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Plant-based Foods and their Implications in Brain Health
14.5 GENERAL BIOSYNTHESIS OF INDOLE ALKALOIDS (FIGURE 14.3)
14.6 TOXICITY OF EDIBLE ALKALOIDS
Since the earliest time, mankind has been using different kinds of plants in various aspects of life.
In today’s era, it is known that plants possess numerous potent medicinal values because of the
presence of different types of secondary metabolites like alkaloids, phenols, glycosides, terpenoids,
etc. Among these, alkaloids is a large group of secondary metabolites, which produce different
FIGURE 14.3 General Biosynthesis of Indole Alkaloids.
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Effect of Edible Alkaloids on Memory and Behaviour
physiological changes in humans and animals when consumed. This is due to the presence of a
nitrogen atom within the heterocyclic ring of alkaloids. However, some alkaloids are also found to
produce toxic effects in humans and animals. Toxic Alkaloids may come in contact with animals
and humans via inhalation, swallowing, or direct contact, which may produce hepatotoxicity, neuro-
toxicity, genotoxicity, and musculoskeletal deformities. They also produce various side effects like
hypersensitivity, nausea, vomiting, psychosis, paralysis, gastrointestinal problems, arrhythmias, and
sometimes death. Some alkaloids that have been reported to produce toxic effects are listed below.
1. Pyrrolizidine Alkaloids (PA):
Pyrrolizidine alkaloids (PA) are ester alkaloids found in the plant families Asteraceae,
Boraginaceae and Fabaceae. These alkaloids are toxic because they include necine and necic
form a heterocyclic nucleus with a single nitrogen atom at position 4. A 1– 2 double bond in the
in one of the ester side chains all contribute to hepatotoxicity. PAs occurs spontaneously in plants
in the form of free base and n- oxide. Both of these forms are non- toxic; however, hepatic cyto-
chrome P- 450 quickly dehydrogenates the free base forms of PAs to ester pyrrole intermediates
and dehydro- alkaloids (DHA), which are powerful electrophiles [16]. These electrophiles can
or glutathione (GSH). PAs are hepatotoxins that can act chronically or acutely depending on the
dose and time of exposure [17]. PAs have been associated with liver centrilobular haemorrhage
and necrosis, also known as veno- occlusive liver disease (VOD) [18]. VOD is the cause of cir-
rhosis and death. Several cases of PA poisoning have been reported in the United States [19],
Afghanistan [20], Jamaica [21], the United Kingdom [22], Egypt [23], India [24], Israel [25], and
Scotland [26]. There have also been some documented cases of VODs induced by PAs: as stated
by [27], a newborn baby got VOD from nursing from a lady who had consumed herbal tea for
almost the entire pregnancy. VOD outbreaks have occurred in places like Central India [24] and
Afghanistan [20]. There is currently no antidote for natural compounds that cause liver damage,
such as veno- occlusive disease. It can be treated by minimizing and managing its use.
