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Plant-based Foods and their Implications in Brain Health
EILE Enzyme- assisted ionic liquid extraction
EO Essential oils
EPR Electron paramagnetic resonance
FDA Food and drug administration
FRAP Ferric reducing antioxidant power assay
FST Force swimming test
FT- IR Fourier- transform infrared spectroscopy
GC- MS Gas chromatography mass spectrometry
GRAS Generally recognized as safe
HPLC High performance liquid chromatography
I.P Intraperitoneal
LC- MS Liquid chromatography mass spectrometry
LD Lethal Dose
MAE Microwave- assisted solvent extraction
MCI Mild cognitive impairment
MMSE Mini-mental state examination
MWM Morris water maze test
PA Passive avoidance
PEG Polyethylene glycol
PLGA Poly lactic- co- glycolic acid
RAM Radial arm maze
ROS Reactive oxygen species
SC- CO
2
Supercritical carbon dioxide
SCF
SE Synergistic effect
SFE
SMP Spatial memory performance
SOD Superoxide dismutase
STZ Streptozotocin
TPC Total phenolic content
TQ Thymoquinone
UAE Ultrasonication- assisted solvent extraction
USC- CO
2
Ultrasound- assisted supercritical carbon dioxide
WME Working memory error
XRD X- Ray diffraction
95
DOI: 10.1201/9781003300502-5
5
Herbs with Nootropic Efficacy
Olakunle J. Onaolapo and Adejoke Y. Onaolapo
5.1 INTRODUCTION
Cognition encompasses all the different processes that are employed in learning, understanding, and
retention of information [1.2]. It also refers to a capacity for processing information and application
of knowledge. These processes include memory, attention, language, vigilance, executive functions,
perception, and psychomotor functions [3, 4
individual’s ability to plan, reason, think abstractly, solve problems, understand complex ideas, and
learn from experience [1]. Although noncognitive factors such as zeal, hard work, endurance, and
of unusual success in life or academics has, however, been attributed to the individual’s level of
intelligence or cognitive ability [1, 5, 6]. Therefore, extensive research is dedicated to uncovering
ways of improving or enhancing cognitive ability [6– 9].
Cognitive enhancers or nootropics are chemical or natural compounds that can facilitate and/
or improve attentional abilities, as well as the storage and retrieval of information in health; and
10– 13]. Since 1972,
when the term nootropics was coined following the discovery of the memory- enhancing potential
of piracetam, hundreds of compounds have been examined for their nootropic ability [14]. Most
drugs with nootropic ability enhance cognition through their ability to increase the brain’s supply of
oxygen as well as improve the levels and activities of neurotransmitters such as acetylcholine and or
neurotransmitter enzymes in the brain [11, 14, 15]. The earliest known nootropic drug, piracetam,
and others in its class, including oxiracetam and aniracetam, act through the glutamatergic/ cholin-
-
minergic and serotonergic (5- hydroxy- tryptophan) systems [11].
healthy individuals and persons with cognitive decline have been reported [11]. However, they have
also been associated with undesirable adverse effects that limit their use. The growing demand for
nootropic agents for the management of ageing and disease- related memory loss, as well as the need
for improvement of cognitive abilities in the healthy [16, 17], is necessitating the continued search
for newer sources of nootropics such as plants and plant- based compounds that may be associated
with lesser side effects.
Plants and plant- derived compounds have been used for centuries in the maintenance of health
as well as the prevention and management of disease [18]. Herbal medicines are becoming popular
because they are generally believed to have limited or no adverse side effects [19]. A number of
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Plant-based Foods and their Implications in Brain Health
in the improvement of cognition and in the management of ageing and disease- related memory
support the cognition- enhancing capacity of these plants [14, 18, 21– 27].
In this chapter, we examine existing literature dealing with plants and plant- based compounds
with preclinically or clinically reported nootropic properties. This is with a view to improving our
understanding of the different compounds and the possible mechanisms through which they might
enhance cognitive performance.
