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Panosssian Wiknam Effectofadaptogenson CNS2005
Panosssian Wiknam Effectofadaptogenson CNS2005
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Abstract
It has been found empirically that some plants, such as Eleutherococcus senticosus, Rhodiola
rosea, Schizandra chinensis and Bryonia alba etc, used in traditional medicine to increase stamina
and general well-being, also increase the state of non-specific resistance in stress. These plants have
been named adaptogens and are defined as metabolic regulators which reduce the damaging effects
of various stressors by virtue of a reduction of the reactivity of the host defence system. Adaptogens
increase the ability of the organism to cope with stress, thus implying a curative effect on stress-
induced disorders. Such drugs are often classified as preparations which stimulate the central nervous
system (CNS) in manuals and handbooks on pharmacology. However, adaptogens differ in significant
ways from classical CNS-stimulants. Experiments on frogs show that adaptogens do not have direct
anti-narcotic effects on the CNS unlike other stimulants such as phenamine, caffeine etc. The
mechanisms of action of adaptogens are related to the regulation of the stress system – neuroendocrine
– immune complex, and are associated with the biochemical adaptation of cells and organisms to
stress.
Key words: stress – adaptation – central nervous system – work capacity – fatigue – psychiatric disorders – adaptogens –
Schizandra chinensis – Rhodiola rosea.
1998, also in the USA (FDA, Notice of proposed Aralia schmidtii Araliaceae
rule marketing, Federal Register of April 29, 1998). Asparagus racemosus Liliaceae
Table 1 lists the plants most frequently described Atragene sibirica L. Ranunculaceae
as adaptogens. Too often, however, the term Azardirachta indica (Al, Neem) Melaceae
adaptogen has been carelessly employed in the Bergenia crassifolia (Fritsch) Saxifragaceae
absence of sufficient experimental evidence in support Bryonia alba L.* Cucurbitaceae
of the criteria demanded by the formal definition, and Cicer arietinum L. Fabiaceae
few of the agents referred to as adaptogens comply Codonopsis pilosula (Franch.) Nannf. Campanulaceae
fully with the formal definition. However, extracts of Cordyceppt sinisis (Berk.) Pyrenomycetales
Eleutherococcus senticosus, Rhodiola rosea, Echinopanax elatum Nakai Araliaceae
Schizandra chinensis and Bryonia alba (Brekhman
Eleutherococcus senticosus Maxim.* Araliaceae
1957; Brekhman and Dardymov 1968; Lebedev
Emblica officinalis, (Phyllanthus emblica L.) Euphorbiaceae
1971; Saratikov 1973; Dardimov 1976; Lupandin
Eucommia ulmoides Oliver Eucommiaceae
and Lapajev 1981; Panossian et. al. 1997) appear
Hoppea dichoroma Wild. Gentianaceae
to meet the criteria on the basis of their abilities to
increase non-specific resistance to stress involving a Ocimum sanctum L. Lamiaceae
significant general or universal protective effect Panax ginseng C.A. Meyer Araliaceae
concerning the whole organism and its main organ Pfaffia paniculata (Marius) Kuntze Amarantaceae
and functions: this latter point relates to the most Rhaponticum carthamoides (Willd.) Iljin. Asteraceae
important feature of adaptogens. After a large number Rhodiola crenulaya (Hook, f. et Thoms)
of pharmacological and clinical studies had been H. Ohba Crassulaceae
carried out on these medicinal plants, they have been Rhodiola rosea L.* Crassulaceae
incorporated into the official medicine in USSR. Scutellaria baicalensis (Georgi). Lamiaceae
Adaptogens are now being produced industrially Schizandra chinensis (Turcz.) Bail.* Magnoliaceae
based on these plant extracts (e.g. rodakson tablets Sterculia plantanifolia L. Streculiaceae
from R. rosea, and loshtak tablets from B. alba) and Terminalia chebula Combretaceae
they show stimulating, restorative as well as anti- Tinospora cordiflora Miers Menispermaceae
stress activities. In manuals and handbooks on Trichopus zeylanicus Gaerten. Trichopodaceae
pharmacology (Mashkovskij 2000), adaptogens are Withania somnifera L. Solanaceae
presently grouped together with psychotropic drugs
30 - Arquivos Brasileiros de Fitomedicina Científica • Vol. 3 • número 1 • abril 2005
Table 2. The differences between CNS medicines, adaptogens may be prescribed to enhance
stimulants and adaptogens.
curative effects in chronic conditions such as chronic
Stimulants Adaptogens pneumonia, chronic tuberculosis, vascular dystonia,
1. Recovery process after
cancer (through reduction of metastasis), and to relieve
exhaustive physical load Low High
the debilitating effects of radiotherapy and
2. Energy depletion Yes No
chemotherapy.
