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44
DOI: 10.1201/9781003300502-4
4
Potential Impact of
Indian Herbs and Spices
in Prevention of Pathogenesis
of Alzheimer’s Disease
Paramita Bhattacharjee*, Anamika Das, and Sanjukta Datta
*Corresponding author
4.1 INTRODUCTION
India is a land rich in spices, and the multitudinous uses of these spices have earned them a
distinguished position globally. The term ‘spice’ has been coined from the Latin words ‘Species
aromatacea’, which means ‘aromatic spices’. Traditionally used spices are obtained from several
plant parts such as roots, stems, barks, buds, pistils, leaves, seeds, etc.
1
The Spices Board of India
(under Ministry of Commerce and Industry, Government of India) documents important spices
belonging to the families Zingiberaceae (cardamom, turmeric), Piperaceae (pepper), Iridaceae
(saffron), Myrtaceae (clove), Fabaceae (fenugreek), Myristicaceae (nutmeg, mace), Solanaceae
(chilli), and Lauraceae (cinnamon) to be the commonly used spices in India. According to reports,
India currently has an overwhelming record export of 15,31,154 tonnes of spice/ spices products
(2021– 2022) valued at Rs. 30,576 crores (4102.29 million US$)
2
.
-
eral bioactive components known as ‘active principles’, which are reportedly known to have a myriad
1
; and many
of them, such as gingerol, carvacrol, curcumin, thymol, hydroquinone, and linalool to name a few,
effects in prevention of pathogenesis of mild to moderate Alzheimer’s disease (AD)
3,4,5,6,7,8
. Table 4.1
exhibits important Indian spices/ herbs and their bioactive principles, which are reportedly known to
reverse AD pathology.
The major pathways of AD pathogenesis have been illustrated in Figure 4.1. AD pathogenesis
the formation of senile plaques (considered to be the hallmark of AD progression), and/ or by intra-
the enzyme acetylcholinesterase). These two effects eventually lead to neurodegeneration through
apoptotic cell death of the cholinergic neurons and synapses and interfere with the normal synthesis
of acetylcholine, the key neurotransmitter that aids in learning- memory processes
9
. Acetylcholine is
rapidly hydrolyzed to acetate and choline in the presence of acetylcholinesterase (5,000 molecules
10
present in humans and thus brings about inactivation of acetylcholine
9
. AD is basically an oxidative
stress disorder caused by an imbalance between the production of reactive oxygen species
(ROS) and the ability of the human biological system to detoxify them, which results in cytotoxicity,
45
Impact of Indian Herbs and Spices on Alzheimer’s Disease
viz. oxidative damage
11,12
. Chronic stresses induced by ROS production and accumulation cause
impairment of learning- memory processes, which leads to a progression of AD
13,14,15
. Figure 4.1 also
depicts the multifunctional roles the drugs need to play in ameliorating AD progression, such as by
in an AD brain, inhibiting the activities of acetylcholinesterase and/ or displaying anti- tau protein
aggregation effects
16,17
.
Table 4.2 presents the individual spice compounds, their extracts, and their formulations, along
with their modes of action in targeted pathways of AD pathogenesis and their success in preclin-
ical/ clinical investigations (further elaborated in Tables 4.3a and 4.3b). Common spices such as
AD pathogenesis
3,46,57,60,73
by manipulating the reported pathways illustrated in Figure 4.1. A critical
assessment of the consolidated information presented in Table 4.2 reveals that most studies have
been performed using the spice bioactive principle in raw form i.e., as a pure chemical standard, and
not as a component of the spice extract or isolate.
TABLE 4.1
List of biologically active components of some common Indian spices reportedly known
to have potential impact in prevention of AD pathogenesis and their targeted pathways
associated with AD progression
Name of the spices Bioactive components Targeted pathways of AD pathogenesis
Turmeric
(Curcuma longa L.)
Curcumin and its
derivatives
• Reduction in oxidative stress as an antioxidant
• Inhibition of tau protein aggregation
Black pepper
(Piper nigrum L.)
Piperine • Inhibition of AChE activity
• Oxidative stress reduction as an antioxidant
• Inhibition of tau phosphorylation
Small cardamom
(Elettaria
cardamomum L.)
1,8- cineole and its
derivatives
• AChE- inhibitory activity
• Neurotoxicity activity by lowering Bax, caspase - 3, - 8 and - 9 and
enhancing the B- cell lymphoma 2 (Bcl- 2) levels
pathway
Saffron
(Crocus sativus L.)