5.2 HERBAL MEDICINES IN HEALTH AND DISEASE
In the last few decades, the use of herbs and phytonutrients as nutritional supplements, nutraceuticals
or medicines has increased exponentially. Globally, an increasing number of people in developed
and developing economies now depend solely on these herbal remedies for the maintenance of
health and the management of diseases [12, 28, 29]. Overall, there has been a global surge in the
public interest and acceptance of natural compounds, with a number of these products being freely
available in drug stores, food stores, and supermarkets.
There is anecdotal evidence demonstrating the ability of plants and plant- derived compounds to
improve brain functions, including learning, memory, and attention. Approximately one hundred
herbal medicinal plants are reported to have been used traditionally for the improvement of learning
and memory function [30- 32]. A global demand for increased workplace productivity as well as a
rise in the prevalence of age- related memory impairment and dementias due to neurodegenerative
disorders [33], have led to a surge in the demand for nootropics agents, particularly those from nat-
ural sources which are believed to cause little or no adverse effects [14, 34]. In the last few years,
there has been growing preclinical and clinical evidence supporting the anecdotal reports of the
nootropic abilities of several plants and plant bioactive compounds.
5.3 PLANT AND PLANT- BASED COMPOUNDS WITH COGNITION-
ENHANCING ABILITIES
For centuries, the Ayurvedic, Chinese, and Native American medicine systems have documented the
use of plants for the treatment of cognitive disorders, particularly in the elderly [35– 37]. The results
-
35, 37– 40]. Due to the fact that
a number of the currently available conventional drugs were isolated from plants or derived from
compounds isolated from plants, there has been increased research into developing or discovering
novel plant and plant- based nootropic agents.
In the last two decades, a number of anticholinesterase alkaloids, such as galantamine, isolated
from Alzheimer’s dementia [35, 37]. Galantamine is a bioactive compound derived from plants like
Lycoris radiata, long used in traditional Chinese medicine for the treatment of memory loss in the
elderly. Several plant species and their bioactive compounds have been reported to have pharmaco-
logical activities that are relevant to the improvement of memory and the management of cognitive
[23, 40]. A number of these plants exert their nootropic abilities through the modulation of the
cholinesterase system, activities at nicotinic receptors, and antioxidant potential [31, 32]. Several
a large number of plants, herbs, and plant bioactive compounds [31, 32]. The subsequent sections
will review recent data on the nootropic effect of plants, herbs or bioactive compounds, as well as
their respective mechanisms of action.
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Herbs with Nootropic Efficacy
5.4 PLANTS AND HERBS WITH NOOTROPIC ABILITIES
Gingko biloba, Bacopa monieiri, Hypericum perforatum, Withania somnifera Centella asiatica
Camellia sinensis, and Panax ginseng are plants with a centuries- long history of use in traditional
medicine systems as memory enhancers. Extensive research (Table 5.1) of these plants and their
standardized extracts have continued to provide evidence in support of not only their nootropic prop-
erties but also their adaptogenic and antioxidant potentials [14, 41]. Plants like Camellia sinensis
have, for centuries, been used in the Chinese traditional medicine systems [18, 21]. A 2017 system -
atic review of the effects of Camellia sinensis on cognition and working memory reported that the
nootropic effects of green tea could be attributed to the combined effects of caffeine and l- theanine,
which are bioactive constituents of green tea [42]. There have also been reports that enriching green
tea with (- )- gallocatechin gallate, another of its bioactive constituents, has the ability to improve age-
related cognitive impairments through the restoration of long- term synaptic plasticity [43]. A formu-
lation of green tea known as matcha tea, which is tea made from drying and powdering of tea leaves
(Camellia sinensis), has also been shown to have nootropic effects. Studies have demonstrated that
daily intake of matcha improved attention and executive functioning in healthy young, middle- aged,
and older subjects. Its cognition- enhancing effects have been attributed to its catechin, theanine,
and caffeine content [44, 45]. For centuries, the memory- enhancing effects of Centella asiatica
have been reported. Results from a number of preclinical studies have demonstrated that Centella
asiatica extracts have the capacity to enhance cognitive function in rodents [46, 47