3. Performance in stress Decreased Increased
In healthy individuals, adaptogens may also
4. Survival in stress Decreased Increased improve stamina and tolerance to infections. A large
5. Quality of arousal Bad Good number and a wide range of clinical studies (both
6. Insomnia Yes No uncontrolled and controlled) have been carried out
7. Side effects Yes No in Russia, and the results consistently demonstrate
8. DNA/RNA and protein the capacity of adaptogen preparations efficiently to
synthesis Decreased Increased increase mental and physical work capacity against a
background of fatigue and stress. However, relatively
As adaptogen drugs have been found to be few of the studies reported to date have been placebo-
unusually safe, they may be used both in self-care controlled, randomised and double-blind (Engels and
situations and in medical treatments as prescribed by Wirth 1997; Darbinyan et. al. 2000; Spasov et. al.
physicians. As self-care remedies they can be used 2000a,b).
(in single or repeated doses) by healthy individuals The active ingredients of adaptogen preparations
as a stimulant or tonic in fatigue, or after somatic can be divided into two groups, namely, phenolic
infections or diseases. They may be advantageous: compounds and tetracyclic triterpenoids. The phenolic
(i) in sports medicine to promote quicker recovering constituents, such us phenylpropanoids, phenylethane
after hard exercise or to reduce damage from over- derivatives and lignans (Kochetkov et. al. 1962;
training; (ii) in occupational medicine to protect against Kurkin and Zapesochnaya 1986; Norr 1993; Wagner
harmful environmental factors such as exposure to et. al. 1994; Wagner 1995), are structurally related
low temperatures (in polar regions), to high noise to the catecholamines which are important mediators
levels or to mechanical vibration (in heavy industry of the sympathoadrenal system (SAS) involved in the
or in mining); and (iii) in acute medicine in cases of activation of the stress system in the early stages of
poisoning (especially with respect to liver poisons) stress response. On the other hand, the tetracyclic
or ischemia (through reduction of tissue damage from triterpenoids (Elyakov and Ovodov 1972; Ghosal et.
oxygen deprivation), and also as restoratives to speed al. 1989), such as cucurbitacin R diglucoside
up recovery after surgery. (Panossian et. al. 1997, 1999) and ginsenoside Rb 1
The paradigm ‘one drug for one disease’ is not (Wang and Lee 2000) are structurally similar to the
appropriate for adaptogens since they have many corticosteroids which are stress hormones involved
indications and can be used in the treatment of many in the inactivation of the stress system and in protecting
stress-induced disorders such as asthenia, psychiatric the organism from over-reaction in response to
disorders (neurosis, psychogenic depression, stressors (Munck et. al. 1984; Tache and Rivier 1993;
astheno-depressive states, alcoholism), certain Chrousos et. al. 1995; Panossian et al. 1999; Fink
cardiovascular disorders, ischemia (stroke, heart 2000). In this context, extracts of roots and rhizomes
attack), impaired visual functions of the eye, acute of E. senticosus and R. rosea, as well as extracts of
gastrointestinal diseases, liver poisoning, non-insulin berries of S. chinensis, belong to the first group of
dependent diabetes II, rheumatic heart disorders, and adaptogens, while extracts of roots of B. alba and
even the common cold. As adjuvants to other Withania somnifera are members of the second
Arquivos Brasileiros de Fitomedicina Científica • Vol. 3 • número 1 • abril 2005 - 31
group (Wagner et. al. 1994; Wagner 1995). cells and the whole organism from over-reacting to
Accordingly, there is a difference in the mode of action the activating messengers. This system includes some
and the pharmacological activity of the various important enzymes and mediators of intra- and extra-
adaptogens (Kudrin and Rodina 1986; Boon- cellular communications at the cellular (anti-oxidant
Niermeijer et. al. 2000). system - superoxide dismutase, catalase, glutathione-
Available documentation strongly suggests that one peroxidase, eicosanoids, NO),- organ (eicosanoids,
should use extracts, i.e. mixtures of active substances, NO) and - system levels [corticotropin-releasing
rather than pure substances in order to obtain the factor (CRF), corticosteroids, prostaglandin E2, NO].