Crocin and its
derivatives
• AChE- inhibitory activity
• Oxidative stress reduction as an antioxidant
• Inhibition of tau phosphorylation
• Reduction in Superoxide dismutase (SOD) value
Black cumin
(Nigella sativa L.)
Thymoquinone and its
derivatives
• AChE- inhibitory activity
• Inhibition of tau protein aggregation
pathway
Bay leaf
(Laurus nobilis L.)
1,8- Cineole • Memory enhancement effects through AChE- inhibitory activity
• BChE inhibitory activity
Coriander
(Coriandrum
sativum L.)
Linalool
aggregation
• Reduction in lipid peroxidation
Reviews/ articles that are indexed by Scopus and/ or Web of Science have been selected for this compilation
46
Plant-based Foods and their Implications in Brain Health
Despite the existing volumes of reports, systemic studies on the elucidation of the effects of
spice antioxidants on animal models of AD or in human AD patients are rare. In fact, a few studies
found several studies based on in vitro biochemical assays and ex vivo experiments using brain cell
lines/ cultures
58,67
. Turmeric is one of the most researched Indian spices in relation to AD, although
when critically assessed, there are obvious indications that more work needs to be conducted to
establish curcumin- based natural medicine as an alternative to existing synthetic drugs of AD.
The second spice noteworthy in this context is saffron. Studies strongly indicate how its bioactive
components (crocin and its derivatives) present in a saffron capsule could act as anti- amyloidogenic
agents as effectively as donepezil
63,64
. However, what is lacking is the meticulous execution of any
reported study.
This chapter has critically compiled and assessed literature reports that describe methodologies
Figure 4.2 illustrates a systematic approach for the
successful formulation of spiceutical- based medicines, which could be promising futuristic natural
alternatives to conventional drugs prescribed for AD.
4.2 CRITICAL APPRAISAL OF THE EXISTING NATURAL DRUGS USED IN THE
PREVENTION OF AD PATHOGENESIS
The positive outcomes of the pure biochemicals enumerated in Table 4.2, observed in both in vitro
pathways and preclinical animal trials, may not reliably predict their success in human clinical trials,
since these bioactives, in their pure chemical forms, cannot be consumed by human volunteers.
FIGURE 4.1 The major pathways of AD pathogenesis.
47
Impact of Indian Herbs and Spices on Alzheimer’s Disease
Although there are few published literature reports on human administration trials using pure
-
fore, yet to be Food and Drug Administration (FDA)- approved natural medicines. One study on
the administration of a combination of pure curcumin chemicals along with ginkgo leaf extract to
human volunteers has shown preliminary success; the compounds responsible for therapeuticity
31
. It is rationally opined by us that a synergistic
consortium of bioactives, including curcumin and those from ginkgo leaf extract, have possibly
contributed to the prevention of AD pathogenesis involving at least one of the pathways elucidated
in Figure 4.1
mixtures of bioactives since if the bioactives (principally the antioxidants) are not in synergism in
the mixture, it would be health- debilitating rather than therapeutic.
These drawbacks could certainly have been circumvented by the usage of the bioactive(s) in
the extract form in compliance with the principle of ‘food synergy’ wherein biomolecules function
in synergistic harmony in extracts of its native botanical
110,111,11 2
. The majority of the extracts
mentioned in Table 4.2 are derived by conventional non- selective extraction procedures such as
hydrodistillation and/ or involving non- GRAS (generally regarded as safe) solvents for solvent extrac-
tion, ultrasonication- assisted solvent extraction (UAE), and microwave- assisted solvent extraction
(MAE)
23,60
; wherein food synergy in the extracts have not been assessed by the researchers. It is
extremely important that the principal bioactive in the extract should be in synergistic harmony
with its co- extracted biomolecules, viz. present in antioxidant synergy as was present de novo in the
spice/ herb. This synergistic harmony must remain unperturbed during reductionism (extraction) for
natural herbal medicines
4,113,114
to be effective alternatives to conventional synthetic drugs prescribed
for AD patients.
Moreover, reports on the extracts of the bioactives are substantially incomplete since the
ones that have exhibited potencies in vitro-
ical trials
67,68,115
; except for one reported work on piperine (related to AD) where investigators
have tested a vacuum- dried Soxhlet extract of black pepper suspended in propylene glycol in
AD- induced rats
38
. Although piperine was not thermally degraded under the said extraction
conditions, the possibility of artefact generation in the extract during prolonged thermal pro-
cessing cannot be ignored. It is therefore advisable not to employ thermal processing (such as
the Soxhlet method of extraction) for obtaining bioactives from spices/ herbs since the thera-
peutic potency of the extract would be compromised due to the presence of undesirable heat
labile compounds of potential harm to the human health. Therefore, we advocate green tech-
nologies of solvent extraction for the formulation of herbal medicines, which encompass the
green principles of use of a safe solvent(s) for both humans and the environment, and involve
non- thermal processes for product development
116,117
.
