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74
Plant-based Foods and their Implications in Brain Health
Formulations
Spices
Raw/
Extract
Method of
extraction
Extracted
compositions Yield
AD
pathways
evaluated
Native
extract
Macro/ micro-
encapsulate Nano- vehicle
Hydro distillation 33.1 % - - Extracted oil - - - - - - EPR spectrum for
Hydro distillation
(oil extracted
from fruits)
- - C Volatile oil - - - - - - EPR spectrum for
Reviews/ articles that are indexed by Scopus and/ or Web of Science have been selected for this compilation.
Ultrasound- assisted supercritical carbon dioxide (USC- CO
2
) extraction, Ultra- sonication– assisted solvent extraction (UAE),
-
tion (SFE),
Supercritical carbon dioxide (SC- CO
2
), Enzyme- assisted ionic liquid extraction (EILE), Not reported (N.R.), Thymoquinone
(TQ), Poly lactic- co- glycolic acid (PLGA), Essential oils (EO),
Mild cognitive impairment (MCI), AD Assessment Scale- cognitive subscale (ADAS- cog), Clinical dementia rating scale
: sums of boxes (CDR- SB), Cerebellar granules (CGNs), 3- (4,5- dimethylthiazol- 2- yl)- 2,5diphenyltetrazolium bromide
mass transfer modelling of the extraction process) and the extract thus obtained is neat (solvent-
free) and therefore safe to be consumed per se
53,118,120,121,122,123,124,125,126
. Selectivity in extraction
cannot be achieved by conventional or other green extraction technologies, wherein the solu-
bility of the antioxidants is limited by the polarity and/ or temperature of the extracting solvent(s).
Besides, SC- CO
2
extraction can successfully preserve antioxidant synergy in a cardamom seed
extract rich in its bioactive principle 1,8- cineole, wherein it was found to be synergistically present
and limonene
54,55
. This antioxidant harmony showed success in vitro
oligomerization
4
. In fact, the said extract could be a putative multifunctional biotherapeutic since
of iron- induced cell death in human neuroblastoma SHSY5Y cell line
4
, and as an acetylcholin-
esterase inhibitor
56.
TABLE 4.2 (Continued)
Spice compounds, their extracts and formulations: Mode of action in targeted pathways
of AD pathogenesis
75
Impact of Indian Herbs and Spices on Alzheimer’s Disease
Nasal
formulations
Characteristics of
the extract or the
formulations and
their pharmaceutical/
pharmacokinetic profiles
Preclinical/
Clinical study Remarks References
validation of antioxidant
potency: N.R
SE value: N.R
LD
50
: >5000 mg
Release kinetics
Concentration:
50- 800 µg/ mL
In vitro study on cortical
neurons derived
from enzymatically
and mechanically
dissociated cortex of
day 18 embryonic
Wistar SPF rat brain
(in vitro assays)
Target(s):
Effect
on various aspects of CNS
Major nding(s)
reported: Oil
containing linalool
showed effect on rat
SH- SY5Y neuronal
cells
5, 86
validation of antioxidant
potency: N.R
SE value: N.R
LD
50
: >5000 mg
Release kinetics
Dose:
200 µl (1% & 3%)
Duration:
21 days
Route of
administration:
Nasal
Subject:
Male Wister rats
Target(s):
Chronic inhalation of
coriander volatile oil in
induced Wister
male rats
Major nding(s)
reported: Effectively
restored brain
antioxidant status and
spatial working memory
5, 87
4.3 LIMITATIONS OF EXISTING AD DRUGS AND SUGGESTIVE
ALTERNATIVES
The FDA- approved synthetic drugs such as donepezil, tacrine, rivastigmine, and galanthamine
prescribed for AD have shown success in slowing down neuro- degeneration but are known to
have negative impacts on human health because they pose adverse side effects such as aggression,
depression, gastrointestinal disturbances, hepatotoxicity, and cardiac problems
127
. Moreover, these
drugs do not have a long- lasting effect (effective only for 1– 3 years) because of their poor penetra-
bility, i.e., their inability to cross the blood- brain- barrier (BBB) and reach the targeted areas, pri-
marily the blood cells in the hippocampal area and/ or acetylcholinesterase accumulating neuronal
junctions
128,129
. As a result, the huge intake of these chemicals adds to the toxic insult to the cells,
resulting in more harm to individuals than arresting the progression of AD
130
.