overexpressing mice and aged mice, Centella asiatica improved memory function and executive
functioning [46, 47]. Its memory- enhancing effects have been attributed to its ability to attenuate
hippocampal mitochondrial dysfunction in these animals [46, 47]. Bacopa monnieri’s nootropic
effects have also been reported, with its nootropic effects supported by clinical [48, 49] and preclin -
ical studies [50]. By using a rodent model of Alzheimer’s disease, Uabundit et al. [50] reported that
an alcoholic extract of Bacopa monnieri reversed memory loss and mitigated Alzheimer’s disease-
induced loss of cholinergic neurons [50]. Similar effects have also been reported in a mouse model
of vascular dementia [51]; in this study, however, the memory- enhancing and neuroprotective
effects of Bacopa monnieri were attributed to bacopaside I, which acts via PKC and PI3K/ Akt
mechanisms [51]. Phan et al. [52] also observed an improvement in memory function in healthy
adolescent mice. Several systematic reviews and metanalysis have also reported that there is ample
48, 49, 53]. In aged humans, standardized Bacopa monnieri was associated
with enhanced auditory verbal learning, delayed word recall, and executive functioning compared to
those administered placebo [54]. For more than two decades, research has continued to demonstrate
the nootropic effects of Hypericum perforatum [55– 57]. The memory- enhancing effects of over- the-
counter supplements containing Hypericum perforatum have also been examined [57]. The result
of a single- dosage, randomized, double- blind, placebo- controlled study examining the effect of
Remotiv (one of such supplements) on short- term memory performance in healthy adults revealed
that acute treatment with small (250 mg) doses of the supplement was associated with improved
short- term verbal memory [57]. Centella asiatica has several bioactive constituents, including
asiaticoside, asiatic acid, madecassoside, and madecassic acid [58]. Its memory- enhancing effects
have been attributed to its ability to inhibit acetylcholinesterase activity, reduce phospholipase A
2
activity and protect against the formation of ß- amyloid [58].
The development of novel enhancers of cognition from plants with antioxidant properties is
also gaining attention (Table 5.1), and this has been attributed to the current understanding of the
importance of oxidative stress in the development of cognitive impairment [59, 60]. Plants and
-
tropic abilities include Zingiber ofcinale, Curcuma longa, Murraya koenigii, Phyllanthus emblica,
Ocimum tenuiorum, Spirulina maxima, Cucumis melo, and Citrullus lanatus [41, 61– 64]. The
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Plant-based Foods and their Implications in Brain Health
nootropic effects of Zingiber ofcinale in preclinical and clinical studies have been reported [59,
65]. Saenghong et al. [59] reported that a standardized extract of Zingiber ofcinale improved
working memory and cognitive function in healthy middle- aged women. In another study, Zingiber
ofcinale was combined with Cyperus rotundus (another plant that had been reported to have a
high polyphenol content and antioxidant capacity) in adult Wistar rats with age- related dementia
-
bination of extracts of the two plants was associated with improvement in memory, increased neur-
onal density, decreased acetylcholinesterase activity, decreased oxidative stress, and activation of
hippocampal pERK1/ 2 [66]. Spirulina maxima is a microalga with high protein and polyphenols
content and has been shown to exert memory- enhancing effects. Ethanolic extract of spirulina
67]. In other studies,
spirulina maxima alone [68] or fermented with lactobacillus planetarium HY- 08 [62] mitigated
scopolamine- induced memory loss in mice. Its memory- enhancing effects have been attributed to
its antioxidant activity [62, 68] and the inhibition of the increased phosphorylation of glycogen
1- 42
in mice [67] Curcuma
longa is another herb with documented antioxidant properties. Also known as turmeric, Curcuma
longa contains curcuminoids, which have antioxidant and neuroprotective properties. Studies have
demonstrated its nootropic abilities [61, 69]. The results of the study evaluating the nootropic
effect of its rhizome extract on trimethyltin- treated Sprague- Dawley rats revealed that at 200 mg/
kg/ body weight, Curcuma longa
the reduction in the number of pyramidal neurons in the hippocampal cornus ammonis [69]. In
another study examining the effect of fermented Curcuma longa (using 5% Lactobacillus plantarum
K154) on memory in mice, it was revealed that fermented Curcuma longa
scopolamine- induced impairment of memory in mice and prevented scopolamine- induced decrease
in acetylcholinesterase activity in the hippocampus [61].
