Environmental Toxicology and Pharmacology 21 (2006) 331337

Datura stramonium in asthma treatment and possible effects

on prenatal development
E. Pretorius , J. Marx
Department of Anatomy, School of Health Sciences, Medical Faculty of the University of Pretoria, Pretoria 0001, South Africa
Received 11 July 2005; accepted 19 October 2005
Available online 6 January 2006

Abstract
Southern Africa has a variety of medicinal plants, used as remedies; however, little information is available regarding the cytotoxic potential,
particularly when used during pregnancy. One such plant is Datura stramonium (DS) (Solanaceae), used frequently as an anti-asmatic treatment.
DS contains a variety of alkaloids including atropine and scopolamine that can cause anticholinergic poisoning if taken in large doses. Atropine
and scopolamine act on the muscarinic receptors by blocking them (particularly the M2 receptors) on airway smooth muscle and submucosal gland
cells. However, this will cause a continuous release in acetylcholine (Ach). Ach also act on nicotinic receptors; however, it is known that over
exposure of nicotinic receptors may cause desensitization. We suggest that exposure of the foetus to DS when a mother uses it for asthma, will
cause a continuous release of Ach, resulting in the desensitizing of nicotinic receptors, this could ultimately result in permanent damage to the
foetus. Therefore we conclude that this African herbal remedy should be used with caution during pregnancy.
2005 Elsevier B.V. All rights reserved.
Keywords: Datura stramonium; Asthma; Muscarinic and nicotinic receptors

1. Introduction
South Africa has great cultural diversity, with many people
using a wide variety of plants in their daily lives for food, water,
shelter, fuel, medicine and the other necessities of life. This
country is exceptionally rich in plant diversity with more than
30,000 species of flowering plants, of which approximately 4000
species are used as medicine. In the last few decades the country
has experienced positive changes in access to modern health
care and education (Van Wyk and Gericke, 2000), but despite the
westernization through urbanization and education, the belief in
traditional healers and remedies, made mostly from indigenous
plant material, remains firm.
Mulholland and Drewes in 2004 estimated that there are 27
million indigenous medicine consumers in Southern Africa and
a significantly large number of these patients consult traditional
healers for potentially life threatening conditions (Mulholland
and Drewes, 2004). Traditional healers have been around for
Corresponding author at: BMW Building, P.O. Box 2034, Faculty of Health
Sciences, University of Pretoria, Pretoria 0001, South Africa.
Tel.: +27 12 319 2533; fax: +27 12 319 2240.
E-mail address: resia.pretorius@up.ac.za (E. Pretorius).

1382-6689/$ see front matter 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.etap.2005.10.006

thousands of years and are an established part of many African

cultures, but it is interesting that in order to become a traditional
healer, it is done through spiritual endowment and not through a
course of study (Dickinson, 1990). Traditional healers are most
commonly known by the Zulu people as inyangas or herbalists
and isangomas or diviners; however, the distinction between the
two has become blurred, with both using herbal medication (Van
Wyk et al., 2000).
The broad use of traditional medicine by particularly rural
African communities is attributed to its accessibility and affordability and therefore the use of herbal medicine is becoming progressively more popular worldwide (Steenkamp, 2003). However, despite routine use of herbal medicine, the pharmacological
properties are essentially unknown (Gundidza, 1985).
One of the plants used as traditional medicine is Datura
stramonium (DS) (Solanaceae), also known as jimson weed
or thorn apple, is a wild growing plant, used frequently as an
anti-asmatic treatment and it is also known for its hallucinogenic and euphoric effects (Muller, 1998; Weitz, 2003; Ertekin
et al., 2005). This plant not only occurs indigenously in Southern Africa, but also on other areas of the world, and was e.g.
also used by Red Indians for many years as euphoric agent and
since the 1800s, used as a therapeutic agent and in Great Britain

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E. Pretorius, J. Marx / Environmental Toxicology and Pharmacology 21 (2006) 331337

