Drugs with Adaptogenic Effects for strengthening the powers of resistance

Translator’s Summary

Adaptogens, first defined in the 1950s by Lazarev are substances that normalize
body functions, strengthen systems and functions compromised by stress and
have a protective effect against a wide variety of environmental and emotional
stress. In this article, German researchers define the term and identify
ways in which science can identify medicinal plants that have these abilities.
A number of plant adaptogens are reviewed, including ginseng, eleuthero,
and the Japanese Kampo medicine, Shosaikoto.



What is meant by Adaptogens?

The concept “Adaptogen” was coined in 1947 by the Russian scientist,
Lazarev (1). He discovered the adaptogenic effect of dibasol (2-benzylbenzimidazol)
in tests aimed at the stimulation of non-specific powers of resistance in
test subjects. Lazarev, who called this new group of medically-effective
substances, “adaptogens,” defines them as substances meant to
put the organism into a state of non-specific heightened resistance in order
to better resist stresses and adapt to extraordinary challenges.



It was Selye who examined the actions and consequences of such stresses
on the healthy organism (2). He formulated the “General Adaptive Syndrome”
(GAS). As a consistent, non-specific response of the organism to stressful
influences of totally diverse types, the adaptive reaction enables the body
to heighten its power of resistance towards stresses, and to adapt to external
conditions. The limiting factor within this adaptive capacity is, according
to Seyle, determined by the so-called “Adaptations Energy” (3)
of the organism. This means that the resistance reserves towards unfavorable
influences are not inexhaustible, but they diminish by extreme stressfullness.
The consequences are mis-adaptation and diseases.



Brekhman, who examined the effects of adaptogenic drugs at a later point,
summarized the concept “adaptogen” in 1958, as follows (4):



1. It must show a non-specific effect (raising the power of resistance to
toxins of a physical, chemical or biological nature).



2. It is to normalize, independent of the type of pathological condition.



3. It must be harmless and disturb the body functions as little as possible.
Accordingly, adaptogens are to strengthen the non-specific powers of resistance
to non-infectious stresses, raise the general performance capacity during
stress situations and thereby prevent diseases that could develop due to
over-stressing the organism.



Adaptogens and their Definition and Differentiation from other Drugs
with Related

Pharmacological Effects


If one accepts the concept of adaptogenic effects in the medical sense,
it is necessary to define and differentiate them from other remedies of
related action. Although a strict differentiation is not possible, there
is a number of criteria which allow a formal arrangement of these other
drugs in immune stimulants, Nootropics, anabolics, tonics and geriatric
aids. Immune Stimulants are substances which bring about a heightened resistance
through the stimulation of non-specific defensive processes which are largely
independent of antigens (5). There occurs a rise in non-specific resistance
towards bacterial, and especially viral infections, as also in chronic inflammation.
Nootropics (cognition enhancers), according to Giurgea (cited in ref. 6)
are effective psychopharmacological agents which are said to improve the
higher integrative brain functions, such as memory, learning, understanding,
thinking and the capacity for concentration. No specific mechanism is known.
It is assumed that nootropics stimulate existing neural synapses to optimum
performance (adaptive capacity), and also for damaging influences, such
as disturbances of the energy and neurotransmitter metabolism or ischemia
(protective capacity).



A delineation of adaptogens from nootropics is difficult simply because
the analysis of the effective action of nootropics is undertaken with animal
experiments, whereby biochemical changes, physiological regulatory systems
and types of behavior are registered. Thus it applies also to nootropics
that there exists no typical model for the analysis of their effects, but
only a broad palette of diverse experimental approaches. Recently, in an
announcement of the BGA, “recommendations for establishing effectiveness
of nootropics in the indications area of dementia (phase III) are given,
whereby 5 groups of models are quoted for analysis of activity (7).



Anabolics are substances which activate the anabolic metabolism. They promote
the synthesis of nucelic acids and protein metabolism; thereby in general,
growth. No precise conceptual definition can be given for tonics and geriatric
remedies. They fall into the category of wellness enhancers and are therefore
without pharmacological significance.



Tonics, according to a very generalized definition, are substances
which mitigate conditions of weakness or lack of tone within the entire
organism, or in particular organs. Being adaptogenic, like all the others,
generally, adaptogens raise one’s capacity, therefore may also be included
in the group of “tonics.”



Geriatric remedies are substances serving as a preventative treatment
of “old-age diseases.” “Stiffness and age-conditioned rigidity,
are possibly the outer manifestations of diminished or lacking ability to
adapt.



It is seen as characteristic of adaptogens that their anti-stress
effect towards stresses of a non-infectious variety, always stands in the
foreground. Although in so-called adaptogens,” immune-stimulating,
nootropic, or metabolic effects have also been observed.



Physiological Foundations of the Adaptogenic Effect; Goals of Adaptogenic
Application


Selye (2,8) placed the reactions of the body to affecting stresses under
the (wellness enhancing) concept of general Adaptations Syndromes (GAS).
This syndrome, which manifests independent of the damaging agent, has been
divided into three phases by Selye, based on rat experiments (Fig. 1)



1. The “Alarm Reaction”



The first phase of the GAS, observed in rats, normally 6 to 48 hours after
the initial effect of a damaging agent, leads to changes which are always
of the same nature, and independent of the type of stressor, comparable
to shock symptoms.