highest efficacy. Extension of this line of reasoning When the stress system is in the normal state
has led to the concept of a fixed combination of (homeostasis) the activities of the switch-on and
standardised extracts based on the adaptogens from switch-off systems are in balance at a certain level of
E. senticosus, R. rosea and S. chinensis and known equilibrium which reflects the “reactivity” of the stress
as ADAPT-232: this is the active ingredient of the system, i.e. its sensitivity to a stressor and the degree
Swedish registered herbal medical product chisan of protection of the organism against damaging effects.
(Swedish Herbal Institute) which has been popular In the process of adaptation to the effects of a stressor,
in Scandinavia in recent years. the reactivity is decreased as a result of an increase
in the basal levels of the mediators of the switch-on
Mechanisms of Action of and switch-off systems resulting in transition to
Adaptogens heterostasis (Fig. 1). Plant adaptogens can thus be
defined as agents which reduce the damaging effects
The mechanisms of action are difficult to define of various stressors by virtue of a reduction of the
and to rationalise. It is clear (Panossian et. al. 1999), reactivity of the host defence system (Panossian et.
however, that the mechanisms are related to the al. 1999): they adapt an organism to the stress and
regulation of the stress system – neuroendocrine – have a curative effect in stress-induced disorders. The
immune complex (Selye 1950; Chrousos and Gold primary site of action of adaptogens is thus the HPA
1992; Chrousos et. al. 1995; Fink 2000) and are axis where the key mediators are tropic hormones
associated with the biochemical adaptation of cells [e.g. adrenocorticotropic hormone (ACTH)],
and living organisms to stress (Meerson 1981; releasing hormones (e.g. CRF), corticosteroids, sex
Hochachka and Somero 1984). Stress itself is a hormones, catecholamines, eicosanoids and NO. The
defence response of an organism to external factors secondary sites of action are the liver and components
(strain) which results in the stimulation of formation of the immune and cardiovascular systems where the
of endogenous activating messengers such as key mediators are peroxides, eicosanoids, cytokines,
catecholamines, prostaglandins, cytokines, nitric NO, c-GMP and c-AMP.
oxide (NO), PAF, etc which in turn activate the There is plethora of evidence indicating that single-
energetic and other resources of the organism and dose administration of adaptogens activates
induce diseases. This is the so-called “stress- corticosteroid formation, and that sub-chronic pre-
executing” complementary (switch-on) system treatment with adaptogens normalises the stress
involving the SAS (in acute response and adaptation) hormone levels (Dardimov 1976; Panossian et. al.
and the hypothalamus – pituitary – adrenal (HPA) 1987). The increase in corticosteroid secretion is an
axis (in long term adaptation), as well as various evidence of the stress-protective response of the
mediators at the cellular, organ and system level. organism in order to protect itself from over-reaction
Counteracting these switch-on signals is the so-called to stress factors (Panossian et. al. 1999). It is known
“stress-limiting” (switch-off) system which protects that the level of corticosteroids increases as a result
32 - Arquivos Brasileiros de Fitomedicina Científica • Vol. 3 • número 1 • abril 2005
Immediate General adaptation syndrome
stress Repeated or chronic stress
Performance
response
Reactivity (sensitivity) to stressor
Biosynthesis of LTB4
ADAPTOGENS Lipid peroxidation
ADAPTATION
Homeostasis
of long-time training or adaptation, and that a trained physical loading does not then increase the levels of
organism responds insignificantly to stress signals by cortisol and NO in such athletes. Plant adaptogens
virtue of the increased activity of the hypothalamus – present in S. chinensis and B. alba show pro-
hypophysis – adrenal axis (HHA). In contrast, the stressor effects in that they activate the formation of
activation of the HHA by stress in an untrained both cortisol and NO in blood and saliva, and this
organism is very pronounced (Viru 1981). In animals activation then adapts the organism to further heavy
which had been treated with adaptogens (Panossian physical loading. Thus, adaptogens increase the
et. al. 1987, 1999), a moderate increase in the production of both deactivating (cortisol) and
production of corticosteroids could be observed and, activating (NO) messengers of the stress system and
as a result of adaptation to the pro-stressor effects of are hence challengers of the defence response of the
adaptogens, further stress effects did not induce an organism. In other words, adaptogens increase the
acute increase in the formation of corticosteroids as capacity of the stress system to respond to external
was detected in control groups which had received signals at the higher level of the equilibrium i.e.