These research gaps need to be addressed for natural drug candidates to be successful in the
prevention of the pathogenesis of AD. In this context, the green technology of supercritical CO
2
extraction (for extraction of bioactives from spices/ herbs) is superior not only to the conventional
solvent extraction technologies but also when compared with other non- thermal green technologies
of extractions (viz. UAE and MAE with GRAS status solvents) since it delivers a ‘neat’ solvent-
because this high- pressure extraction process can be tuned to make it highly selective for extrac-
tion of desirable biomolecules, thereby conserving the natural antioxidant synergy in the extr
act
4,113,114,118,11 9
. Conventional extracts are non- selective and have several undesirable compounds
(artefacts) in abundance. The selectivity of the SC- CO
2
extraction process can be realized through
vigorous engineering exercises (such as statistical optimization of process variables of extraction,
namely, pressure to modify density, viscosity, and diffusivity of SC- CO
2
for enhancing solubility
of the desirable molecules in the same, and concomitantly for enhancing penetrability of SC- CO
2
solvent into the sample matrix to ensure its greater accessibility to the extractible molecules; and
48
Plant-based Foods and their Implications in Brain Health
TABLE 4.2
Spice compounds, their extracts and formulations: Mode of action in targeted pathways
of AD pathogenesis
Formulations
Spices
Raw/
Extract
Method of
extraction
Extracted
compositions Yield
AD
pathways
evaluated
Native
extract
Macro/ micro-
encapsulate Nano- vehicle
Turmeric Extract USC- CO
2
Curcumin 1.69 % w/ w - - - - - - - - - - - - - - - - 3,18
treatment)
Oleoresin,
Curcumin,
Volatile oil
10.35 ±
0. 30% w/ w
3.92 ±
0.33% w/ w
2.72 ± 0.27%
w/ w
- - - - - - - - - - - - - - - - 19
EE
(Glucoamylase
treatment)
Oleoresin,
Curcumin,
Volatile oil
11.15 ±
0.34% w/ w
4.10 ±
0.21% w/ w
2.46 ± 0.16%
w/ w
SFE (SC- CO
2
) Oleoresin,
Curcumin,
Total volatiles
35.37 ±
3.43 mg/ g
187.09 ±
7.62 ± 0.73
mg/ g
- - - - - - - - - - - - - - - - 20
EILE (solvent:
ethanol)
Oleoresin,
Curcumin
4.41 % w/ w
2.82 % w/ w
- - - - - - - - - - - - - - - - - 21
EILE (solvent:
Acetone)
Oleoresin,
Curcumin
5.56 % w/ w
3.11 % w/ w
EILE (solvent:
DPCARB)
Oleoresin,
Curcumin
6.99 % w/ w
5.73 % w/ w
- - - - - - C; D; E - - Curcumin C3
Complex® (an
orange- yellow
crystalline
powdered plant
extract
Encapsulate
contained 95%
curcuminoids
with
70% to 80%
Curcumin)
- - - - - - C; D - - Longvida
(containing
approximately 80
mg curcumin
in a solid- lipid
formulation)
49
Impact of Indian Herbs and Spices on Alzheimer’s Disease
(continued)
Nasal
formulations
Characteristics of
the extract or the
formulations and
their pharmaceutical/
pharmacokinetic profiles
Preclinical/
Clinical study Remarks References
- - - - EPR spectrum for
validation of antioxidant
potency: N.R.