(MTT) assay, Mini-Mental State Examination (MMSE): The best-known and the most often used short screening tool
for providing an overall measure of cognitive impairment in clinical, research and community settings. MMSE (Folstein
1975) is a simple pen-and-paper test of cognitive function based on a total possible score of 30 points; it includes tests of
orientation, concentration, attention, verbal memory, naming, and visuospatial skills.
stress reduction as an antioxidant,
E: Inhibition of tau phosphorylation, F: Superoxide dismutase (SOD) value reduction
76
Plant-based Foods and their Implications in Brain Health
TABLE 4.3a
Role of spices and their respective bioactive components on behavioural tests in in vivo
animal model
Name of
spices
Bioactive
components
In vivo behavioural tests in
animal model Remarks References
Turmeric Curcumin Y- maze test in 3xTg- AD rat
model
Improved performance in Y- maze test 29
Morris water maze test (MWM)
in Sprague Dawley rats
Morris water maze test
25
Black
pepper
piperine Force swimming test (FST) in
albino Wistar rats
P- 80- PIP- SLN results increased
immobility time by FST
47
Morris water maze test in male
Wistar rats
improvements in escape latency or
retention of memory
48
Impaired memory evaluated
through passive avoidance
apparatus in male Wistar rats
PIP- loaded cubs formulations
increased retention latency which
adequate cognitive improvement
49
Evaluation of cognitive abilities
in adult Wistar rats through
passive avoidance test
Cognitive performance partially
improved after treatment with
PIP- loaded micro emulsion
formulations
46
Morris water maze test,
forced swimming test and
spontaneous motor behaviour
assessment were performed in
adult male Wistar albino rats
Decreased escape latency and
increased retention time in MWM,
decrease in immobility assessed
cognition and assured the same as
an antidepressant
50
Small
cardamom
1,8 cineole,
acetate,
limonene, linalyl
acetate, linalool
Morris water maze test, elevated
plus maze test, passive
avoidance test and locomotor
activity in AlCl
3
- treated male
Wistar albino rats
the increase in escape latency,
recovery in retention latency and
improved locomotor activity
57
Saffron Crocin and its
derivatives
Morris water maze test, memory
Al- treated mice
Crocin improved cognition and
memory abilities substantially as
measured by their coordination of
movements and reduced escape
time
88
Water maze tests of learning
and memory on chronic stress
induced male Wistar rats
The extract prevented chronic stress
and memory and oxidative stress
in the hippocampus
61
Morris Water Maze test
performed in male Wistar rats
induced with multiple sclerosis
(Intrahippocampal injection of
ethidium bromide)
Learning and spatial memory status
was improved after administration
of saffron extract
6
Passive avoidance test conducted
for learning and memory ability
of Al- exposed Balb- c mice
Dried saffron extract had no effect
short duration of time (six days)
89
77
Impact of Indian Herbs and Spices on Alzheimer’s Disease
(continued)
TABLE 4.3a (Continued)
Role of spices and their respective bioactive components on behavioural tests in in vivo
animal model
Name of
spices
Bioactive
components
In vivo behavioural tests in
animal model Remarks References
Passive and active avoidance
tests performed on D- galactose
and NaNO
2
administered (i.p)
ovariectomized mice (induced
amnesia)
Hydro alcoholic saffron extract could
improve learning and memory
90
Morris water maze test in male
adult Wistar rats
Intraperitoneal administration of
an aqueous solution of crocin or
water- alcoholic saffron extract
induced by chronic cerebral
hypoperfusion in rats
91
Morris water maze test conducted
in intracerebroventricular STZ
treated male Wistar albino rats
improved memory consolidation
92
Morris water maze test conducted
in male albino Wistar rats
Intraperitoneal and intrahippocampal
administration of crocin
memory conditions
93
Passive avoidance paradigm
and Y- maze task for spatial
cognition evaluation in STZ
induced male Wistar rats
prevented cognitive impairments
in STZ induced rats
94
Passive avoidance tests
performed in mice
Alcoholic saffron extract
demonstrated ameliorative on
learning and memory processes
95
Object recognition test and the
step- through passive avoidance
task in scopolamine- induced
male Wistar rats
Intraperitoneal injection of aqueous
saffron extract had ameliorative
effect on cognitive memory
96
Black cumin Thymoquinone and
its derivatives
Morris water maze test and
passive avoidance tests
conducted in juvenile and
neonatal stages of Wistar rats
Improvement in learning- memory
during juvenile and neonatal
growth
97
Spatial working memory
performance on a radial arm
maze
Better performance showed in
passive avoidance tests by
the animals. Thus, the extract
prevented scopolamine- induced
98
Spatial memory performance
(SMP) was investigated using
eight- arm radial arm maze
(RAM) in male Sprague
Dawley rats
decrease in the mean number of
working memory error (WME)
was observed
99
78
Plant-based Foods and their Implications in Brain Health
Name of
spices
Bioactive
components
In vivo behavioural tests in
animal model Remarks References
Morris water maze and Y-
maze tests conducted on
scopolamine- induced Wister
rats
The extract (oil) showed protective