placebo instead of adaptogens. heterostasis. It is noteworthy that, following treatment
A recent study involving athletes has shown that with adaptogens, physical exercise does not increase
stress, in the form of acute physical exercise, activates both NO and cortisol levels in saliva. Furthermore,
the formation of cortisol and NO in blood plasma in subjects which have already adapted to chronic
and saliva of beginners and of more sedentary subjects heavy physical exercise (e.g. the well-trained athlete)
(Panossian et. al. 1999). On the other hand, chronic and with increased basic levels of cortisol in blood or
physical exercise, as experienced by well- and long- saliva, the stress of physical exercise as well as the
trained athletes, increases the basal levels of these application of adaptogens can have an opposite effect,
stress mediators in blood and saliva, and acute namely, a decrease in NO and cortisol levels probably
Arquivos Brasileiros de Fitomedicina Científica • Vol. 3 • número 1 • abril 2005 - 33
owing to their increased utilisation. simple and complex reflexes of animals after ischemia
Tests carried out using developing snail (Lymnaea and reperfusion; (v) the prevention of decrease in
stagnalis) embryos, silk worm (Bombix mori) milk-induced leukocytosis; (vi) the improvement in
larvae, Reuber H35 hepatoma and isolated cardiac survival against toxic chemicals or bacteria; (vii) the
cells (Chernykh et. al. 1985; Boon-Niermeijer et. al. improvement in emotional behaviour of animals; (viii)
2000) have shown that the adaptogens present in E. the improvement in cognitive abilities; (ix) the
senticosus, S. chinensis, R. rosea etc are able to improvement in coordination functions; (x) the
enhance resistance against a number of different stress prevention of increase in locomotor activity; (xi) the
conditions i.e. cold-induced viral infection, infection prolonged maintenance of body temperature during
by Bacillus thuringiensis, formalin, heat, oxidative cold stress; (xii) oxygen consumption and ECG
stress induced by menadione, and toxic ions (Cu+2, parameters during physical loading; (xiii) the recovery
Cd+2, Hg+2). The degree to which resistance was of ECG parameters during physical stress; and (xiv)
enhanced depended on the type of stressor applied. the NO content in blood, saliva and exhaled air during
The results confirm that these adaptogens are universal physical loading.
enhancers of non-specific resistance in living Endocrine activity tests have included the
organisms at various levels of organisation. It seems determination of the effects of adaptogens on the levels
clear that they can adapt cells and organisms to stress of: (i) ACTH, CRF, and steroid hormones in blood,
by mechanisms associated with biochemical adrenal cortex and other endocrine tissues and cell
adaptation (Hochachka and Somero 1984). cultures in various in vivo and in vitro models; (ii)
free arachidonic acid (AA), prostaglandin E 2,
Pharmacological leukotrienes (LTB4) and other AA metabolites in
Assessment of Adaptogens adrenals, brain, adrenocortical cells and blood using
in vivo and in vitro models; (iii) catecholamines in
Typically, the pharmacological assessment of blood, adrenals, brain and cell cultures in various in
adaptogens has included evaluation of stimulation, vivo and in vitro models; and (iv) NO in blood, saliva,
tonic and stress-protective activities. The most adrenals, brain and cell cultures using in vivo and in
important feature in the pharmacological profile of vitro models. It has also been shown that NO donors
adaptogens is that they increase the resistance of increase (NO synthesis-inhibitors reduce) the duration
animals to physical exhaustion and other stresses, such of swimming of rats with load, decrease survival of
as freezing, heat, altered atmospheric pressure and rats and their longevity in hypoxia, and increase
oxygen content, immobilisation, radiation, toxic drugs stomach ulcers induced by immobilisation (Malishev
and chemicals, noise, starvation, anxiety, fear, and and Manukhina 1998).