2. Aconitine:
Aconitine is a diterpene alkaloid produced by various plant species belonging to the family
Aconitum. It is mainly found in plants like Aconitum napellus and Aconitum vulparia. It is a
highly toxic alkaloid, and in our history, it is well known for its usage in arrow poisons for
assassinations or common poisons in homicides. Greek mythology refers to Aconitum napellus
to be aconite. [28]. Aconitine is highly lipophilic and can be readily reabsorbed through the
skin. Aconitine induces quick paralysis and anaesthesia by inhibiting the presynaptic release of
acetylcholine and activating Na+ channels. All the species aconitine genus are highly toxic and
poisonous to humans and animals. A study was conducted [29] examining the neurotoxic effects
of aconitine on cerebral cortex neuron cells generated from newborn SD rats and the underlying
mechanisms responsible for those effects. Aconitine had an impact on the morphology of neuron
cells, causing synapse fracture, membrane fragmentation, mitochondrial swelling, cytoplasmic
vacuoles, and nuclear chromatin condensation and accumulation. The study reported that acon-
itine was neurotoxic to neuron cells of SD rats, which was caused due to the inhibition of
in the cells and resulted in the injury of these cells. Another study conducted by [30] reported
brain tissue damage caused by aconitine. This study investigated the neurotoxicity of acon-
itine and the underlying mechanism. The rats were administered intragastrically with different
concentrations of aconitine solution. After an interval of 30 mins, it was found that at lower
concentrations of 0.5mg/ kg and 1.5 mg/ kg showed mild neurological symptoms like increased
286
Plant-based Foods and their Implications in Brain Health
oral secretion, shortness of breath and unsteady gait. At higher concentrations, like 2.5 mg/
kg, the previous symptoms got worse, including weakness in the hind limb. Blood capillaries
had enlarged, neurons were sparse and had a disordered arrangement, the neuronal nucleus had
shrunken, and the matrix structure had become critically swollen. Evans blue (EB) extravasation
and evaluation of tight junction protein expression were carried out to determine the blood- brain
barrier’s permeability. When compared to the control rats, the rats in the treated groups had con-
siderably more EB in their cerebral tissue. Using the TUNEL assay, the toxic effects of aconitine
on rat neurons were determined. Aconitine was found to cause rat brain tissue damage, with the
severity of the damage increasing with dosage. The colour of the neurons’ nucleus became even
more intense in the group that received drug treatment, indicating severe apoptosis. The MTT
assay was used to assess the cell damage caused by aconitine. According to the results, raising
the aconitine concentration made the drug’s effect on PC12 cell viability much more restrictive.
The results concluded that aconitine induces brain tissue damage by increasing the penetrability
of the blood- brain barrier in the cerebral region and over- activating the endoplasmic reticulum
stress.
3. Tropane alkaloids:
Tropane alkaloids (TA) are important secondary plant metabolites that are primarily concentrated
in the Solanaceae and Erythroxylaceae groups of plants. The TAs can be categorized into hyos-
cyamine and scopolamine, cocaine, and calystegines. Their unique bicyclic tropane ring system
distinguishes them. Although all TAs have a similar basic structure, their biological, chemical,
and pharmacological characteristics vary greatly. Due to its effectiveness in treating nausea,
vomiting, motion sickness, and smooth muscle spasms, scopolamine, also known as hyoscine,
has the largest legitimate pharmaceutical market, whereas cocaine is the second most often used
illicit substance worldwide. TA from the Solanaceae family are common in poisonous plants
(Hyoscyamus niger, Datura, Atropa belladonna, Scopolia lurida, Mandragora ofcinarum), as
well as the Erythroxylaceae family (Erythroxylum coca). These substances have anticholinergic
effects because they can bind to either muscarinic or nicotinic receptors, inhibiting the function
of the neurotransmitter acetylcholine in the central and peripheral nervous systems. They are
utilized as bronchodilators, anaesthetics, antispasmodics, antiemetics, and mydriatics and are
hence of major therapeutic value. TAs also serve as lead components to develop new drug
molecules with great therapeutic value. The hallucinogenic properties of Atropa belladonna and
Datura stramonium have been well- known for centuries. They are freely accessible everywhere
in the globe and have been utilized by individuals for religious and medicinal causes. Accidental
consumption can result in intoxication, particularly in youngsters. A study [31] reported the
effects of Jimson weed (Datura stramonium L.) alkaloid extracts on cognitive performance,
antioxidant state, and activity of enzymes of rats involved in the monoaminergic and cholin-
ergic systems of neurotransmission. For 30 days, rats received extracts at doses of 100 and 200
mg/ kg body weight. The rats underwent behavioural tests using a hole board and spontaneous
of the antioxidant enzymes catalase, glutathione S- transferase (GST), superoxide dismutase
(SOD), and acetylcholinesterase (AChE), as well as malondialdehyde (MDA) and total thiol
(TSH) contents of their brain homogenates were assessed. According to the results, rats that
were given the extracts displayed a lower memory index and an increase in anxiety- like behav-
iour. Hyoscyamine (atropine), scopolamine, amphetamine, cathine, phenlyephirine, and Tropine
-
ization. As a result, one of the main biochemical mechanisms facilitating the ability of Jimson
weed fruit and leaf alkaloid extracts to induce cognitive function impairment that could be sig-
antioxidant systems in the brain of rats that were administered with the alkaloid extract from leaf
and fruit of Jimson weed (Datura stramonium L).