The activity of the sympathetic nervous system is heightened, catecholamine
levels are raised. On the basis of the increased corticosteroid production
the content of cholesterin and ascorbic acid, in the adrenals, is diminished.
The weight of the adrenal gland increases, the weight of the thymus, spleen,
lymph glands and liver diminish. Body temperature is lowered_there occurs
acute damage in the digestive tract, with the frequent formation of stomach
ulcers. Through the condition of the catabolic metabolism, the organism
is in a degenerative phase, and the non-specific stress resistance capacity
is raised.



2. The “Stage of Resistance”



If the stressor continues to act on the organism, there follows the second
phase of AAS after a few days. The organism now responds with heightened
capacity of resistance to the damaging factors. The changes observed during
the alarm phase normalize themselves gradually and anabolic functions prevail.
The organism is becoming increasingly resistant towards the damaging agent.
The optimal adaptation has been reached.



This adaptation is strictly stressor-specific. The heightened stressor non-specific
power of resistance observed during the alarm phase is no longer observable.



3. The Stage of Exhaustion”



If the impact of a stressor goes beyond a certain limit, the third phase
of AAS is reached:



The resistance of the organism is exhausted. The “energy of adaptation,”
according to Seyle (3) is used up. The condition of adaptation reached in
phase 2 is lost. In animal experiments, death usually occurs at this stage.
The damage in organs correspond to those occurring during the alarm phase
(8).



In human beings, the exhaustion phase leads to the development of diseases
such as stomach ulcers.



Besides the general adaptation syndrome of Seyle, the “stress proteins”
or “heat-shock proteins,” which have been proved in Procaryotes
and Eucaroyotes need to be pointed out in this connection (9,10). The syntheses
of these proteins is induced during a stressful event, such as heightened
temperature. Many of the “stress proteins” play an important role
for normal cellular function under stress-free conditions, especially in
periods of development, differentiation and growth. Which types of stressors
in particular lead to the induction of “stress proteins,” is to
this day still quite unclear. Heightened prostaglandin concentrations or
an accumulation of damaged cell proteins are, for example, discussed as
possible trigger factors for “stress proteins.” It is certain
that the prompt induction of “stress proteins” in stressful situations
is a vitally-necessary protective function for the cell. “Stress proteins”
can for instance, protect sensitive cell proteins from irreversible denaturalization?,
influence RNA- and protein-synthesis in a specific way, temporarily inactivate
certain receptors or initiate immune reactions.



The general hope regarding adaptogens is the reduction of stress-reactions
in the alarm phase, the delay or avoidance of the exhaustion stage, thereby
providing a certain protection towards stress. In a similar way, Brekhman
(4) describes the adaptogenic effect as a strengthening or extending of
the physiological adaptation. He bases this effect on the attempt of the
body to protect energy resources from depletion and to accelerate the biosynthesis
of proteins and nucleic acids.



Drugs Known for Adaptogenic Effects

Because the concept of the “adaptogenic effect” is of relatively
recent occurrence, one cannot find it in old drug lists. The assignment
into the group of adaptogens happens, therefore retrospectively, on the
basis of xx criteria, based on experiential medical data and in a few cases,
on data gained from in vitro and in vivo tests. Adaptogenic
drugs are found in the most diverse families they are distinctly different
in the pattern of their constituents. Table 1 lists drugs described in the
literature as having adaptogenic effects.



Ginseng

Panax ginseng C.A. Meyer, Araliaceae



The tonifying effect of the ginseng root has been described in a Chinese
text as early as the 1st century after Christ. According to current understanding,
the adaptogenic effect of the drug is ascribed to the ginsenosides or panaxosides.
We are dealing here with diversely glycosolized triterpene saponins which,
with the exception of ginsenoside R0, belong to the tetracyclic dammarane-type.
Ginsenoside R0 has oleanolic acid as the aglycone. The chief glycones are
the ginsenosides Rb1 and Rg1 (Fig. 2).



Additional constituents previously cited include essential oil, the sesquiterpene
beta-elemene, polyacetylenes (12,13), salicylic- and vanillic-acid (14),
polysaccharides, as well as ubiquitously-occurring amino acids, fatty acids,
sterines and sugar.



In animal experiments, heightened powers of resistance from diverse stresses
through an adaptogenic effect is noted (Table II):



Beyond these, pharmacological examinations using ginseng extracts, ginseng
fractions and ginsenosides have revealed, besides adaptogenic effects, anabolic
and nootropic properties.



In endocrinological examination for testing ACTH and corticosteroid profiles
after i.p. application of ginseng saponin fractions, as well as diverse
purified ginsenosides (Rb1, Rb2, Rc, Rd, Re), all applications have led
to a distinct rise in ACTH and corticosteroids (19). After pre-medication
with Dexamethasone, which has a blocking effect on the hypothalamus and
the pituitary gland?, the release of ACTH and corticosteroids through ginseng
saponins, did not occur.



Consequently, the site of activity of the saponins seems to be on the pituitary
or the hypothalamus and not on the adrenals. Accordingly, the secretion
of the corticosteroids after an application of ginseng seems to be not directly
caused, but indirectly via the release of ACTH by the pituitary gland.



In vitro studies on the binding of steroid receptors showed a ginseng saponin
affinity toward gestational, mineralcorticoid and especially glucocorticoid
receptors (20). In vitro examinations with rat testes showed that a ginseng
saponin fraction affected a rise in DNA- and protein-synthesis (21). In
the animal model, an increase of physical capabilities has been proven (17,
22):



In the swimming test, ginseng saponin fractions, given to mice either i.p.
or p.o., led to a postponement of exhaustion (17). Brekhman (22) performed
tests with mice in which he registered, after an application of diverse
ginsenosides, in a “climbing test on a moving rope,” an antifatigue
effect by stages. In these, the effect of the single ginsenoside was far
superior to that of the total extract.