Standardized extracts of plants (Table 5.1) have also been examined for their memory- enhancing
properties. Kim et al. [70] examined the effects of HemoHIM, a medicinal herbal formulation of three
plants Angelica gigas, Cnidium ofcinale, and Paeonia lactiora on scopolamine- induced memory
loss in mice and reported attenuation of memory impairment through the inhibition of acetylcholin-
esterase activity, increase in acetylcholine levels; and upregulating of choline xcetyltransferase,
muscarinic acetylcholine receptors and activation of the CREB and ERK signalling pathways [70].
Interest in the combined effect of these herbs is also increasing, as evidenced by research or clinical
trials examining polyherbal formulations of their extracts [71– 73]. Steiner et al. [71] examined the
effects of Sailuotong, a standardized herbal formulation containing Panax ginseng, Ginkgo biloba,
and Crocus sativus
working memory scores in these healthy subjects [71]. Cave et al. [73] registered a randomized,
double- blind, placebo- controlled clinical trial to study the effects of BioCeuticals Cognition Support
Formula®, a standardized formulation of three herbs including Bacopa monnieri, Ginkgo biloba,
Panax ginseng, and alpha- lipoic acid on cognition in older adults with subjective cognitive impair-
73].
Another standardized phytochemical formulation is BacoMind™ which is an enriched phytochem-
ical composition derived from Bacopa monnieri. Acute administration of BacoMind™ was shown
to enhance memory acquisition and retention in healthy rats and following scopolamine- induced
amnesia in rats [74].
5.5 PLANT BIOACTIVE COMPOUNDS WITH NOOTROPIC ACTIVITIES
In the last few decades, bioactive compounds which include carotenoids, polyphenols, omega- 3
fatty acids, vitamins, organic acids, phytosterols, nucleosides, and nucleotides, have continued to
99
Herbs with Nootropic Efficacy
(continued)
TABLE 5.1
Plants and Herbs with nootropic abilities
Plant Type of study Effect Mechanism of action references
Camellia sinensis
Powdered Camellia sinensis
leaves (Matcha tea)
Systematic review
Healthy young, middle- aged and
aged humans
Improved age- related cognitive impairments
Daily intake of matcha improved attention and
executive functioning in healthy young, middle- aged
and older subjects
Attributed the combined effects of caffeine and
l- theanine, which are bioactive constituents
of green tea. (- ) - gallocatechin gallate another
bioactive constituent restores long- term
synaptic plasticity
Actions of catechin, theanine, and caffeine
content
[42, 43]
[44, 45]
Centella asiatica
overexpressing mice
Systematic review of six
randomized clinical trials
Increased hippocampal synaptic density and
improvement of memory and executive function
Improvement of memory function
Attenuation of hippocampal mitochondrial
dysfunction
Inhibition of acetylcholinesterase activity,
reduction of phospholipase A
2
(PLA
2
)
activity, protection against ß- amyloid
formation, and protection from brain damage
[46, 47]
[58]
Bacopa monnieri
Standardized Bacopa
monnieri
Mouse model of Alzheimer’s
disease and vascular dementia
Aged Humans
Reversal of memory loss and mitigation of Alzheimer’s
disease induced loss of cholinergic neuron
Enhanced auditory verbal learning test delayed word
recall and stroop test
The high concentration of its active principle
(bacopaside)I which acts via PKC and PI3K/
Akt mechanisms
[50, 51]
[54]
Hypericum perforatum Single dosage, randomized,
double- blind, placebo- controlled
study
Acute low dose of Hypericum perforatum improved
short- term verbal memory
Activities at amine neurotransmitters including
the inhibition of the reuptake of serotonin,
dopamine, norepinephrine
[56, 57]
Zingiber ofcinale
(standardized extract)
Zingiber ofcinale and
Cyperus rotundus
co- adminoistration
Healthy middle- aged women
Wistar rats with age- related
dementia and ethylcholine
mustard aziridinium ion- induced
Improved working memory and cognitive function
Improvement in memory function, increased neuronal
density, decreased acetylcholinesterase activity
and decreased oxidative stress status together
with activated pERK1/ 2 were observed in the
hippocampus