(Dessanges, 2001). However, over dosage can result in severe

toxicity (Ertekin et al., 2005). Furthermore, this plant as herbal
remedy is also frequently given to pregnant mothers with asthmatic complaints. DS contains a variety of alkaloids including
atropine, hyoscamine and scopolamine that can all cause anticholinergic poisoning if taken in large concentrations (Ertekin
et al., 2005); however, it is also these anticholinergic alkaloids
that contribute to the anti-asmatic properties and it is therefore
classified as a plant with anticholinergic properties (Friedman,
2004). Atropine is found to have more exciting properties, while
scopolamine has more relaxing and hallucinogenic properties
(Weitz, 2003). These compounds inhibit or block the physiological action of acetylcholine at a receptor site, and specifically at
the muscarinic receptor.
However, the question that arises is, how will this plant
with its two active ingredients affect the unborn baby, as it is
known that non-selective anticholinergic agents such as atropine
block both the pre-junctional (M2 ), post-junctional (M3 ) receptors (Rodrigo and Rodrigo, 2002) as well as the M1 receptors
(Barnes, 2000) (discussed in detail in later paragraphs). Due
to the blockade of the M2 receptors in particular, non-selective
antagonists may increase the amount of acetylcholine that is
released by cholinergic nerve stimulation (Rodrigo and Rodrigo,
2002). Furthermore, how will the physiology of the nicotinic
receptors, which are also part of the cholinergic receptor family,
be influenced?
Here we hypothesize that prenatal exposure to DS will cause
increased acetylcholine release, which will result in damage to
particularly neural tissue. In the following paragraphs the cholinergic mechanism in the physiology of asthma will be discussed
in order to provide background on how DS, and mainly its anticholinergic properties may contribute to its use as anti-asthmatic
herbal medicine. Also, functioning of muscarinic and nicotinic
receptors will be discussed, mostly because muscarinic receptor
dysfunctioning is implicated in asthma. In order to substantiate our hypothesis, an understanding of the physiology of these
two receptors is crucial, as we suggest that blocking of muscarinic receptors in the foetus, due to the use of DS will result
in increased acetylcholine (Ach), which will ultimately affect
all areas where these receptors are found, but particularly neural
tissue functioning. Also, nicotinic receptor functioning will be
negatively affected.
2. Cholinergic mechanism in the physiology of asthma
DS possess anticholinergic properties and anticholinergics
have proved to be of particular value not only in the treatment of
asthma, but also chronic obstructive pulmonary disease (COPD),
where vagal cholinergic tone appears to be the only reversible
component of airway narrowing, opposite to what happens in
asthma (Abad Santos et al., 2003). In order to understand the
reason why DS is classified as an anticholinergic and apparently
used with success as traditional herbal remedy in the treatment
of asthma, we give background on the physiology of asthma and
review the physiological action of anticholinergic products.
Asthma, characterized as acute respiratory distress, is a serious global health problem that has steadily increased in preva-