The oral intake of a watery ginseng extract, as well as the ginsenosides
Rb1 and Rg2 by mice, during a pre-treatment phase, clearly affected an improvement
of the learning behavior that had been influenced by negative stress (passive
avoidance response model). Ginsenoside Rb1 proved to be especially effective.
In vitro, ginsenoside Rb1 potentized the stimulating effect of the “nerve-growth
factor” on the production of nerve fibers in the embryonal cerebral
cortex. Moreover, it gave protection against cellular toxins, such as colchicine
(18).



The results seem to confirm that ginsenosides are the responsible chief
constituents of the Panax ginseng root for causing these effects.
The theory put forth by Han (14)_namely that it is principally the “antioxidant
effects” of phenolic compounds which brings about the adaptogenic reaction_is
less convincing because there are many other plant substances with “antioxidant”
effects; such as for example, flavonoids, vitamin C, etc. These substances
have not been officially ascribed an adaptogenic effect.



Taiga root, Siberian Ginseng root

Eleutherococcus senticosus Maxim., Araliaceae



In search of a drug which could replace the expensive ginseng root, one
came across the Taiga root, originating from Siberia. Its phytochemical
and pharmacological processing goes back to Russian works, in particular,
that of Brekhman and his circle. The chief constituents are considerably
different than those of the ginseng root (Fig. 3). They may be arranged
in the following groups (23).



1. Phenyl propane compounds: syringin = eleutheroside B, sinapin alcohol,
coniferyl aldehyde, chlorogenic acid, caffeic acid derivatives.



2. Lignanes: syringaresinol-4-4′-0-beta-D-diglucoside = Eleutheroside E
(D), syringa-resinol monoglucoside, syringaresinol, sesamin.



3. Cumarins: e.g. Isofraxidin-7-0-glucoside and its aglycon, isofraxidin.



4. Polysaccharides.



5. Additional constituents, such as sterins, oleanolic acid, essential oil,
sugar.



The anti-stress effect of Eleutherococcus extracts have been demonstrated
in animal experiments, through a raised protection from the typical organic
changes during the alarm phase, as described by Seleye (24).



Improved resistance occurred in diverse models, with regard to a series
of stressors (Table 3).



In experiments with healthy probands, stress-mitigative effects have been
proven by giving single doses from 2.0 up to 16.0 ml of the extract (p.o.).
No side-effects have been observed (29). The required normalizing effect
for adaptogens(Brekhmann) has been confirmed (29) in diseased patients.
The tolerance of the Eleutherococcus extract was very good. Only
a few patients complained of side-effects of a mild nature, such as headaches,
raised blood-pressure, sleeplessness.



Eleutheroside B stimulates in vitro the activity of the yeast-hexokinase.
The inhibition of hexokinase by beta-lipoprotein or by the beta-lipoprotien-corticoid-complex,
which is formed in the blood during stressful situations, has been neutralized
by eleutheroside B (30).



Endocrine effects of Eleutherococcus can be read from an increase
in the weight of the adrenal cortex, while the simultaneous decrease in
the content of cholesterol and ascorbic acid indicates an increased formation
of corticosteroids (4). In recently-performed examinations, a rise in corticosterone-serum
values after the application of intra-peritoneal application of Eleutherococcus
extracts on rats has been proven (31).



After the i.p. application of Eleutheroside B and E, the weights of the
testicle and the prostate gland of young mice was raised, the RNA-content
of the testicles was simultaneously increased. A corresponding testosterone-like
effect has been observed after castration, whereby the deterioration of
the testicles and prostate has been avoided by Eleutherococcus intake
(32). Active constituents Eleutherococcus, similar to constituents
of ginseng, bind with receptors of gestation-, mineralcorticoid- and glucocorticoid-
receptors; but beyond these, also with estrogen receptors (20). The reduction
of the c-AMP-phosphodiesterase through eleutheroside E (33), which was already
proven in vitro by Nikaido and collaborators, may be the explanation for
the rise in the c-AMP-panel already found by Brekhman.



In some performance tests on humans, as also in swimming tests with mice,
the improvement in the capacity of physical performance described
for adaptogens has been confirmed also for Eleutherococcus (29, 34).
The improved endurance of rats in the swimming test after application of
Eleutheroside has been cut short by giving proteic- or nucleic- acid synthesis
blockers (35).



The anabolic effect of Eleutherococcus extracts has been proven,
after an i.p. application in rats, as a stimulant of protein synthesis in
the pancreas, liver and adrenal cortex (36). Also in frog embryos, an anabolic
effect has been proven, which was neutralized by puromycin (37). The injection
of Eleutherococcus extract led to improved circulation in the brain
of anesthetized cats (38), and a rise in the content of biogenetic amines
in the CNS of rats, (39).



Eleutherococcus improves the non-specific immune defense, as has
been proven in a double-blind study with 36 probands, through quantitative
(Durchflusszytometrie). Immune-competent cells, particularly T-lymphocytes
and natural killer cells, were increased after intake for 4 weeks (40).
Purified prepared polysaccharides stimulated the phagocytic activity in
vitro and in vivo (41).