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Effect of Edible Alkaloids on Memory and Behaviour
14.7 EFFECT OF β- CARBOLINE ON MEMORY & BEHAVIOUR
has a similar structure to tryptamine. Harmane (HA; 1- methyl- carboline), 9H- pyrido [3, 4- ] indole
methoxy- 1- methyl- 9H- pyrido [3, 4- b] indole). They have been found in plant- derived beverages,
common plant- derived meals (rice, wheat, corn, mushrooms, barley, soybeans, vinegar and grapes)
Peganum
harmala were harmane, norharmane, and harmine [32].
Peganum harmala L. (P. harmala) is a plant endemic to North Africa and China. Because of
P. harmala is used in traditional medicine to treat a variety of
ailments. P. harmala yields seven alkaloids: harmaline, harmine, harmalol, harmole, vasicine,
pharmacological actions, including sedative, hypnotic, anxiolytic, anticonvulsant, anticancer,
antithrombotic, antiseptic, antibacterial and antiviral properties. Harmine is a naturally occurring
Syrian rue (Peganum harmala) and the Banisteriopsis caapi vine, both of which are often used to
make ayahuasca (Hallucinogen beverage). Preclinical research suggests that harmine may have
neuroprotective and cognitive- enhancing effects and retrospective/ observational studies of the
mental health of long- term ayahuasca users suggest that longer use of this harmine- rich hallu-
cinogen is associated with improved neuropsychological functioning. Acute systemic treatment
memory (LTM).
aversive memory tasks, enhancing principally LTM memory, and electrophysiological evidence
reveals that harmaline induced tremor by activating the inferior olivary nucleus and cerebellum
[33; 34]. It has also been studied that harmaline blocks both associative and motor learning,
although it is unknown whether the inferior olive or another area mediates this effect on learning
and memory. The behavioural effects of harmine on rats were investigated. The effects of harmine
indicated that harmine reduced immobility while increasing climbing and swimming duration
compared to the saline group. Harmine demonstrated an anti- naloxone- induced morphine with-
drawal syndrome effect in morphine- dependent rats. Harmine activates the CNS by inhibiting the
metabolism of amine neurotransmitters and enhancing dopamine release, suggesting its use in
treating brain illnesses [35]
(Table 14.2)
TABLE 14.2
Effects of β- carbolines on depression and memory [36]
Depression
carbolines bind to in the brain. We also know that these alkaloids increase extracellular norepinephrine,
Memory
they can cause memory impairment in certain investigations. Benzodiazepines and beta- CCM seem to
target the acquisition (learning) phase of memory processing.
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Plant-based Foods and their Implications in Brain Health
14.8 EFFECT OF MURRAYA KOENIGII ON MEMORY & BEHAVIOUR
Murraya koenigii Linn. In Hindi, belonging to the family Rutaceae is commonly known as
of Asia. Fresh or dried leaves are added to the vegetables, other curry food items, and some-
and astringent [37]. The leaves of this plant are reported to have hypoglycaemic and anti- diabetic
[38], antibacterial [39], antioxidant [40; 41], hepatoprotective [42], chemo modulatory [43],
immunomodulatory [44], wound healing [45][46]. All aspects of
perception, learning, reasoning, and memory are part of cognition. Behavioural issues, dementia,
and delirium are examples of cognitive dysfunctions. As documented by [47] the alkaloidal extract
of M. koenigii leaves (MKA) was used to determine the cognitive functions and brain cholin-
esterase activity in Swiss Albino mice. In this study, about (2 kg) of fresh leaves of M. koenigii
were collected and dried in the shade. The dried leaves were crushed into coarse powder form and
subjected to extraction. The extraction was carried out in a Soxhlet apparatus using methanol as the
0.5 M H
2
SO
4
, and then it was washed with chloroform. The aqueous acidic fraction was collected
and again extracted with chloroform. Preliminary phytochemical evaluation and NMR analysis
groups according to various interoceptive and exteroceptive memory models. MKA (10, 20, and
30 mg/ kg) was given orally for 15 days. The mice were exposed to a training session utilizing an