effects on cognitive function
and cortico- hippocampal neural
alterations in male Wistar rats
100
Morris water maze test (long-
term and short- term working
memory)
spatial cognitive preservation
in rats with chronic cerebral
hypoperfusion
72
T- maze alternation task and
object recognition test on
scopolamine- induced male
Wistar rats
Reversal of amnesic effect of
scopolamine- induced spatial and
non- spatial working memory
impairment
101
Behavioural tests (PA, MWM) on
LPS induced male Wistar rats
Memory impairments was improved
by reducing hippocampal cytokine
levels consequent brain tissue
oxidative damage
102
Morris water maze test
conducted in female Sprague
Dawley rats
TQ had an ameliorative effect on
spatial learning
103
Morris water maze test conducted
on nonylphenol induced male
Wistar rats
spatial memory and learning
104
Fear learning behaviour in
passive avoidance test in an
AD rat model
TQ improved learning function 105
Bay leaf 1,8- Cineole Y- Maze Spontaneous Alternation
Test, radial arm Maze and
novel object recognition test
conducted on scopolamine-
induced male Wistar rats
Bay leaf incense positively attenuated
scopolamine- induced memory
impairments
82
Coriander Linalool Y- maze task and radial arm maze
task in Wistar rats
improvement in spatial memory
formation
87
Morris water maze test and
elevated plus maze tests in
transgenic AD model (3xTg-
AD) and non- transgenic (non-
Tg) mice
Linalool restored cognitive and
emotional functions
106
Morris water maze test and
passive avoidance task
performed with male C57BL/
6J mice
Linalool administration was
successful in improving cognitive
impairment
107
Reviews/ articles that are indexed by Scopus and/ or Web of Science have been selected for this compilation.
TABLE 4.3a (Continued)
Role of spices and their respective bioactive components on behavioural tests in in vivo
animal model
79
Impact of Indian Herbs and Spices on Alzheimer’s Disease
(continued)
TABLE 4.3b
Role of spices and their respective bioactive components in characteristic AD clinical trial
Name of
spices
Bioactive
compounds Clinical trial in humans (AD patients) Remarks References
Turmeric Curcumin • Mini Mental State
Examination (MMSE)
• Enzyme- linked immunosorbent assay
and antioxidants in plasma
• Liver and kidney function
Major nding(s) reported:
disaggregation, anti-
also improves cognition;
no adverse side effects on health,
hence can be recommended for
longer trials
31
Primary outcomes:
• Changes in clinical laboratory
tests, MMSE
• Alzheimer’s Disease Assessment
Scale – Cognitive Subscale (ADAS-
Cog) at 24 weeks
Major nding(s) reported:
No differences among groups, and
no serious adverse events
22
Secondary outcomes:
• Neuropsychiatric Inventory (NPI)
• Alzheimer’s Disease Cooperative
Study – Activities of Daily Living
(ADCS- ADL) scale
Computerized Mental Performance
Assessment System:
• Immediate word recall task
• Simple reaction time task
• Two choice reaction time tasks
• Rapid visual information
processing task
• Digit vigilance task
• Serial three and serial seven
subtraction tasks
• Delayed word recall task
• Delayed word recognition task
• Delayed picture recognition task
Major nding(s) reported:
Curcumin showed potential in
improving important cognitive
functions even at a low dose
(approximately 80 mg) and
delayed detrimental effects of
psychological stresses
23
Saffron Crocin • Psychometric measures
included MMSE
• Alzheimer’s Disease Assessment Scale-
cognitive subscale (ADAS- cog)
• Clinical Dementia Rating Scale— Sums
of Boxes (CDR- SB)
Major nding(s) reported:
Saffron capsule [30 mg/ day
(15 mg twice per day) for a
22- week study was found to be
as effective as donepezil in the
treatment of mild to moderate AD
after 22 weeks]
63
• Psychometric measures
included MMSE
• Alzheimer’s Disease Assessment Scale-
cognitive subscale (ADAS- cog)
• Clinical Dementia Rating Scale— Sums
of Boxes (CDR- SB)
Major nding(s) reported:
Saffron capsule [30 mg/ day (15
mg twice per day) for a 22- week
study was found to be safe and
effective treatment of mild to
moderate AD after 16 weeks
64
80
Plant-based Foods and their Implications in Brain Health
TABLE 4.3b (Continued)
Role of spices and their respective bioactive components in characteristic AD clinical trial
Name of
spices
Bioactive
compounds Clinical trial in humans (AD patients) Remarks References
• Mini Mental State Examination
• Severe Cognitive Impairment Rating
Scale (SCIRS)
• Functional Assessment Staging (FAST)
Major nding(s) reported:
Administration of saffron extract
(30 mg/ day) capsules could
be compared to memantine in
reducing cognitive decline in
patients with moderate to severe
AD for a 12- month study
65
• Psychometric tests- Geriatric
Depression Scale, GDS
• Functional Rating Scale of Symptoms
of Dementia
• Neuropsychiatric Inventory, NPI
• Montreal Cognitive Assessment, MoCA
• MMSE
Major nding(s) reported:
Saffron improved MMSE, MRI,
EEG, and ERP scores
108
Black
cumin
Thymoquinone • Neuropsychological tests- logical
memory test, digit span test, Rey-
cancellation test, trail making test
• Cognitive test- stroop test
Major nding(s) reported:
NS capsule (500 mg) have shown
positive modulatory effects on
memory of elderly volunteers
109
Reviews/ articles that are indexed by Scopus and/ or Web of Science have been selected for this compilation.