The question as to the active compounds responsible for these effects is
yet to be determined. Because the Eleutherococcus root has no compounds
which are comparable to ginsenosides, either as yet unknown compounds or
the phenylpropane glycoside syringin (= eleutheroside B) and syringaresinol-4-4′-0-beta-D-diglucoside
(= eleutheroside E), which have already been used in animal experiments,
are to be accepted as responsible.



Ashwaganda, Indian ginseng



Withania somnifera L., Solanaceae



The leaves of this plant are used in India as a folk medicine for a local
treatment for skin tumors (42). The root drug is considered a tonic and
roborant. It is said to “protect the organism from illness through
maintaining the healthy balance of the physical energies (43). The root
contains the steroid lactone withaferin A and related withanolides, beside
various alkaloids. The sitoindosides IX and X isolated by Ghosal et al.
represent C-27-glycowithanolides (44), the sitoindosides VII and VIII, acylesterylglucosides
(43) (fig. 4).



By examinations of the anti-stress effect, Singh et al. (45) found in albino
rats, that extracts of the seeds of Withania somnifera, when given i.p.,
significantly improved the protection against stomach ulcers that were induced
by aspirin or stress (45). Oral intake over 3 days of this extract (60 mg/kg)
effected a weakening of the milk-induced leucocytosis in mice (45). Similar
anti-stress effects were shown by the sitoindosides VII and VIII: the induction
of stomach ulcers through stress was hindered by a pre-treatment with sitoindoside
VII or VIII (43). The Porsolt-test, in which mice fall into behavioral despair
through forced swimming stress, showed a distinct shortening of the duration
of immobility, after giving sitoindoside VII and VIII (i.p.). This anti-depressive
effect can come about through a diminishment of the stress effect, or through
intervention in the monoamine metabolism of the brain (43). Examinations
showed that stress effects in rats led to a significant increase of the
dopamine receptors in the Corpus striatum and that this effect can
be suppressed through pre-treatment with Withania somnifera or with
Panax ginseng extracts (46). The sitoindosides IX and X protected
rats after oral application from stress-induced stomach ulcers (44). Withaferin
A showed no effects.



In contrast to the immuno-stimulating total effect of Withania extracts,
withaferin A has an immune-suppressive effect (44).



The testing of the physical endurance of mice, after pre-treatment with
withania-extract (i.p.) showed a near-doubling of the length of perseverance
in the swimming test (45). The significantly increased body weight in albino
rats, after one month of extra intake, speaks for the anabolic effect (45).



In learning and memory patterns in mice, sitoindosides IX and X, given p.o.
effected a significant improvement in the “step-down test”, both
in short range and long-range memory. Here, too, the withafern A showed
no effects (44). The results indicate that sitoindosides VII, VIII, IX,
and X represent the adaptogenic-active substances of Withania somnifera,
in spite of diverse steroidal structures.



Tulsi, Holy Basil

Ocimum sanctum L., Lamiacea



Ocimum sanctum is a plant that is known in India as Tulsi, and “Holy
Basil.” It has gained a solid place as a tonic in traditional Indian
medicine (fig. 5). Ocimum sanctum leaves contain an essential oil of varying
compositions. The chief components are eugenol, methylchavicol, alpha- and
beta-bisabolen (47). Additional constituents are the flavonaglyca luteolin
and apigenin and their 7-0-glucuronides as well as the C-glycosides orientin
and molludistin and the triterpene acid ursolic acid (48).



After p.o. application of the 70% ethanolic extract of the drug, in animal
tests, non-specific resistance from stomach ulcers and carbon tetrachloride
poisoning was improved (49).



The physical endurance of mice, after i.p. application of the extract, was
strengthened, without any increase in the weight of the adrenal gland, and
without a lowering of the ascorbic acid-content of the adrenal glands (49).



The CNS-effect of the 70% ethanolic extract (p.o.) in animal tests, was
comparable with the effect of low-dose barbiturate rates (50): cramps were
mitigated, the pentobarbital-effect was lengthened. However, stimulating
effects also showed up in the form of increased motor activity (50).



In the “Prosolt-test” (behavioral despair) (50) the oral intake
of the extract led to a shortening of the immobile condition, and thereby
to an imipramin(e)-like effect, which could be blocked by giving haloperidol.
This behavior allows one to assume an eventual dopamine-like effect.



Godhwani and collaborator (51) describe immune-stimulating effects in albino
rats after p.o. intake for 10 days for the watery and methanol extracts.
Because the examinations at hand have been made with the total extract from
the herb or leaves, no statement can be made about the inherent active constituents.
The constituents described until now (see fig. 5) occur as plant components
in many drugs, so that their participation in the described adaptogenic
effect has little likelihood.



Goldroot

Rhodiola rosea L., Crassulaceae



Rhodiola rosea is used by the ancient Siberians for the prevention
of tiredness and reduced interest in work (52). Besides salidrosid, the
thyrosol-glucoside, cinnamol alcohol glycosides are considered to be the
active constituents. Especially notable is the rosavidin, the cinnamyl-0-(6′-0-L-arabinopyranosyl-D-glucopyranosid)
(fig. 6). Additional constituents are thyrosol and cinnamic alcohol, essential
oil, anthraglycosides, beta-sitosterin, daucosterol, monoterpenes, flavonoids
and 16-18% tannins (53, 54).