chronic diseases. Anabolic activity tests have included assessment
The effects of adaptogens on resistance to stress of the increase of body weight and accelerated
have been studied by evaluation of: growth, as well as the increase of DNA, RNA and
(i) ATP, creatine phosphate hexokinase, protein synthesis. CNS activity tests have included
glycogenesis etc in dynamic and static physical swimming and Rota-rod treadmill running tests, tests
performance tests (swimming, running, holding); (ii) of evaluation of improved reflexes after ischemia and
the prevention of formation of stomach ulcers induced reperfusion, and catecholamine metabolism assays
by immobilisation, aspirin, cold stress, etc; (iii) the (COMPT inhibition). Immuno-tropic activity tests
prevention of decrease of weight of the thymus and have included: (i) measurement of the level of
increase of weight of adrenals induced by corticosteroids, prostaglandins, leukotrienes,
immobilisation and other stresses; (iv) the duration of cytokines, and NO in blood or in various blood cells;
34 - Arquivos Brasileiros de Fitomedicina Científica • Vol. 3 • número 1 • abril 2005
(ii) phagocytosis tests (chemiluminescent); (iii) flow- reinforcement, it has been shown that application of
cytometry studies of blood cells, T h/T s, NK, an extract of R. rosea in a single dose of 0.1 mL per
granulocytes, monocytes, and macrophages. Anti- rat essentially improved learning and retention after
oxidant activities have been determined through assay 24 h. Significant improvement in long-term memory
of lipid peroxidation. was also established in memory tests performed 10
days after treatment with the same dose of extract
Effects of Adaptogens on (Lazarova et. al. 1986; Petkow et. al. 1986). Ten
the Central Ner vous days after oral administration of an aqueous extract
System of R. rosea at a dose of 0.1 mL per rat (body weight
180-200 g), the levels of norepinephrine (NE),
Experimental pharmacology dopamine (DA) and serotonin (5-HT) in the
brainstem of the experimental animals rose
Whilst the most important characteristics are considerably compared to the levels in the same
common to all adaptogens, their effects may be cerebral structure in control animals. In the cerebral
different in various circumstances. The effects of two cortex, the levels of NE and DA decreased
of the most interesting adaptogens, namely, significantly whilst the 5-HT level increased sharply.
Schizandra chinensis Bail. and Rhodiola rosea L., In contrast, in the hypothalamus of rats treated with
on the CNS are discussed below. extracts of R. rosea, the formation of NE and of DA
The suggestion that adaptogens may stimulate the increased about 3-fold compared to the control
CNS was originally made in order to explain the group, whilst the 5-HT content decreased (Stancheva
stimulating effects of these agents on physical and and Mosharrof 1987). Treatment with adaptogen also
mental performance in numerous experiments enhanced the effects of neurotransmitters on the brain
involving animals (Lupandin 1965, 1989; Aksyonova by increasing the permeability of the blood brain
1968; Ovsyanikova 1970; Lupandin and Lapajev barrier to precursors of DA and 5-HT.
1981; Lupandin et. al. 1986) and humans (Astanin It may be concluded that treatment with extracts
et. al. 1943; Karo 1945; Lazarev 1946; Murtazin of R. rosea promotes release of NE, DA and 5-HT
1946; Lebedev 1951a, 1967; Eglit et. al. 1965; in the ascending pathways of the brainstem thus
Korolevich and Lupandin 1967; Levchenko 1971; activating the cerebral cortex and the limbic system.