To circumvent such complications of existing drugs, botanical ingredients (Table 4.1) are
increasingly gaining popularity in the treatment of AD. However, the applications of these active
ingredients in the treatment of AD pathogenesis have not delivered their desirable effects, mostly due
to improper extraction methods or drug delivery systems (vide supra). The extracts, when consumed
and also several carrier proteins and pathways that can interfere with their proper utilization by body
cells
131
. Moreover, the solvent extraction methods used in isolating the phytochemicals might show
other harmful effects since their extracts house carcinogenic solvent residues
132,133
. We advocate
the usage of green solvents for extraction to deliver safe extracts, and especially supercritical CO
2
extraction to obtain a safe- cum- neat- cum- selective extract (with intact antioxidant synergy) for for-
mulation of herbal drugs in ameliorating AD pathogenesis
4
.
4.4 EXTRACT CHARACTERIZATION NEEDED FOR SAFE USAGE AS
NATURAL DRUG
In the pursuit of formulation of a safe herbal medicine for AD, it is vital to perform- detailed
spectroscopic- cum- chromatographic studies for elucidation of the consortium of antioxidants
extracted from the spice/ herb, evaluation of synergistic effect (SE) value (which must be greater
than unity) of the antioxidants’ consortium in the spice/ herb extract, assessment of LD
50
values of
constituents (Table 4.2).
81
Impact of Indian Herbs and Spices on Alzheimer’s Disease
FIGURE 4.2 A systematic approach for the successful formulation of promosing spiceutical- based medicines
as futuristic natural alternatives to conventional AD drugs.
82
Plant-based Foods and their Implications in Brain Health
4.5 EXTRACT FORMULATIONS AND CHARACTERIZATIONS FOR
ENHANCED EFFICACIES
The solvent extracts, including the SC- CO
2
extracts per se (Table 4.2), have not been highly
successful in demonstrating desirable therapeutic effects in the prevention of AD pathogenesis,
and thereby necessitated further processing of the extracts, such as formulating their encapsulates
for enhanced bioavailabilities. Macro- encapsulated formulations such as commercial capsules and
micelles
32,65
; micro- emulsions such as those of piperine
46
, and crocin extracts (from black pepper
and saffron, respectively); and nano- formulations such as nanoparticles of commercially available
standard piperine
47,48
; nanoliposomes of- curcumin
34
, - commercially available standard piperine
50
, -
1,8- cineole- rich extract of small cardamom seeds
134
, when administered orally or intraperitoneally,
vis- à- vis the native
extracts. Among all these, the nano- formulations have exhibited relatively enhanced BBB pene-
trability and, therefore, have been more effective as anti- cholinergic as well as anti- amyloidogenic
agents over their macro/ micro counterparts. Moreover, a solitary publication on nanoliposome (of
vis- à- vis its nanoliposome
even at lower dose- duration
50
.
For formulation of extracts into bioavailable forms, it is pertinent that in addition to studies
also be investigated. It is important to consider the choice of GRAS status excipients for extract
formulations.
From Figure 4.1 and Table 4.2, it is evident that most herbal formulations target in vitro preven-
40
42
oligomerization, while the commercial drugs are primarily acetylcholin-
esterase inhibitors in vivo
135
. For drugs targeting acetylcholinesterase inhibition pathway, it is vital
to conduct in silico molecular docking and dynamics studies
136,137
in tandem with pharmacokinetic
studies. However, the herbal medicines, whose modes of action have been indicated, have not been
Table 4.2).