elevated plus maze and a passive avoidance apparatus on the 15th day following the last MKA
treatment, and retention memory was recorded after 24 hours on the 16th day. On the 15th day,
the animals were given scopolamine (0.4 mg/ kg, i.p.). This well- known centrally acting cholin-
ergic probe interferes with memory and cognitive function in human and experimental animals
or diazepam (1 mg/ kg, i.p.) to produce amnesia in separate groups of young mice (Interoceptive
models). After 45 minutes of scopolamine and diazepam injection, the animals were subjected to a
training session and the retention memory was assessed after 24 hours on the 16th day. Piracetam
nootropic drug. MKA (10, 20, and 30 mg/ kg) was administered orally to separate groups of young
and elderly mice for 15 days as part of a biochemical study. Metrifonate (50 mg/ kg, i.p., and 60 min
before dissecting the brain) was used as the positive control for comparison of brain cholinesterase
activity. Memory was tested using exteroceptive behavioural models such as the elevated plus
maze and the passive avoidance apparatus. The interoceptive behavioural models were diazepam,
scopolamine, and age- induced forgetfulness. In elevated plus maze and passive avoidance para-
digm maze models, mice given MKA extract (20 and 30 mg/ kg, p.o.) had inhibitory effects against
acetylcholine levels in the brain.
14.9 EFFECT OF ANONAINE ON MEMORY & BEHAVIOUR
Anonaine is a bioactive benzylisoquinoline alkaloid, largely found in members of plant families
like Magnoliaceae and Annonaceae. Annona squamosal Linn, is one of the plants from the family
Annonaceae. It is a native plant of the West Indies, and it is also cultivated throughout India. It
is commonly known as sitaphal and custard apple or sugar apple. It has been reported to have a
wide range of biological activities like vasorelaxant, antibacterial, antifungal, antioxidant and anti-
depressant effects [48] and epilepsy [49]. The plant leaves are reported to possess several alkaloids
50]. A study was conducted on Annona squamosa’s
neuroprotective effects on epileptic rats’ spatial learning and memory as well as GABAergic receptor
289
Effect of Edible Alkaloids on Memory and Behaviour
binding in the cerebral cortex. The leaves of Annona squamosal were collected and extracted using
a hydro- alcoholic solvent in the Soxhlet apparatus for 24 hours. Adult male Wistar rats were used
to screen the neuroprotective effect of the plant’s extract and its isolated content Anonaine. The rats
were injected with pilocarpine to produce status epilepticus, which was allowed to continue for 1
hour, and then all the animals were treated with diazepam. Rats that showed recurrent seizures were
used for further experiments. The objective of the research was to reveal that Annona squamosa,
which contains the active alkaloid (- ) Anonaine, protects against epilepsy by acting on GABA
receptors. Confocal microscopy was used to examine the prospective uses of Annona squamosa and
its isolated chemical component (Anonaine), as well as variations of GABA, GABAA, and GABA
receptors in the cortical region of the brain of epileptic rats. In the radial arm and y- maze models, the
extract of Annona squamosa leaves and its isolated constituent, Anonaine, demonstrated memory-
improving and memory- recovering properties. The data from the results concluded that Anonaine,
an alkaloidal component of Annona squamosa leaves, improves the behaviour of epileptic rats and
their diminished GABA receptors [51].
14.10 CONCLUSION
Alkaloids are considered one of the major plant sources that can produce marked physiological
effects in humans and animals and are also major contributors to different types of drugs and
pharmaceuticals. Throughout history, alkaloids have been found to produce several toxicity effects.
The authors have enlisted some of the major alkaloids known to produce toxic effects and some
alkaloids had been found to promote brain health and behaviour. The information provided in this
chapter mainly focused on the edible alkaloids that produce marked effects on memory and behav-
iour, which will support and strengthen research in exploration of potent memory enhancers and the
treatment of major neurodegenerative diseases.