Antioxidant properties
Enhanced cholinergic function and decreased
neurodegeneration and oxidative stress
[59]
[66]
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Plant-based Foods and their Implications in Brain Health
Plant Type of study Effect Mechanism of action references
Spirulina, maxima
Spirulina, maxima fermented
with lactobacillus
planetarium HY- 08
Preclinical study
mitigated scopolamine- induced memory loss in mice
mitigated scopolamine- induced memory loss in mice
and the inhibition of the increased
phosphorylation of glycogen synthase
Antioxidant activity
Antioxidant activity
[67]
[62]
[68]
Curcuma Longa rhizome
extract
Fermented Curcuma longa
Trimethyltin - treated Sprague-
Dawley rats
Brain cell lines (rat glioma C6 and
murine microglia BV2)
and partially inhibits the reduction of the number
of pyramidal neurons in the hippocampal cornus
ammonis
Prevention of oxidative stress- induced cell death,
scopolamine- induced memory loss
Inhibition of acetylcholinesterase activity
[69]
[61]
HemoHIM (a standardized
formulation of three herbs)
Mice Attenuation of scopolamine- induced memory loss Inhibition of acetylcholinesterase activity,
increase in acetylcholine (ACh) levels
upregulating of Choline Acetyltransferase,
Muscarinic ACh receptors and activation of
the CREB and ERK signalling pathways
[70]
BioCeuticals Cognition
Support Formula® a
standardized formulation
of three herbs
Proposed Randomized placebo-
controlled clinical trial
outcome measures of visual short- term memory and
attention; mean speed (ms), accuracy (%), and total
number of hits, misses, and anticipations) compared
with placebo
Combined effects of the three herbs [73]
Sailuotong a standardized
herbal formulation
containing Panax ginseng,
Ginkgo biloba, and Crocus
sativus
Randomized placebo- controlled
clinical trial
Resulted in small improvements in working memory Combined effects of the three herbs [71]
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TABLE 5.1 (Continued)
Plants and Herbs with nootropic abilities
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Herbs with Nootropic Efficacy
role in the prevention of several chronic diseases and more recently their ability to enhance memory
as well as prevent and/ or mitigate age- related cognitive decline. Bioactive compounds are present
effects on health that exceed basic nutritional value [75
76, 77]. The results of numerous
epidemiological studies have suggested that the consumption of diets rich in bioactive compounds,
development of neurodegenerative diseases and age- related functional decline [75, 78]. A number
of preclinical studies have also reported the memory- improving effects of a bioactive compound-
rich diet in rodent brain function [79– 81]. Bioactive compounds with nootropic abilities (Table 5.2)
include bacosides, l- ascorbic acid, resveratrol, curcuminoids, berberine, lycopene, ginkgolides,
epigallocatechin- 3- gallate, ginsenosides, and loganin.
Bacosides are considered the putative bioactive constituents of Bacopa monnieri [82]. Studies
Bacopa monnieri
enhancing acetylcholine synthesis, preventing the accumulation of lipofuscin accumulation and
inhibiting lipid peroxidation [83
suppression of lipid peroxidation, apoptosis, free radical scavenging and regulation of neurotrans-
mitter levels and their activities [84]. Although the nootropic effects of Bacopa monnieri have been
attributed to its bacoside content, with several over- the- counter supplements containing bacoside-
enriched Bacopa monnieri extracts, the result of a recent study by Arora et al. [85] revealed that
enrichment of Bacopa monnieri
Bacopa monnieri.
Curcumin is an active constituent of Curcuma longa. Curcumin has potent antioxi-
Curcuma
longa to improve learning and memory function [86]. In recent times, several studies have
examined the nootropic effects of curcumin itself in learning and memory paradigms [86–
88]. Chang et al. [88] examined the memory- enhancing effects of curcumin in middle- aged
working memory decline. The study also suggested that for effective prevention of age- related
memory decline, interventions should commence in the early middle age period. Han et al.
