-
sis (66). Other studies elaborated that
these Ginsenosides directs microglial
activity to digest neurotoxic plaques
and provide neuroprotection by se-
questering reactive oxygen species to
alleviate neuroinflammation to slow
down the neurodegeneration (67–70).
All these research studies shows the
therapeutic eciency in Alzheimer’s
disease but the outcome of clinical
trials suggest otherwise (71). Accor-
ding to Kim et al., 2018 suggest that
ginseng extract could be ecacious by
combining it with Acetylcholinesterase
(AcHE) inhibitors or N-methyl-D-aspar-
tate (NMDA) receptor antagonist (72).
Thus future studies are required to
address the safety, tolerability and e-
cacy of ginseng bioactive components
to ameliorate treatment outcome.
Emblica Ocinalis
Emblica Ocinalis also known as Indi-
an gooseberry is a tropical region me-
dicinal plant and it is found mainly in
China, Indonesia, India and Malay Pen-
insula. Their fruits (Amla) is generally
used for therapeutic reasons due to
rich phytochemical constituents pre-
sent in them (73). These constituents
are composed of high concentration of
vitamin C followed by Emblicanin (A,
B), penigluconin and peduculagin (74).
Other phytochemicals are also procu-
red which are already reviewed by Vari-
ya et al., 2016 (75)having great elemen-
tary and therapeutic importance, are
the gi to mankind to acquire healthy
lifestyle. Emblica ocinalis Gaertn. or
Phyllanthus emblica Linn. (Euphorbea-
ceae. Therapeutic potenzial of Emblica
ocinalis extract was rst studied in
dementia induced by scopolamine and
diazepam mouse models (76). It was
observed that, by administering high
doses of E. ocinalis extract signi-
cantly reversed dementia and ameli-
orated memory and cognitive skills.
Further molecular studies conrmed
that, these extract negative intervenes
with the production of beta amyloid
plaques by blocking the expression of
secretase enzymes that facilitate the
processing and cleavage of amyloid
precursor proteins (77–79). Besides,
anti-amyloid activity, these are also in-
volved in initiating NRF2-ARE pathway
that directs the production of anti-oxi-
dant proteins (80)when consumed in
the long term, have also shown to be
a precursor to several disorders such
as the metabolic disorder and conse-
quently, various other diseases, inclu-
ding cognitive decits. In the present
study, we used a high salt and choles-
terol diet (HSCD. The function of these
proteins is to capture reactive free radi-
cal oxygen species and to revive neuro-
ReviewF. H. Shah et al. | Therapeutic approaches of prominent medicinal plants for targetting Alzheimer's disease

18
nal mitochondrial dysfunction caused
by inflammatory protein markers and
amyloid plaques. Thus, reducing the
oxidative stress causes neuronal and
cognitive rejuvenation in AD mouse
models. However, there is no scientic
literature or clinical data available con-
cerning use of Emblica Ocinalis Fruit
in age associated dementia or AD.
Withania somnifera
Withania Somnifera is a renowned Indi-
an medicinal plant commonly called as
Indian Ginseng or Ashwagandha. The-
se plants are found growing in tropical
and subtropical regions of world and
possess exorbitant therapeutic appli-
cations that were previously exploited
in traditional medicine for all sorts of
deleterious bodily and neurological ail-
ments (81). W. sominfera phytochemi-
cal constituents contain low concentra-
tion of sitoindosides, 12 alkaloids and
40 numerous withanolides isolated
from aerial and root region of the plant
(82). Mainly leaf and root extracts are
generally employed as main bioactive
phytoconstituent resides and it is uti-
lized for dierent pharmacological ac-
tivities (83). These plants are equipped
with diverse bioactive compounds that
are pharmacologically used for many
psychosomatic diseases i.e anti-anxie-
ty, anti-cancer, anti-inflammatory, anti-
microbial, hepato and neuroprotective
agent and many other geriatric illnes-
ses (84–86). Various studies described
the anti-oxidant property of W. somni-
fera leaves and root extracts (87). As
these extract contain withanolides that
initiates the expression of anti-oxidant
proteins such as superoxide dismu-
tase, glutathione peroxidase and free
radical scavenging enzymes to reduce
the level of reactive oxygen species
and other free radicals that are invol-
ved in the pathogenesis of Alzheimer’s
disease (88–90). These withanolides
have the capability to promote synaptic
reconstruction and neurite regenerati-
on of cortical neurons that are interrup-
ted with oxidative stress and microglia
inltration (91–93). Moreover, these
compounds suppresses inflammato-
ry protein markers (TNF-a, NFκB, Cy-
clooxygenases) that negative impact
neurons and their corresponding mito-
chondria, hence causing their dysfunc-
tioning (94–96). However, there is lack
of understanding regarding the use of
withanolides in terms of safety, ecacy
and tolerability among AD aected in-
dividuals. Therefore, for future studies,
it is advised to evaluate the eect of
these withanolides on dementia and
AD to further understand their mecha-
nics by subjecting them for human cli-
nical trials.
Conclusion
In this review, we encompassed the
current literature about these dis-
cussed medicinal plants and how they
exhibit therapeutic and neural rege-
nerative potenzial to revive cognitive
and hippocampal integrity. Although,
the exact mechanism of Alzheimer’s
disease pathogenesis still remain elu-
sive to the scientic community due
to several intricate protein factor in-
volvement in the onset of this disease.
Yet, there is no complete information
regarding potenzial molecular targets
to design ecient curative therapy to
inhibit the progression of this disease.
By employing these medicinal plants
extract could possibly serve as an
alternative therapeutic intervention
to alleviate the symptoms and reju-
venate neural regeneration system to
sustain neuroprotective activity and
impede neurodegeneration. This ap-
proach could spare sensitive neurons
from getting degenerated and help
patients to retain their cognitive and
memory skills. It is suggested that,
instead of using monotherapeutic ap-
proach (single medicinal plant com-
ponent) synergistic or combinational
use of various extract might overcome
neurodegeneration and improve pati-
ents quality of life (97). These plants
extracts could be added as adjuvants
with standard anti-Alzheimer’s medi-
cines to improve treatment outcome,
rapidly intervene with the disease
progression and might counteract the
adverse eect that possibly arise with
conventional anti-Alzheimer’s therapy
(72). Majority of bioactive compounds
procured from these plants have not
been subjected to clinical trials and
also their pharmacological mechanics
is still remain obscure in humans de-
spite their excellent activity in mouse
models and cell lining studies. There-
fore, further studies are required to
eciently translate these mouse and
cell lining based studies by understan-
ding these medicinal plant extracts
mechanism of action and to evaluate
their therapeutic eect by organizing
extensive clinical trials.
Reference
References are available from the au-
thors
Addresses of the authors
a Centre of Biotechnology and Micro-
biology, University of Peshawar, Paki-
stan
b Department of Pharmacy, The Uni-
versity of Lahore, Islamabad Campus,
Pakistan
c Islamia College University Peshawar,
Pakistan
Z Arznei- Gewurzpa | 24 (1): 15–18 | ERLING Verlag GmbH & Co. KG | 2020
Review