Adaptogenic properties were observed in several tests (52): salidroside-application
protected, in the animal model, from an experimental leucocytosis created
by terpentine oil (52). After adrenaline injection, the substance showed
an antihyperglycemic effect, and after insulin application an antihypoglycaemic
effect (52).



In human studies, doses of 10 mg of salidrosid (p.o.), led to improved mental
capacities: in the “corrections test?”, the error rate fell nearly
50% (52). The alcoholic total extract goldroot raised the learning and memory
capacity of rats in the “irrgartenmodell-” (maze-model), with
a dose of 0.1 ml/animal. Salidrosid raised the physical capacities, or the
working capacity, in white mice: the subcutaneous application of the substance
lengthened the time of “multiply-forced clinging” by white mice
(52).



Until now, especially salidrosid and rosavidin have been presented as the
inherent active constituents, however, the plant contains additional glycosides
of similar structure (for instance the cinnamylglucoside rosin). The chemical
relationship of the compounds to syringin (=eleutheroside B), which has
been isolated from the Eleutherococcus senticosus root which also
showed adaptogenic effects, is interesting. This substance also has a phenylpropane
structure and is glycosilated, although, in another place.



Chickpeas

Cicer arietinum L., Fabaceae



In India, the chickpea is an important food. It is considered especially
nutritious because of its high content of proteins, carbohydrate, fat and
minerals. The strengthening and “performance elevating” effects
seem, however, to go beyond those of a mere food. In the search for the
responsible active substance, Singh and collaborators found pangamic acid
(fig. 7), also called vitamin B15 (56).



Pangamic acid does indeed show endurance-raising effects in the mouse swimming
test (57), however, besides Cicer arietinum, corn, soybean, peach
kernels and peanuts also contain pangamic acid in comparable concentrations,
without these foods having ever been described as adaptogenic.



Hoppea dichotoma Wild.

Gentianaceae



Hoppea dichotoma is used in Ayurvedic medicine for the treatment
of hemorrhoids, dropsy, and as a nerve tonic. Constituents acting adaptogenically
have been isolated from a root extract of the plant, and have been identified
as the flavan glycosides dichotosin, dichotosinin and diffutin (58) (fig.
8).



The adaptogenic effect of these compounds (i.p. Appl. in white rats) showed,
for instance, in raised endurance during the swim test and improved protection
towards stress-induced ulcers in the stomach (58). Their corticosteroid
profile in the serum had been raised in unstressed rats by 1.5 (58). When
the glycosides were given in combination with the relevant aglyca, the anti-stress
effect was noticeably raised, which has been interpreted as a synergistic
effect (58).



The drugs Leuzea carthamoides [Willd.] DC. (root), Trichopus zeylanicus
Gaertn. (leaves) and Codonopsis pilosula [Franch.] Nannf. (root)
also seem to have anti-stress effects.



For Leuzea, predominantly anabolic effects have been measured, which
apparently are caused by the phytoecdysones which they contain. Trichopus
zeylanicus
has been described by Pushpangadan as a potent adaptogen
(59). No phytochemical analysis has been performed. Codonopsis pilosula
“Dangshen”, is used in traditional medicine, either by itself,
or in diverse combination preparations. In phytochemical examinations, besides
other constituents, phenyl propane compounds, such as syringin have been
found (60).



Shosaikoto

Shosaikoto is a drug mixture that is used in Japan as a water-extract in
Kampo medicine, and is primarily known for its liver-protective and antiinflammatory
effects. For the composition of Shosaikoto, see Table IV.



For testing its adaptogenic effectiveness, mice have been put into
stress through immobilization (forced fixation) (61): the lowering of body
temperature caused by this stress, did not occur after peroral Shosaikoto
as also after Diazepam. Also, the diminished motor activity caused by stress,
has been mildly improved by both preparations. The hypertrophy of the adrenals,
induced by stress, however, was influenced neither by Shosaikoto or Diazepam
to any significant degree (61).



An immune suppression caused by stress, was mildly improved by the extract
p.o. (61). this could either be based on the immunomodulatory activity
(62) or an anti-stress effect.



Age-conditioned reduced learning capacity was significantly improved
in “passive avoidance response” models of 110-weeks-old rats,
after peroral Shosaikoto application. In comparison to the control group,
the brains of the treated animals showed raised dopamine and lowered noradrenalin
and 4-hydroxy-3-methoxymandelic acid (63).



Because we are dealing in Shosaikoto, with a combination of seven diverse
drugs, the total adaptogenic effect cannot be assigned to any single drug.



Bupleurum falcatum root (Saiko), the chief component in Shosaikoto,
contains triterpene alcohols, the so-called Sakogenins, and their glycosides,
the Saikosaponins. The watery drug extract (extracted hot) showed in vitro
a c-AMP-phosphodiesterase-blocking effect of about 40% (64). In the animal
model, Saikosaponins A and D caused an increase in the plasma concentration
in ACTH and cortisol, while Saikosaponin c remained without effect (65).



The influence of Panax ginseng and Glycyrrhiza glabra on the
glucocorticoid metabolism is already known (19, 66).



Although there are numerous phytochemical works relevant to the four other
drugs, one cannot ascribe an adaptogenic effect to any of the isolated constituents.



Examinations up until now on the scientific method of proof of the biological
activity of Adaptogens



Testing the Antistress Activity


Because an adaptogen is meant to raise the non-specific resistance toward
every king of stress, one exposes animals (mice, rats) after pre-treatment
with the assumed adaptogen to diverse stresses and measures the changes
in resistance towards toxins, on the basis of a control group.