[86] examined the effects of curcumin on memory in transgenic mice and reported that dietary
increase in percent alternation when compared with control mice. Also, curcumin supplemen-
tation resulted in a decrease in the expression of high- mobility group box- 1 protein, Toll- like
B in the hippocampus of these transgenic mice. ElBini- Dhouib et al. [81] also examined the
effects of curcumin in aluminium chloride- induced neurotoxicity and observed that curcumin
Ortiz- Romero et al., [87] also examined the impact of the coadministration of curcumin and
verapamil on memory domains in Williams- Beuren syndrome (a rare neurodevelopmental dis-
order characterized by a distinctive cognitive phenotype). The results showed that co- treatment
the reduction of activated microglia [87]. Numerous mechanisms, including free radical scav-
enging, metal chelation, modulation of enzyme activities, and modulation of gene expression,
have been suggested as possible mechanisms through which curcumin acts [86– 88].
Green tea contains a large amount of catechins although when fully fermented, catechins undergo
3- gallate (ECCG), (– )- epigallocatechin, (– )- epicatechin- 3- gallate, and epicatechin make up
more than two- thirds of all tea polyphenols. In brewed green tea, EGCG is the most abundant
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Plant-based Foods and their Implications in Brain Health
TABLE 5.2
Plant Bioactive constituents with nootropic abilities
Plant Study Effect References
Bacoside 200 mg/ kg of bacoside was orally administered for
3 months to middle- aged and aged rats
Results suggested that bacosides may act as a potential therapeutic intervention in
forestalling the deleterious effects of ageing
[83]
Curcumin
Curcumin and
verapamil
model of AD
Middle- aged and aged rhesus monkeys
Transgenic mice
Williams- Beuren syndrome complete deletion (CD)
mice
Reduced oxidative stress, improvement of spatial memory and decreased the hallmarks
Middle- aged subjects given curcumin exhibited better working memory performance
and less neuronal excitability compared to control subjects.
expression of high- mobility group box- 1 protein, Toll- like receptors- 4, advanced
expression in the cortex and the reduction of activated microglia
[81]
[88]
[86]
[87]
Epigallocatechin- 3-
gallate
AD mouse model
Williams- Beuren syndrome complete deletion (CD)
mice
Decrease in the escape latency period, increase in the time at the target quadrant,
decrease in the hyperphosphorylation of Tau, expression and activity of BACE1
expression and increase in acetylcholine levels
Long- term oral administration of EGCG ameliorated spatial learning and memory
impairments and rescued the reduction in synaptic proteins
mitigate short- term memory loss in Williams- Beuren syndrome
[91]
[93]
[92]
[87]
Berberine 3×Tg AD mice
Mice
Diabetic rats
of tau hyperphosphorylation via modulation of the activity of Akt/ glycogen synthase
Chronic administration at 5 mg/ kg body weight improved long- term memory acquisition
in mice, and increased concentration of parvalbumin- immunoreactive neurons and
[94- 96]
[97]
[98]
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103
Herbs with Nootropic Efficacy
Bilobalide Rat model of vascular dementia and Alzheimer’s
dementia
[101, 102]
Ginkgolide B
Ginkgolide K
Rat model of vascular dementia
APP/ PS1 mice
Improved learning and memory function in rats with vascular dementia through the
reversed memory impairment and downregulated the expression of mitochondrial
calcium (Ca
2+
) uniporter
[99]
[100]
Ginsenoside
Rg5 or Rh3
Ginsenoside Rg2
Ginsenoside Rh1
Scopolamine- induced cognitive impairment in mice
25- 35
Mice
reversed scopolamine e induced decrease in latency time, increased spontaneous
alteration and shortened escape latencies. Decreased acetylcholinesterase activity,
modulated the expression of hippocampal brain- derived neurotrophic factor and the
activation of cAMP response element- binding protein
Improved learning and memory through its ability to increase the ratio of Bcl- 2/ Bax
ratio, attenuate the cleavage of caspase- 3, and enhance the phosphorylation of Akt
Long- term administration enhanced learning and memory in the passive avoidance test
and Morris water maze through the enhancement of hippocampal dentate gyrus cell
survival and the upregulation of brain- derived neurotrophic factor expression
[103]
Cui et al., 2021
Hou et al., 2014