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DOI: 10.1201/9781003300502-15
15
Caffeine and Motor Skills
Robert Lalonde and Catherine Strazielle
15.1 INTRODUCTION
15.1.1 pharmaCologiCal profile and pharmaCokinetiCS
Over 80% of people in the world drink caffeine products every day [1], all the more because of its
blood half- life of 4 hours among regular drinkers [2– 4]. It is mainly catabolized in the liver by cyto -
chrome P450 and excreted in urine [5]. Also named 1,3,7- methylxanthine or methyltheobromine,
caffeine is an alkaloid from the methylxanthine class [6] known for its bronchodilator properties due
to antagonism of adenosine receptors and inhibition of phosphodiesterase [5, 7].
15.1.2 Stimulant propertieS
Caffeine is known as a stimulant by virtue of its antagonism of adenosine receptors, the neuromodulator
acting as an inhibitor of neuronal activity [8– 11]. More precisely, caffeine is an antagonist at A
1
,
A
2A,
A
2B,
and A
3
adenosine receptors [12, 13] widely distributed in the brain (Figure 15.1), with high
levels found for A
1
receptors and lower levels for A
3
ones in cerebral cortex, striatum, cerebellum,
and thalamus, while A
2A
receptors are abundant in basal ganglia and blood vessels and A
2B
in hippo-
campus, nucleus accumbens, and hypothalamus [14- 16], all of these furnishing explanations as to
why caffeine affects sensorimotor functions, arousal, selective attention, emotions, and cognition. In
1
and
A
2A
receptors, but higher concentrations are necessary to activate A
2B
and A
3
ones [17]. Its appealing
stimulant properties by day are hampered as a disrupter of circadian rhythms due to the delayed
release of melatonin at night [18].
mg/ kg) every other day over a 2- week period in rats [19] or caffeine injected acutely at 10 mg/ kg in
mice [20] or rats [21], but this dose was without effect in the latter after one week of injections [22].
Caffeine- induced hyperactivity was also evident when rats explored a Y- maze [23]. Hyperactivity
was correlated with A
1
receptor binding in mouse whole brain membranes when a series of
methylxanthines were examined [24]. Caffeine- induced hypermobility in mice was prevented by
removing A
2A
receptors from the shell region of the nucleus accumbens via the Cre/ loxP gene tech-
nique [25]. At higher doses, caffeine sometimes increased [26,27] and sometimes decreased [28]
-
action [28, 29], hole- board [29], elevated plus- maze [28, 30], and light- dark box [30] tests. Because
-
31].
292
Plant-based Foods and their Implications in Brain Health
Since adenosine receptors are heavily concentrated in sensorimotor brain regions, the effects
of caffeine on motor coordination are a worthwhile point of investigation, all the more so when
considering that 10 mg/ kg caffeine increased glucose utilization in rat brains at the level of substantia
nigra, dorsal striatum, globus pallidus, red nucleus, pontine grey, cerebellar cortex, and vestibular
nucleus [32]. Moreover, coffee drinkers displayed different levels of connectivity from non- coffee
drinkers in motor- related regions based on functional magnetic resonance imaging [33]. The main
purpose of the present review is to answer the following interrogations: 1) caffeine is known to
improve selective attention and vigilance tasks [34– 36], but does it help to coordinate movements
in normal subjects? 2) Is caffeine helpful in coordinating the movements of patients with neural
disorders? 3) Under which conditions does caffeine worsen motor coordination? The inclusion of
animal studies targeting motor coordination should contribute more precisely to our understanding
of caffeine’s role in human motor skills.
FIGURE 15.1 Cartography of the adenosine subtype receptors in the sensorimotor control regions of the
brain, i.e. the fronto- parietal (M1 as primary motor and S1 primary sensory areas) and prefrontal cortices,
the cerebellum, and the striatum with the caudate nucleus (1), the lenticular nucleus (2), the pallidal regions
with the globus pallidus (3), the nucleus accumbens (4), the putamen (5) as well as the subthalamic nucleus
(6) and substantia nigra (SN). Two limbic structures, the amygdaloid body (AB) and a part of the hippocampal
formation presented as a complement. The densities of different receptor- subtypes (A1, A2A, A2B, and A3)
appear as a function of the size of the letters used, the highest density presented with the larger letters.