lence during the past two decades (Marx and Pretorius, 2004).
The National Asthma Education Program (NAEP) defines
asthma as a lung disease with the following characteristics: airway obstruction (or airway narrowing) that is reversible (but
not completely so in some patients) either spontaneously or
with treatment; airway inflammation and airway hyperresponsiveness to a variety of stimuli (Marx and Pretorius, 2004).
Although asthma is considered to be an inflammatory disease
of the airways, neural mechanisms remain very important. The
neural control of the airways is very complex with at least
three types of neural mechanisms recognized namely: cholinergic pathway, adrenergic pathway and the non-adrenergic noncholinergic (NANC) pathway. The efferent cholinergic pathway
represents a key mechanism in the control of airway smooth
muscle tone as well as a number of other physiological and
pathophysiological reactions (Gabella, 1987). Because DS is
classified as a plant with anticholinergic properties, the focus of
this article will only be on the cholinergic mechanisms.
2.1. Muscarinic receptors
Muscarinic receptors are intimately involved in asthma, and
are expressed in almost every cell type of the airway and lung
tissue, including airway and vascular smooth muscle, different
glandular and surface epithelial cells, endothelial cells and various inflammatory cells (Racke and Mathiesen, 2004). These
receptors belong to the G-protein coupled receptors and are
formed by a polypeptide that spans the membrane seven times,
and the N-terminus is outside and the C-terminus is inside the
cell (Racke and Mathiesen, 2004). The inside contains a Gprotein binding site, which is activated when acetylcholine binds
to the receptor. Five different muscarinic receptors have been
identified (Coulson and Fryer, 2003) and the airway and lung tissue contains three subtypes, namely: M1 , M2 and M3 (Campbell,
2000).
In the airways, M1 receptors found in parasympathetic ganglia facilitate cholinergic neurotransmission, and are expressed
mainly in peripheral lung tissue and alveolar wall (Racke
and Mathiesen, 2004). M1 enhances noradrenaline release,
which, in turn, opposes cholinergic-induced bronchoconstriction (Coulson and Fryer, 2003). In the lungs, M1 receptors on
parasympathetic ganglia inhibit the opening of K+ channels,
resulting in depolarization of parasympathetic ganglion cells
(Coulson and Fryer, 2003).
In 1984, Fryer and Maclagan demonstrated that the functional
M2 muscarinic receptors were present in the post-ganglionic
parasympathetic nerves supplying the lung where it inhibits the
release of Ach and therefore act as feedback inhibitory receptors
(autoreceptors) (Campbell, 2000). Ach is an important neurotransmitter of the parasympathetic nervous system, both at
the ganglionic transmission and the neuroeffector junctions of
the airways (Barnes, 2004). Ach is synthesized in the nerve
endings and accumulate in synaptic vesicles. Depolarizationinduced Ca2+ influx triggers the release of Ach into the extra
cellular space, which interact with receptors on target cells as
well as on the cholinergic nerves. Ach act on both the nicotinic and the muscarinic receptors (Racke and Mathiesen, 2004).

E. Pretorius, J. Marx / Environmental Toxicology and Pharmacology 21 (2006) 331337

333

Fig. 1. Diagrammatic representation of acetylcholine (Ach) release from nerve endings.

Fig. 1 represents the action of Ach as neurotransmitter. The

enzyme choline acetyltransferase (ChAT) synthesizes Ach using
acetyl-CoA and choline as substrates. ChAT is expressed in both
neurons and non-neuronal cells (Wessler and Kirkpatrick, 2001).
The action of Ach is terminated by acetylcholinesterase, which is
expressed both pre- and post-junctional in the vicinity of cholinergic nerves.
Originally M2 receptors were classified as cardiac-like
receptors (Fryer and Maclagan, 1984), however, they were subsequently classified as M2 receptors (Coulson and Fryer, 2003).
The activation of M2 receptors on the smooth muscle appears
to inhibit any relaxation of the smooth muscle caused by Badenoreceptor coupling (for detailed review see Racke and
Mathiesen, 2004). Relaxation of smooth muscle requires a conversion of ATP to cAMP, via activation of adenylate cyclase.
Protein kinases are activated by cAMP to mediate the effects
such as relaxation of airway smooth muscle. Therefore the M2
receptors inhibit adenylate cyclase to prevent relaxation (Fryer
and Jacoby, 1998; Coulson and Fryer, 2003).
The M3 muscarinic receptors mediate smooth muscle contraction (Racke and Mathiesen, 2004). M2 receptors support