Any raised capacity for resistance may manifest as an


  • increased capacity for the maintenance of body temperature during the
    stress of exposure to cold
  • Improvement in the coordinative capacity
  • Improvement in the cognitive faculties
  • Rise in locomotor and explorative activity
  • Improvement in emotional behavior
  • Avoidance of the formation of stomach ulcers after aspirin, stress due
    to cold or immobilization
  • Lowering of the milk-induced leukocytosis
  • Improvement of resistance toward diverse toxins
  • increase in general immune defense



The connection between stress and the its resulting ACTH and corticosteroid
output has long been known and it is reflected in the chain of reaction
represented in Table 9.



This mechanism seems to be a key function for the action of adaptogens.



In animal experiments, a stressed rat will have



clearly raised glucocorticoid blood levels. If one treats the animal with
an effective adaptogen, nearly normal corticosteroid values are measured
after the application of stress. Consequently, the cholesterin and the ascorbic
acid values of the adrenal cortex are not lowered and the weight of the
adrenal cortex remains nearly constant. After a single application of adaptogens,
the ACTH and corticosterin values in the blood rise in non-stressed rats,
and after several



days of application, the hormone panels appear unchanged. The capacity for
adaptation is raised, even with a single application, but it becomes optimal
only with use over several days (67). Filaretov and collaborators show in
the animal model, that a blockage of the pituitary-adrenal cortex axis leads
to



a total loss of the adaptive capacity of the organism, and the anti-stress
activity of adaptogens fails to occur (67). In endocrinological tests, a
rise of ACTH and corticosteroid panels, after the administration of a preparation
to unstressed rats, is taken to be an indication of adaptogenic effectiveness.



Testing the Changed Physical Labor Performance Capacity

The improvement of physical performance capacity seems to be based on a
more economical use of energy, although the reasons for this phenomenon
have not been researched until now. ATP, creatin phosphate and glycogen
deliver energy to the muscles. Table IV: Summary of the Ingredients in Shosaikoto



Plant Family Part Used Amount (g)



Bupleurum falcatum L. Umbelliferae root 7.0

Pinellia ternata Breitenbauch Araceae tuber 5.0

Zingiber officinale Roscoe Zingiberaceae rhizome 1.0

Scutellaria baicalensis Georgi Labiatae root 3.0

Zizyphus vulgaris Lam. Rhamnaceae fruit 3.0

Panax ginseng C.A. Meyer Araliaceae root 3.0

Glycyrrhiza glabra L. Leguminosae root 2.0



Brekhman et al. (68) were able to show that the decrease in these energy
supplies during a rat swim test of two hours can be reduced through the
i.p. application of an eleutheroside total extract.



For measuring changed physical endurance, the so-called swim test
is usually undertaken: after giving adaptogens, one makes mice swim in a
porcelain tank filled with water at the temperature of 26-30 deg. C. until
they are exhausted. The increased performance is measured in the form of
increased endurance, compared to a control group.



Another endurance test is the “climbing the endless rope test:”
A mouse in an enclosed case must climb a constantly moving (from above to
below) endless rope (like a conveyer belt effect), in order to escape the
bottom of the chest, which is under a mild electric charge. The physical
energy is exhausted when the mouse remains sitting on the bottom.



Testing the Anabolic Effectiveness

Along with the anti-stress effect of adaptogens, there seems to be also
an anabolic effect. The actual cause for this remains to be clarified. The
anabolic effect could be a response by the endocrine system to the influence
of the glucocorticoid level and it may come about through increased releases
of growth hormone GH. The stimulation of GH secretion by dopamine and dopamine
agonists (see the results of the Porsolt-test) needs to be pointed out (69).
In the animal model, the increase in body weight and the acceleration of
growth of younger animals point to the anabolic effect of the adaptogens.
Beyond that, directly stimulating effects on DNA, RNA or protein synthesis
has been observed.



Testing of Changes of Brain Metabolism

The reasons for improved mental capacity after adaptogen intake have not
yet been researched. The influence on learning and memory performance can
be measured with the “passive-avoidance response” test. One typical
test of this type is the “step-down” test (44): Mice are placed
on the platform, which is located on top of a metal grid with a weak electric
current. If the mouse leaves the platform, it experiences a “light”
foot shock by stepping on the grid. A mouse with improved learning and memory
capacity will more quickly recognize the platform as a pain-free zone, than
the untreated mouse.



Porsolt (70) has developed the “behavioral despair” test, also
called “forced swimming” test for the testing of anti-depressives.
Due to the close connection between stress and the development of depression
(behavioral despair), the test also serves for the testing of adaptogenic
efficacy. After the administration of adaptogens, the influence on the monoamine
metabolism in the brain can be demonstrated (43,50).



If one puts a mouse into a small glass cylinder (about 12 cm), forcing it
to swim in water, it makes desperate attempts to flee or swim in the beginning,
but then falls into an immobile condition, in which it makes but minimal
motions to keep its head above water. After 20 minutes the mouse is taken
out and placed into its usual cage. The test is repeated in 24 hours. This
time, the mouse falls much faster into the immobile condition. The length
of the immobile phase is measured and the total duration of the test is
only 5 minutes. The application of anti-depressives as well as dopamine
agonists (e.g. bromocryptin) leads to a delay of the beginning of the immobile
phase, and consequently, to a shortening of the immobile phase during the
testing period of 5 minutes. Dopamine receptor-blocking substances (e.g.
haloperidol) do not show such effects.