293
Caffeine and Motor Skills
15.2 MOTOR SKILLS IN NORMAL SUBJECTS
15.2.1 human SubjeCtS
37], and
caffeine may improve performances during sporting competitions, results perhaps due to better motor
coordination but also sharper vigilance, endurance, and memory [38– 41]. In particular, 6 mg/ kg caffeine
enhanced ball- passing accuracy and jump performance in simulated soccer [42], accelerated reaction
times to the non- dominant side in a reactive agility test by soccer players [43], and quickened reactive
agility, decision, and movement times in simulated team- sport exercise [44] in men. Likewise, 250 mg
of caffeine increased letter search though not navigational chart accuracy in experienced seamen [45],
and 4.5 mg/ kg of caffeine improved handwriting movements in skilled writers [46]. On the contrary,
3 mg/ kg caffeine had no effect on the accuracy of épée fencers despite a lesser degree of fatigue [47].
Among standard laboratory tests, various results have been obtained in regard to reaction or
selective attention and visuomotor speed, functions that underlie most motor skills. On one hand, 300
though not 600 mg caffeine speeded up reaction times and movement times in normal subjects [48],
and 250 or 500 mg [49] as well as 250 or 500 mg/ 70 kg [50] caffeine improved performances on the
digit symbol substitution task, tapping speed [49], and the repeated acquisition and performance pro-
cedure [50] in healthy adults. Moreover, 100 mg of caffeine speeded up reaction times in the Stroop
51]. A dose of 300 – 350 mg of
caffeine improved balance scores in healthy adults [52]. On the other hand, 120 mg caffeine had no
effect on the digit symbol substitution task in women [53] and neither did 3 mg/ kg caffeine affect the
Stroop test in fencer athletes [47]. Moreover, in healthy young adults, 60 mg caffeine had no effect on
visuomotor tracking and pegboard tasks [54], nor did 200 or 400 mg caffeine affect bimanual tapping,
time discrimination, or grip and lift tasks despite speedier simple reaction times [55], nor did 3, 6, 9
mg/ kg caffeine affect postural stability [56], nor did 5 mg/ kg caffeine affect three motor skill tasks
comprising standing balance, manual dexterity, and running time [57], nor did 6 mg/ kg caffeine affect
standing balance during perceptual- cognitive tasks [58]. A dose of 30 mg caffeine even deteriorated
hand steadiness [59] in healthy women, as did 6 mg/ kg caffeine in adult subjects [60, 61], in all three
cases without disturbing tapping rate, in line with reports of hand tremor felt by 2% of coffee drinkers
[62]. Moreover, 5 mg/ kg caffeine decreased hand steadiness as well as retarding hand tracing and pin-
placement dexterity tests in caffeine- naïve though not caffeine- familiarized women [63, 64]. Caffeine
has been given after training sessions to test the retention of sensorimotor training. Post- trial 200
mg caffeine increased memory as measured by reaction times of a keyboard sequence [65] without
affecting a visuomotor skill task [66] in adult subjects.
In contrast to minimal effects on the dexterity of younger subjects, 100 mg caffeine accelerated
the gait speed of middle- aged women in single and dual tasks [67], and 3 mg/ kg caffeine improved
the Minnesota manual dexterity turning test score as well as upper and lower limb performance in
68]. Yet when two age groups in the range of 20– 25 or
50– 65 years were compared, 250 mg caffeine improved digit symbol substitution and speeded up
reaction times to target letters in both groups but improved rapid information processing and tapping
rate only in young subjects [69]. Thus, at a dose as low as 250 mg/ kg, caffeine improves the speed
of responding underlying all motor skills in young subjects, but results are more limited on tests of
manual dexterity or postural stability when it may have a more favourable impact in older people, a
15.2.2 miCe and ratS
Motor coordination in mice and rats is evaluated with inclined screen, pole- climbing, tube (a.k.a.
chimney), stationary beam, bar- holding, and rotorod tests [70– 74]. As found in human subjects,