M3 -mediated response, but lack any effect when M3 receptors

are blocked. M3 receptors cause contraction of airway smooth
muscle due to the activation of phospholipase C via Gq , resulting in the formation of IP3 and DAG. IP3 are ligand-gated Ca2+
channels at the side of intracellular Ca2+ stores (Coulson and
Fryer, 2003) and IP3 causes liberation of Ca2+ from the internal
stores, resulting in rapid transient increase in free cytosollin Ca2+
concentrations. This leads to activation of myosin light chain
kinase via Ca2+ -calmodulin, resulting in actinmyosin interaction and contraction. DAG triggers translocation and thereby
activation of protein C (PKC). PKC promotes agonist-induced
liberation of Ca2+ from intracellular stores and additional influx
of extra cellular Ca2+ this enhances the contractile process
(Racke and Mathiesen, 2004).
M2 receptors via G1/0 , can induce the opening of nonselective cation channels resulting in influx of sodium and Ca2+
ions. This appears to happen with simultaneous M3 -mediated
generation of IP3 and the resulting release of Ca2+ from intracellular stores. It is therefore seen that M2 and M3 support each
other in facilitating the contractile process of smooth muscles in
the airways.

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E. Pretorius, J. Marx / Environmental Toxicology and Pharmacology 21 (2006) 331337

Antagonism of the M1 and M3 receptors results in bronchodilation, primarily in the larger airways.
In both asthma and COPD, the M1 and M3 muscarinic
receptors on airway smooth muscle, submucosal glands and
blood vessels is fully functional, this is supported by numerous
researchers even under antigen challenge, viral infection, vitamin A deficiency, or ozone exposure in animal models (Coulson
and Fryer, 2003). However, it seems as if there is a loss of
inhibitory neuronal M2 muscarinic receptor function (Coulson
and Fryer, 2003), causing an continued Ach release and results
in an enhanced bronchoconstriction to vagal nerve stimulation.
Under normal conditions, M2 muscarinic receptors limit the
release of Ach from parasympathetic nerves (Coulson and Fryer,
2003) and is responsible for increased airway reactivity.
Mucus secretion in airways also plays an important role
in asthma, and muscarinic agonists can induce mucus secretion from airway tissue (Steel and Hanrahan, 1997; Racke
and Mathiesen, 2004). M3 receptors are involved in mediating
cholinergic stimulation of mucus secretion (Steel and Hanrahan,
1997). Ciliar beat frequency is also stimulated by acetylcholine
and muscarinic agonists and reduced by muscarinic antagonists
(Salathe and Bookman, 1995).
Eosinophils may also play an important role in the dysfunction of M2 muscarinic receptors and have been localized around
nerves in human asthma (Fryer et al., 1997). Eosinophils contain
charged proteins such as major basic protein (MBP), eosinophil
cationic protein and eosinophil peroxidase (Jacoby et al., 1993).
This dysfunction of the M2 muscarinic receptors may be due
to the release of MBP from eosinophils (Costello and Fryer,
1997)these MBP bind to M2 receptors, blocking their function (Jacoby et al., 1993; Fryer and Jacoby, 1998; Jacoby, 2004).
It has been found that eosinophil MBP is a selective, allosteric
antagonist for M2 muscarinic receptors (Jacoby et al., 1993) and
these receptors are particularly prone to blockade by positively
charged proteins, including poly-l-arginine, poly-l-lysine, basic
histone and protamine (Fryer and Jacoby, 1998). These proteins
bind to an allosteric site on the M2 receptor and inhibit agonist
binding (Hu et al., 1992). Interestingly, M3 muscarinic receptors are not affected by positively charged proteins. Fryer and
Jacoby (1998) therefore mentioned that charged proteins from
inflammatory cells might inhibit agonist binding to neuronal M2
muscarinic receptors without altering the M3 muscarinic receptors on airway smooth muscle. Jacoby in 2004 also mentioned
that multiple mechanisms might be involved except for the dysfunctional M2 muscarinic receptors. These include production
of interferons that may down-regulate the expression of the M2
receptor gene.
3. Anticholinergic treatment in asthma and COPD
Anticholinergic treatment is directed towards muscarinic
receptors within the lung by blocking muscarinic receptors
on airway smooth muscle and submucosal gland cells and by
inhibiting increased tone (Coulson and Fryer, 2003).
These products are the bronchodilators of choice in the management of chronic COPD (Barnes, 2004) and they act by blocking muscarinic receptors in airway smooth muscle and improve