The results of the tested adaptogens could be anticipated by a distinct
shortening of the immobile phase to cause a possible dopaminergic effect,
particularly because the effect has been canceled through pre-treatment
with haloperidol.



References

1. Lazarev, N. V.: 7th All- union Congr. Physiol., Biochem., Pharmacol.,
p. 579. Medgiz, Moscow 1947.

2. Selye, H.: Endocrinology 1937; 21/2:169.

3. Selye, H.: Nature 1938;141: 926.

4. Brekhman, 1.1.: .Man and Biologically Active Substances.

5. Wagner, H.: Dtsch. Apoth. Ztg. 1991;131/4:117.

6. Möller, H.-J., und Horn, R.: Apoth.J. 199();12:14.

7. Empfehlungen zum Wirksamkeitsnachweis von Nootropika im Indikationsbereich
Demenz

8. Selye, H.: Nature 1936, 138: 32.

9. Schlesinger, M.J., Santoro, M.G., and Garaci, E. (eds.): >>Stress
Proteins – Induction and Function.

10. Kaufmann, S.H.E. (ed.): >>Heat Shock Proteins and Immuneresponse.

11.Selye, H.:Am.J. Physiol. 1938,123: 758.

12.Shoji,J.: In:>>Adv. Chin. Med. Mat. Res. Tso, W.W., and Koo, A.,
eds.), p. 455. Singapore, Philadelphia, 1985.

13.Kim, S.l., Kang, KS., and Lee, Y.H.: Arch. Pharm. Res. 1989; 12/1 48.

14.Han, B.H., Han, Y.N., and Park, M.H.: In: >>Adv. Chin. Med. Mat.
Res.

15.Takeda, A.N., Katoh, N., and Yonezawa, M.:J. Radiat. Res. 1982; 23. 150.


16.Joo, C.N.: >>Proc. 4th Intern. Gins. Symp. (Korea Gins. a. Tobacco
Res. Inst., ed). p. 63,1984.

17. Bombardelli, E., Cristoni, A., and Lietti, A.: Proc. 3rd Intern. Ginseng
Symp. (Korea Gins. Res. Inst., ed.). p. 9, 1980.

18.Saito, H.: In >>Adv. Chin. Med. Mat. Res.

19.Hiai, S., Yokoyama, Oura, H., and Yano, S.: Endocrinol. Japon. 1979;
26/6: 661.

20.Pearce, P.T., Zois, 1., Wynne, KN., and Fulder, J.W.: Endocrinol,Japon.
1982; 29: 567.

21. Yamamoto, M., Kumagai, A., and Yamamura, Y.: Arzneim. Forsch. (Drug
Res.) 1977, 27 II/7: 1404.

22. Brekhman, 1.1.: Lloydia 1969; 32/1: 46.

23.Bladt, S., Wagner, H., and Wool, W.S.: Dtsch. Apoth. Ztg.1990;130/27:1499.


24. Brekhman, 1.1., and Kirillov, I.O.: Life Sci. 1969, 8:113.

25. Goldberg, E.L)., Shubina, T.S., and Shternberg, B.: Antibiotiki (Moskau)
16/2: 113. 1971; Chem. Abstr. 1971; 74:139196q.

26.Monakhof, B.V.: Vorpr. Onkol. 1967;13/8: 94; Chem. Abstr. 1968; 68:1930.

27. Abramova, Z.l., Chernyi, Z.Kh., Natalenko, V.P., and Gutman, A.M.: Lek.
Sredstva Dal’Vostoka 1972;11:102. Chem. Abstr. 1975; 82: 38659c.

28.Brekhman, 1.1., and Dardymov, I.V.: Ann. Rev. Pharmacol. 1969; 9: 410.

29.Farnsworth, N.R.: In >>Economic Med. Plant Res. 1.

30. Dardymov, 1. V., and Khasina E.l.: Lek Sredstva Dal’nego Vostoka 11:
56.1972 ; Chem. Abstr. 1975; 82: 51855h.

31. Winterhoff, H., Nörr, H., and Wagner, H.: Veröffentlichung
in Vorbereitung.

32.Dardymov, I.V.: Lek. Sredtsva Dal’nego Vostoka 1972; 11: 60. Chem. Abstr.
1975; 82: 51571n.

33. Nikaido, T., Ohmoto, T., Kinoshita, T., Sankawa, U., Nishibe, S., and
Hisada, S.: Chem. Pharm. Bull. 1981; 29/12: 3586.

34.Dardymov, I.V.: Sb. Rab. Inst. Tsitol. Akad. Nauk. SSSR 11: 761971, Chem.
Abstr. 1971; 82: 54331w.

35.Dradymov, I.V., Bezdetko, G.N., and Brekhman, I.I.: Vop. Med. Khim. 1972;18/3:
267. Chem. Abstr. 1972; 77: 97282u.

36. Todorov, I.N., Sizova, S.T., et al.: Khim. Farm. Zh. 1984; 18/5: 529.
Chem. Abstr. 1985;103: 605w.

37. Voropaev, V.M.: Lek. Sredstva Dal’nego Vostoka 1972; 11: 74. Chem. Abstr.
1975; 82: 52153q.

38. Zyryanova, T.M.: Cent. Nerv. Syst. Stimulants, p. 37. 1966. Chem. Abstr.
1966, 66: 114460t.

39. Abramova, Z.I., Chernyi, Z.K, Natalenko, V.P., and Gutman., A.M.: Lek.
Sredstva Dal’nego Vostoka 1972; 11: 106. Chem. Abstr. 1975; 82: 38660w.