SE value: N.R
LD
50
:
Release kinetics
In silico
N. R
Doses:
2g/ day,4g/ day
Duration:
24- 48 weeks
Route of
administration:
Oral
Subjects:
Randomized, double
blind, placebo- controlled
groups of human
subjects (33 patients
with mild to moderate
AD)
Target(s):
MMSE scores; side
effects; plasma
biomarkers
F2- isoprostanes);
curcumin and metabolites
Major nding(s)
reported:
No differences
among groups
and no serious adverse
events
22
- - - - EPR spectrum for
validation of antioxidant
potency: N.R
SE value: N.R
LD
50
: N.R
Release kinetics
In silico
R
Doses:
400 or 800 mg/ day
Duration:
1– 3 h (acute);
4 weeks (chronic)
Route of
administration:
Oral
Subjects:
60 human
subjects: healthy,
aged 60- 85 years old
Target(s):
Cognition; mood and
anxiety;
oligomerization
Major nding(s)
reported:
Cognition and mood
improvements
23
50
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
Raw - - Curcumin - - C; D - - - - - - - - EPR spectrum for
C - - - - - - - - EPR spectrum for
C - - - - - - - - EPR spectrum for
C - - - - - - - - EPR spectrum for
TABLE 4.2 (Continued)
Spice compounds, their extracts and formulations: Mode of action in targeted pathways
of AD pathogenesis
51
Impact of Indian Herbs and Spices on Alzheimer’s Disease
(continued)
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
: N.R
Release kinetics
In silico
Doses:
g); 5000 ppm (13.6
Duration:
6 months
Route of
administration:
Oral
Subjects:
Rat model (Tg2576)
Target(s):
Inhibitory effect on
and oxidative stress
reduction
Major nding(s)
reported:
insoluble and soluble
Aβ plaque burdens
with administration of
the latter dose; lowering
of oxidized proteins
cytokine (IL- 1β) in
the brain at both doses
24
validation of antioxidant
potency: N.R
SE value: N.R
LD
50
: N.R
Release kinetics
In silico
R
Doses:
g);2000 ppm (5.43
Duration:
2 months
Route of
administration:
Oral
Subjects:
Sprague Dawley
rats
Target(s):
oligomerization
Major nding(s)
reported:
Reduction in Aβ
deposition; prevention
spatial memory
25
validation of antioxidant
potency: N.R
SE value: N.R
LD
50
: N.R
Release kinetics
In silico
N. R
Doses:
Duration:
5 months
Route of
administration:
Oral
Subjects:
Rat model (Tg2576)
Target(s):
oligomerization
Major nding(s)
reported:
Reduction in amyloid (Aβ)
plaque levels
26
validation of antioxidant
potency: N.R
SE value: N.R
LD
50
: N.R
Release kinetics
In silico
R
Doses:
7.5 mg/ kg/ day (0.02
mmol/ kg/ day)
Duration:
7 days
Route of
administration:
intravenously in a tail
vein
Subjects:
Rat model (APPswe /
PS1dE9)
Target(s):
Inhibitory effect on
enhancement of BBB
penetrability
Major nding(s)
reported:
Curcumin reached brain
tissue and cleared
existing amyloid (Aβ)
plaques
27
52
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
C - - - - - - - - EPR spectrum for
E - - - - - - - - EPR spectrum for
C - - - - - - - - EPR spectrum for
C - - Capsule or
powdered
extract
TABLE 4.2 (Continued)
Spice compounds, their extracts and formulations: Mode of action in targeted pathways
of AD pathogenesis
53
Impact of Indian Herbs and Spices on Alzheimer’s Disease
(continued)
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
: N.R
In silico
Doses:
Duration:
4 months
Route of administration:
Oral
Subjects:
Rat model (Tg2576)
Target(s):
oligomerization
Major nding(s)
reported:
Reduction in Aβ plaque
burden and dissociation
of insoluble Aβ plaques
28
validation of antioxidant
potency: N.R
SE value: N.R
LD
50
: N.R
Release kinetics
In silico
R
Doses:
Duration:
4 months
Route of
administration:
Oral
Subjects:
Rat model (3xTg- AD)
Target(s):
Inhibitory effect on tau
protein phosphorylation
Major nding(s)
reported:
Reduction in
phosphorylated tau
protein aggregates in
buffer- extracted
hippocampal membrane
pellet fractions;
performance improved in
maze test
29
validation of antioxidant
potency: N.R
SE value: N.R
LD
50
: N.R
Release kinetics
In silico
R
Doses:
Duration:
10 months
Route of
administration:
Oral
Subjects:
Rat model (Tg2576)
Target(s):
oligomerization
Major nding(s) reported:
found in Aβ deposition
but A11 antibody- marked
Aβ oligomers (important
class of oligomers
associated with AD
pathogenesis) decreased
in brain
3, 30
- - - - EPR spectrum for
validation of antioxidant
potency: N.R
SE value: N.R
LD
50
: N.R
Release kinetics
In silico
R
Doses:
1 g/ day,
4 g/ day powdered extract
or one capsule/ day
with 120 mg/ day
standardized
ginkgo leaf
extract
Duration:
6 months
Route of
administration:
Oral
Subjects:
Randomized,
double- blind,
placebo
control study on human
model (36 subjects
with possible or
probable AD)
Target(s):
MMSE scores; blood
biomarkers
curcumin levels;
bioavailability study in
brain and blood plasma
Major nding(s)
reported:
No difference
in MMSE scores or blood
biomarkers among groups
31