Concomitant investigations on routes of administration (oral or intraperitoneal), dose duration,
effects on pathways of AD pathogenesis by standard in vitro assays, and in silico molecular docking-
cum- molecular dynamics studies will holistically contribute to ascertaining safety and for assessing
suitability for use of pure bioactive compound/ extract/ formulation as a drug; and its effectiveness
for desired action(s).
4.5.1 Cell line StudieS
If the chemical/ extract/ formulation meets success in in vitro pathways of AD pathogenesis, it
can be subjected to cell line investigations, using either rat or human brain cells as described in
Table 4.2.
4.5.2 animal model StudieS
If the chemical/ extract/ formulation meets success in in vitro pathways of AD pathogenesis, it can
be safely extrapolated to animal studies. Although it has been reportedly established that trans-
138
, no standardized transgenic AD mouse model exists to date world-
wide. Whether animal studies should primarily involve transgenic AD mice for meaningful elucida-
β- amyloid toxicity, is not yet clearly known.
Several authors have used AlCl
3
- induced Sprague Dawley rats or male Wistar albino rats in their inv
estigations
38,46,50
. Many studies have also involved scopolamine or streptozotocin inductions to bring
about adverse changes in the rat brain cells
82,85,139,
rendering them amenable to drug intervention
83
Impact of Indian Herbs and Spices on Alzheimer’s Disease
studies (Table 4.2). All animal studies reported have used brain cell homogenates and have pri-
and complicated, and availability of similar data with animal models is scarce.
Non- invasive animal behaviour assessments (Table 4.3a), post administration of the herbal
drugs, have been researched upon by many, wherein mostly simple learning- memory enhance-
ment tests such as Morris water maze test
140
, Y- maze test and novel object recognition tests (either
25,49,57,88,94,107
. These widely used visual cognitive tests
in animals do not well simulate human behaviour, and thus, the translation of animal to human may
be skewed
141
. In assessing neurodegeneration, i.e., impairment of cognition abilities, it is necessary
to assess holistically several facets of cognition such as memory, attention, mood and response
inhibition, which could be rendered possible by the use of the Bussey- Saskida touchscreen model
142
for conducting human- apposite visuomotor conditional learning, and continuous performance tests
with rodents
143,144,145,146
. The use of the Bussey- Saskida model will perhaps enable more meaningful
elucidation of strategies for cognitive translation from animal to human. However, reports on the
be explicitly reported.
Advanced investigations on AD pathogenesis by Nobel laureate Prof. May- Britt Moser have
revealed that the novel object recognition test by animals could be substituted by training animals
to link odours of objects with their locations, say, responding to the smell of a banana by navigating
left, and chocolate by going right. Her work has added a new dimension to existing research meth-
odologies for drug formulations for AD. Brain odour mapping of the grid cells of the hippocampus
and the entorhinal cortex in well- trained animals would enable scientists now to learn more about
severe spatial memory loss and navigation problems
147
. This could steer a paradigm shift in the clas-
sical animal behaviour assessment tests for prospective elucidation of the pathophysiology of AD.
Non- invasive investigations on AD pathophysiology must be succeeded by invasive investigations
(Table 4.2
glucose oxidation
148,149
.
emphasizing the reduction of animal studies and encouraging the adoption of animal- free methods in
150
. Thus, computational or in silico studies are increasingly gaining
importance and therefore, pathway F in Figure 4.1 needs special attention. To serve as a futuristic
robust substitute for animal model studies- biochemical or cell- free assays, and those involving
human- derived cell lines, human ex vivo
in
silico studies are warranted.
4.5.3 human CliniCal trialS
in the prevention of AD pathogenesis will be in the successful application of the same in a human
AD patient. The data obtained from preclinical in vitro/ ex vivo/ in vivo studies are extrapolated
to obtain solutions for human subjects (Table 4.3b). However, reports on human clinical studies
involving herbal medicines are not only scanty but less systemized. Very few reports are avail-
able that have used the gold standard for testing interventions in people, viz. the randomized,
placebo- controlled clinical trial with patients aged 60 – 80 years having mild to moderate AD
23
.
Although studies on saffron
63,64
have reported on double- blind placebo interventions with patients
above the age of 60, the formulation details of the capsules prescribed to the patients are missing.
More systematic studies for successful herbal medicines are needed to compete with existing
synthetic drugs.