Lupandin and Lapajev 1981; Lapajev 1982). It has Consequently, the cognitive functions (thinking,
been shown that small doses of an extract of R. rosea, analysing, evaluating, calculating and planning) of the
or of its active ingredient rodosin at a dose of 2-4 cerebral cortex, and the attention, memory and
mg/kg, increased the spontaneous bio-electrical learning functions of the prefrontal and frontal cortex,
activity of the brain, presumably by direct effects on are enhanced. Other neuronal systems also contribute
the ascending and descending reticular formation in to the various aspects of memory such as encoding,
the brainstem (Saratikov et. al. 1965, 1978; Marina sorting, storage and retrieval. The cholinergic system,
1968; Marina and Alekseeva 1968; Saratikov 1973; for example, involves the neurotransmitter
Kurkin and Zapesochnaya 1986). Unlike acetylcholine (Ach) and contributes to memory
tranquillisers, however, medium range doses of retrieval via pathways ascending from the memory
adaptogens enhanced the development of conditioned storage systems of the limbic system to various areas
avoidance reflexes in rats and facilitated learning of the cerebral cortex. Agents which block Ach
based on emotionally positive reinforcement suppress the activity of these ascending pathways and
(Saratikov et. al. 1965; Saratikov 1973). thus interfere with memory. The deterioration (partial
Using the maze method with negative (punitive) blocking) of these systems with age results in age-
Arquivos Brasileiros de Fitomedicina Científica • Vol. 3 • número 1 • abril 2005 - 35
associated memory loss. Treatment with extracts of was administrated 0.5 h before the amytal compared
R. rosea can reverse this type of block (Brown et. al. with treatment where the extract was given at the
2002) and may prevent or ameliorate some age- same time as, or after, the administration of amytal
related dysfunction in these neuronal systems. (Petkov 1956).
With respect to preparations from S. chinensis, It has been suggested that Schizandra
initial experiments with frogs indicated that the plant preparations can have a stimulating effect on the
contains a unique group of stimulators which do not CNS by increasing the excitability of the neuronal
have direct anti-hypnotic effects on the CNS (unlike cells, intensification of excitation processes and other
phenamine, caffeine etc) (Lazarev 1946). Schizandra events (Lazarev 1946; Lupandin and Lapajev
extract induced a relative decrease in reflector activity 1981): treatment with Schizandra extract also
of the spinal cord in frogs which was more prolonged induces sleeplessness (Pozdnyakov 1945). A dose-
than the excitation induced by other chemicals dependent reversal effect on conditioned reflexes
(Zhestyanikov 1945). The anti-narcotic effect of in dogs has been observed: in low doses, Schizandra
Schizandra extract became clear following extract has a stimulatory effect improving the
experiments in which the spinal cord of a frog was conditioned reflex activity, but in higher doses it
preliminary suppressed by ethanol: however, the exerts a negative effect on the higher nervous activity
active components in the Schizandra extract delayed, of dogs disturbing the complex conditioned reflex
but did not prevent, the narcotic effect of ethanol activity (Voyevodina et. al. 1952). The petroleum
(Zestyanikov 1945; Lazarev 1946). Similar effects ether extract of the fruits of S. chinensis mainly
have been observed in experiments on rabbits: in this effects the cholinergic system, and this effect is
case the chloral hydrate-suppressed reflex could be biphasic: small doses decrease the threshold for
eliminated by a fatty oil extract of seeds of S. nicotine convulsions, potentiate the anti-diuretic
chinensis (Kuznetsova 1958). effect of nicotine and the effect of carbachol on
Schizandra preparations show significant effects intestinal motility, whereas higher doses have a
on processes of excitation and inhibition in the higher cholinolytic effect. In contrast to other
brain structures and in the spinal cord of experimental psychomimetic substances, Schizandra extract does
animals: such effects are: (i) an increase in spinal not antagonise the effects of reserpine (catalepsy,
reflexes and motor activity of the part of the body eyelid ptosis, thiopentone anaesthesia in mice) but
innervated with the CNS in dogs (Pozdnyakov 1945; can even enhance the effects (Volicer et. al. 1965,
Lupandin and Lapajev 1981); (ii) a decrease in the 1966b).