COPD by reducing dyspnea and acute exacerbations (Casaburi

et al., 2002). Cholinergic tone appears to be the only reversible
component of COPD. Interestingly also, M2 muscarinic receptors are functional in patients with stable COPD (On et al., 2001).
In asthma, anticholinergic drugs decrease airway hyperreactivity
(Jacoby, 2004; Coulson and Fryer, 2003).
As mentioned in the introduction, DS contains a variety of
alkaloids including atropine and scopolamine, which both have
anticholinergic properties.
The question that now arises, is how does atropine and scopolamine affect muscarinic receptors?
3.1. Atropine and scopolamine as anticholinergics
Atropine is classified as competitive non-selective antagonist
of muscarinic cholinergic receptors (other non-selective anticholinergic drugs include ipratropium bromide and oxitropium
bromide). Wall et al. (1992) found that atropine regulate three
muscarinic receptor subtypes in rat cerebral cortex/dorsal hippocampus. The three subtype receptors were the M1, M2 and
M3 . Receptor density was improved after 14 days of therapy. Non-selective anticholinergic agents such as atropine block
both the pre-junctional (M2 ) and post-junctional (M3 ) receptors
(Rodrigo and Rodrigo, 2002); however, M1 receptors are also
blocked (Barnes, 2004). Thus, due to the blockade of the prejunctional M2 receptors, non-selective antagonists may increase
the amount of Ach that is released by cholinergic nerve stimulation (Rodrigo and Rodrigo, 2002) thus, the increased Ach
release may overcome the blockade of muscarinic receptors
in the muscle (Barnes, 2004). This may weaken the effect of
the post-junctional M3 muscarinic receptor blockade on airway
smooth muscle and submucosal glands. This suggests that antagonists that bind selectively to M3 and M1 receptors may be more
effective in inhibiting cholinergic effects in the airways (Rodrigo
and Rodrigo, 2002).
The natural anticholinergic, atropine, which is readily
absorbed across the oral and respiratory mucosa, is rarely used at
the present time; however, this drug was previously used extensively as a nebulized solution (Rodrigo and Rodrigo, 2002).
When taken orally, atropine is absorbed in the intestine, undergoes hepatic metabolism, followed by excretion via in the urine.
Furthermore, it has a plasma half-life of 23 h. Atropine can
cause an increase in heart rate and tachycardia as well as a
dry mouth and relaxation of smooth muscle in the gut, urinary tract and biliary treethis is due to the fact that it is a
sympathetic cholinergic blocking agent, and signs of parasympathetic block are dryness of the mouth, blurred vision and
increased intraocular tension. Furthermore, atropine may also
readily cross the blood brain barrier. Although atropine itself
has drawbacks, principally related to its rapid absorption and
consequent systemic side effects, its quaternary ammonium
congeners, atropine methonitrate and ipratropium bromide, are
poorly absorbed (Gross and Skordin, 1984). When given by
inhalation, they are as effective bronchodilators as atropine is,
but longer acting and much less prone to side effects (Gross
and Skordin, 1984). They act predominantly at a site that is
different from adrenergic agents and thus afford an alternative,