40. Bohn, B., Nebe, C.T., and Birr, C.: Drug Res. 1987; 37 II/10: 1193.

41. Fang,J.,Proksch,A.,andWagner,H.:Phytochem.1985; 24: 2619.

42. Hoppe, H.A.: >>Drogenkunde

43. Bhattacharya, S.K., Goel, R.K. Kaur, R., and Ghosal, S.: Phytotherapy
Res. 1987; 1/1: 32.

44. Ghosal, S., Battacharya, et al.: Phytotherapy Res. 1989; 3/5: 201.

45. Singh, N., Nath, R., Lata, A., Singh, S.P., Kohli, R.P., and Bhargava,
KP.: Int. J. Crude Drug Res. 1982; 20/1: 29.

46. Saksena, A.K, Singh, S.P., Dixit, KS., Singh, N., Seth, K, Seth, P.K,
and Gupta, G.P.: Planta Med. 1989; 55/1: 95.

47. Laakso, I., Seppänen- Laakso, T., Herrmann- Wolf, B. Kühnel,
N., and Knobloch, K: Planta Med. 1990; 56/6 527.

48. Nair, A.G.R., Gunasegaran, R., and Joshi, B.S.: Ind. J. Chem. 1982;
21 B: 979.

49. Bhargava, KP., and Singh, N.: Ind. J. Med. Res. 1981; 73: 443.

50. Sakina, M.R., Dandiya, P.C., Hamdard, M.E., and Hameed, A.:J. Ethnopharmacol.
1990; 28: 143.

51. Godhwani, S., Godhwani,J.L., and Vyas, D.S.:J. Ethnopharmacol. 1987;
21: 153.

52. Ssaratikov, A.S., et al.: Pharmazie 1968, 23: 392.

53. Zapesochnaya, G.G., Kurkin, V.A., and Shchavlinskii, A.N.: F.E.C.S.
Int. Conf. Chem. Biotechnol. Biol. Act. Nat. Prod. (proc.) 3rd Meeting Date
1985, 4, 404. VCH. Weinheim, BRD, Chem. Abstr. 1989;110: 36720p.

54. Hoppe, H.A.: >>Drogenkunde.

55. Petkov, V.D., et al.: Acta Physiol. Pharmacol. Bulg. 1986; 12/3: 3.

56. Singh, J., Handa, G., Rao, P.R., and Atal, C.K.: J. Ethnopharmacol.
1983; 7: 239.

57. Atal., C.K., et al.: Ind. Drugs 1980; 17; 187.

58. Ghosal, S., Jaiswal, D.K, Singh, S.K, and Scrivasta, R.S.: Phytochemistry
1985; 24/4: 831.

59. Pushpangadan, P., and Sharman, A.K: In: >>First International
Congress on Ethnopharmacology.

60. Wang, Z.T., Xu, G.J., Hattori, M., and Namba, T.: Shoyakugaku Zasshi,
42/4: 339. Chem. Abstr. 1989; 11í 12386d.

61. Amagaya, S., and Ogihara, Y.:J. Ethnopharmacol. 1990; 28: 357

62. Iwama, H., Amagaya, S., and Ogihara, Y.:J. Med. Pharm. Soc. Wakan- Yaku
1987; 4: 8.

63. Amagaya, S., et al.: J. Ethnopharmacol. 1990; 28: 349.

64. Nikaido, T., Ohmoto, T., Nogouchi, H., Kinoshita, T., Saitoh, H., and
Sankawa, U.: Planta Med. 1981; 43:18

65. Hiai, S.: In >>Adv. Chin. Med. Mat. Res.

66. Tamura, Y., Nishikawa, T., Yamada, K, Yamamoto, M., and Kumagai, A.:
Drug Res. 1979: 29: 647.

67. Filaretov, A.A., Bogodanova, T.S., Podvigina, T.T., and Bodganov, A.I.:
Exp. Clin. Endocrinology 1988; 92/2: 129.

68. Brekhman, I.I., and Dardymov, I. V.: Sb. Rab. Inst. Tsitol. Akad. Nauk
SSSr 14: 82. 1971, Chem. Abstr. 1972; 76: 54332x.

69. Forth, W., Henschler, D., und Runmmel, W.: >>Allg. u. spez. Pharmakologie
u. Toxikologie70. Porsolt, R.D., Anton, G., Blavet, N., and Jalfre, M.:
Eur. J. Pharmacology 1978; 47: 379.



Address of the Authors:



Prof. Dr. Hildebert Wagner

Heidrun Nörr

Institut für Pharmazeutische

Biologie der Universität

Karlstr. 29

8000 München 2

Priv.- Doz. Dr. rer. nat.



Hilke Winterhoff

Institut für Pharmakologie und

Toxikologie der Universität

Domagkstraße 12

4400
Münster

Christopher Hobbs LAc AHG Written by Christopher Hobbs LAc AHG

Get the Healthiest Newsletter!

Get a dose of Healthy delivered straight to your inbox. Each FREE issue features amazing content that will elevate your Body, Mind, and Spirit.

Your data is never shared with 3rd parties

Body+Mind+Spirit

TRANSFORM YOUR LIFE?

Try the Internet's Longest-Running Wellness Program.