latent period of reflex in frogs (Pozdnyakov 1945; It has been shown that schizandrin is the main
Zhestyanikov 1945; Lazarev 1946; Lebedev 1951b; active principle of S. chinensis: this compound may:
Kuznetsova 1958; Lupandin and Lapajev 1981), in (i) stabilise the bio-electric activity of the cerebral
rabbits (Voyevodina et. al. 1952; Kuznetsova 1958), cortex at a dose of 1 mg/kg whilst showing an
and in dogs (Yefimova et. al. 1954, 1955); (iii) a activating effect at doses of 2-3 mg/kg; (ii) directly
widening of the range of assimilation of rhythms by excite upraised activating system at a dose of 2-3
the cerebral cortex (Sorokhtin and Minut-Sorokhtina mg/kg; (iii) recover the bio-electric activity of the
1958); elimination of the inhibition of bio-electrical cerebral cortex which has been suppressed by chloral
activity of the cortex and sub-cortical structures hydrate, berbamine or aminazine at doses of 5-10
induced by berbamyl, chloral hydrate or aminazine mg/kg; (iv) increase spinal reflexes in rabbits and
(Volicer et. al. 1966a); (iv) prevention of the narcotic decerebrated cats (Lebedev 1967); (v) inhibit
effect induced by sodium amytal in rats - the effect development of new conditioned reflexes in mice; (vi)
was stronger when a seed extract of S. chinensis enhance the convulsive effect of corazole and
36 - Arquivos Brasileiros de Fitomedicina Científica • Vol. 3 • número 1 • abril 2005
strychnine; and (vii) extend the duration of hexenal Effects of schizandrol A on monoamine
and chloral hydrate induced sleep in mice (Lebedev neurotransmitters in the CNS.
and Kamilov 1966).
It has been shown that schizandrol A (a lignan
Inhibition of inactivation of catecholamines present in Schizandra extract) exerts inhibitory effects
(catechol-0-methyl-transferase; COMT) in on the CNS. For the purposes of elucidating the
adrenergic synapses. mechanism of this inhibition, the concentrations of
monoamine neurotransmitters and their metabolites
A principal hypothesis concerning the mechanism in rat brain and the effects of schizandrol A on some
of action of the active principles of S. chinensis, i.e. receptors were determined by ion-pair reversed-
the lignans, involves the inhibition of COMT, an phase liquid chromatography using electrochemical
enzyme which, along with monoamine oxidases, detection and a competitive binding assay. In the
inactivates catecholamines. Inhibition of COMT neurotransmitter studies, significant elevations of DA
results in an increase in duration of activation of the and its metabolite dihydroxyphenylacetic acid
adreno-receptors: exhaustion of the catecholamine (DOPAC) in striatum, and DA in hypothalamus, were
deposit does not occur, and the release of observed after interperitoneal administration of 50 or
catecholamines from nerve endings of the sympathetic 100 mg/kg of schizandrol A. However, the receptor
nervous system decreases (Lupandin and Lapajev binding experiments showed that schizandrol A had
1981; Lupandin 1991). However, this hypothesis is no affinity for dopamine D1 and D2 receptors,
not supported by incontrovertible evidence since much serotonin receptors, or alpha 1- and alpha 2-
of it is indirect. adrenergic receptors, and it did not affect the binding
One finding is that Schizandra preparations interact of DA to dopamine D1 or D2 receptors. These results
with known competitive and non-competitive inhibitors indicate that the inhibition exerted by schizandrol A
of COMT (i.e. apomorphine and pyrogallol) in on the CNS may be related to the DA system, and
experiments involving mice with apomorphine-induced the increase of DA turnover has nothing to do with
hypothermia and increased duration of stereotypic dopamine receptors. The concentrations of the NE
movements (Lupandin and Lapajev 1981). The lignans metabolite 3-methoxy-4-hydrophenylglycol (MHPG)
in Schizandra extract increased significantly the and the serotonin metabolite 5-hydroxyindole acetic
apomorphine-induced duration of stereotypic acid (5-HIAA) showed changes in rat striatum and
movements of mice particularly after administration of hypothalamus after treatment with schizandrol A, but
precursors of catecholamines (i.e. L-DOPA) (Lupandin NE and serotonin levels themselves were unaffected
1989). A second piece of evidence is based on the (Zhang and Niu 1991).
observation that COMT inhibitors increase the
sensitivity of the organism toward catecholamines: it Studies on healthy subjects
has been found that the LD50 of epinephrine is lower in
mice treated with Schizandra extract (Lupandin and The stimulating effect on working capacity
Lapajev 1981). However, no reports are available and mental performance.
concerning the effect of Schizandra extract on the
biosynthesis of catecholamines or on COMT activity. An initial study on healthy subjects (33 marines)
It has only been reported that the concentration of showed that, compared with a control group (given
catecholamines is not changed in brains of animals a German chamomile decoction), a Schizandra extract
following administration of Schizandra preparations did not have any anti-hypnotic effects unlike other
(Volicer et. al. 1966b). stimulants (i.e. phenamine, caffeine) (Lazarev 1946).