E. Pretorius, J. Marx / Environmental Toxicology and Pharmacology 21 (2006) 331337

complementary approach to the treatment of airways obstruction

(Gross and Skordin, 1984).
Oxitropium bromide is also a non-selective muscarinic antagonist but is based on scopolamine instead of atropine. It has a
longer duration of action (up to 8 h) than ipratropium bromide,
but it has a slower onset of effect (Rodrigo and Rodrigo, 2002).
The peak bronchodilator effect after administration occurs
within 12 h. Scopolamine is also a competitive non-selective
inhibitor, mimicking Ach at the neural synapses and depressing
the central nervous system. It is an antagonist of muscarinic M1 ,
M2 and M3 receptors in airways. Its most potent activity is manifested at the iris, ciliary body and secretory (salivary, bronchial
and sweat) glands. It is extensively metabolized and conjugated
with less than 5% of the total dose appearing unchanged in the
urine. Side effects of scopolamine usage or overdose, resulting in
CNS sedation, can include dry mouth, restlessness, giddiness,
disorientation, memory disturbances, hallucinations, delirium,
constipation and confusion.
We know that DS contains both the anticholinergics atropine
and scopolamine, and that herbalists frequently prescribe this
for asthma, even to pregnant mothers. Ach is affected by both
atropine and scopolamine. Ach also affects nicotinic receptors.
Therefore, although nicotinic receptors are not directly involved
in asthma of COPD, we briefly discuss it here, as enhanced Ach
production due to the use of anticholinergics such as DS during
pregnancy may ultimately also affect these receptors.
4. Nicotinic receptors
Nicotinic receptors produce pharmacologically and physiologically distinct responses from muscarinic receptors and nicotinic responses are of fast onset, short duration and excitatory
in nature. As with muscarinic receptors, nicotinic receptors are
found in a variety of tissues, including the autonomic nervous
system, the neuromuscular junction and neural tissue; here they
transduce cholinergic transmission at the synapses in the peripheral ganglia and in various brain areas (Gotti and Clementi,
2004). In the central nervous system, the cholinergic innervation acting via nicotinic receptors regulate transmitter release,
cell excitability and neuronal integration and play an important
role in physiological functions such us arousal, sleep, fatigue,
anxiety, the central processing of pain, food intake and a number of cognitive functions (Lindstrom, 1997; Gotti and Clementi,
2004). Furthermore, it is becoming evident that the perturbation
of cholinergic nicotinic neurotransmission can lead to various
diseases involving nicotinic receptor dysfunction during development, adulthood and aging (Lindstrom, 1997).
Nicotinic receptors in the brain differ from the muscle-type
hetero-pentameric subtypes because they contain no , or
subunits, and consist of various complements of 210 and
24 subunits (Wang and Sun, 2005). In the brain, nicotinic
receptors are mostly located at the pre-synaptic boutons regulating neurotransmitter secretion (Gotti and Clementi, 2004) and
the pre-synaptic nicotinic receptors have been implicated in the
release of Ach (Wilkie et al., 1993), noradrenaline (Clarke and
Reuben, 1996), glutamate (Alkondon et al., 1997) and GABA
(Yang et al., 1996).

335

There are at least two distinct classes of putative nicotinic

receptors in the nervous system (Lindstrom, 1997; Gotti and
Clementi, 2004; Wang and Sun, 2005) that are divided into many
subtypes:
receptor molecules that which contain the 26 and 24
subunits, and only form heteromeric receptors that bind agonists with high affinity (hereafter referred to as class 1);
which may be homomeric (made up of 79 subunit homopentamers) or heteromeric (made up of 7, 8 or 9, 10
subunit hetero-pentamers) (hereafter referred to as class 2);
In the brain e.g. 3(5)4 subunits regulate ganglion transmission and nicotinic receptors consisting of subunit 7 mostly
modulate glutamate release The 2 subunits control GABA
release and responses to Ach by DA neurons in the mesencephalon, while the 3 subunits located in striatum alter motor
activity by means of modulating DA release (Wang and Sun,
2005).
Nicotinic receptor with subunits 3, 5 and 7 are present in
bronchial epithelial cells, 4 in alveolar epithelial cells and 4,
7 and 2 in neuroepithelial bodies (Gotti and Clementi, 2004).
Gotti and Clementi (2004) mentioned that both homomeric
and heteromeric nicotinic receptors have a pentameric structure
with the subunits organized around a central channel. The homooligomeric receptors have five identical acetylcholine binding
sites per receptor molecule (one on each subunit) and the heterooligomeric receptors (which have two subunits and three
subunits) have two acetylcholine binding sites per receptor
molecule. When acetylcholine binds to the receptor, the membrane becomes more permeable to cations and causing a local
depolarization (producing an influx of sodium through a ligandgated ion channel). The local depolarization spreads to an action
potential or leads to muscle contraction when summed with the
action of other receptors.
The nicotinic receptor subtypes can exist as four distinct
conformations, namely resting, open and two desensitized
closed channel states (I or D) that are refractory to activation
on a timescale of milliseconds (I) or minutes (D), but have a
high affinity (pMnM) for agonists (Gotti and Clementi, 2004).
Nicotinic receptors possess a relatively low affinity for Ach at
rest; however, the affinity for acetylcholine is increased during
activation. Importantly, at high concentrations of acetylcholine,
the affinity for acetylcholine becomes higher and the receptor subsequently becomes desensitized (this also happens as
a result of extended nicotine exposure during smoking (Wang
and Sun, 2005)). The subunits of nicotinic receptors contribute
to receptor desensitization (Wang and Sun, 2005) and desensitization is a general characteristic of ligand-gated channels,
whereby a decrease or loss of biological response occurs following prolonged or repetitive stimulation (Wang and Sun,
2005).
5. Effects of increased acetylcholine
During normal functioning of Ach release from neurons, both
muscarinic and nicotinic receptors are responsible for its uptake

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E. Pretorius, J. Marx / Environmental Toxicology and Pharmacology 21 (2006) 331337

into the post-synaptic neurons. Ach is the neurotransmitter that is

synthesized, stored and released by cholinergic neurons, and the
key molecules that transduce the Ach message are the cholinergic muscarinic and neuronal nicotinic Ach receptors (Gotti and
Clementi, 2004).
If the muscarinic receptors (particularly M2 ) are blocked
when using a anticholinergic product such as DS during pregnancy, it will result in an accumulation of Ach in the synaptic
cleft in the foetus, as under normal conditions M2 muscarinic
receptors limit the release of Ach from parasympathetic nerves
(Coulson and Fryer, 2003). Elevated synaptic Ach levels may
therefore lead to persistent stimulation of cholinergic nicotinic
receptors on post-synaptic cells and subsequent alteration of
cholinergic receptor-mediated signaling pathways, e.g. alteration of intracellular cAMP levels. These cellular changes may
therefore lead to functional changes at the tissue/organism level.
Furthermore, a build-up of Ach in the synaptic cleft my cause
neurotoxicity.
Nicotinic receptors are expressed very early in the nervous system, where they are not only finely regulated during CNS development but probably actively contribute to it.
In humans, class 1 receptors increases steadily during gestation (from 12 to 27 weeks), reaching higher levels than
at any other time during life (Gotti and Clementi, 2004).
The highest concentrations have been observed in the nucleus
basalis of Meynert and the tegmental nuclei, followed by the
globus pallidus, the putamen, the cerebellar-relay nuclei, the
parietal and cerebellar cortex, the thalamus and the spinal
cord; the lowest level is in the medulla (Kinney et al.,
1993).
During the perinatal period and early infancy, the concentration of class 2 receptors in the different brain areas decreases
considerably, with the exception of the major cerebellar nuclei in
which the concentration of receptors remains unchanged (Gotti
and Clementi, 2004). In the human fetal brain, class 2 receptor
binding sites are present as early as 57 weeks of gestational age
and subsequently increase steadily. They are high in the pons,
medulla oblongata, mesencephalon, cerebellum and spinal cord
(Falk et al., 2002).
Therefore, nicotinic receptors are functional from a very early
stage in foetal development. We therefore suggest that exposure
of the foetus to DS will cause a blocking of the M2 receptor resulting in a continuous release of Ach. This will result
in a desensitizing of nicotinic receptors due to prolonged Ach
exposure, which could ultimately result in permanent damage
to cells in the foetus (particularly the brain) containing these
receptors.
We therefore conclude that DS used frequently by herbalists
to treat asthma should be used with extreme care and discontinued immediately during pregnancy.

Acknowledgements
We thank the National Research Foundation of South Africa
(NRF) for funding E. Pretorius (Indigenous Knowledge Systems
(FA2004033100004)).

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