A stimulant whips the tired horse. An adaptogen feeds it.

Abstract

Adaptogens were initially defined as substances that enhance the "state of non-specific resistance" in stress, a physiological condition that is linked with various disorders of the neuroendocrine-immune system. Studies on animals and isolated neuronal cells have revealed that adaptogens exhibit neuroprotective, anti-fatigue, antidepressive, anxiolytic, nootropic and CNS stimulating activity. In addition, a number of clinical trials demonstrate that adaptogens exert an anti-fatigue effect that increases mental work capacity against a background of stress and fatigue, particularly in tolerance to mental exhaustion and enhanced attention. Indeed, recent pharmacological studies of a number of adaptogens have provided a rationale for these effects also at the molecular level. It was discovered that the stress-protective activity of adaptogens was associated with regulation of homeostasis via several mechanisms of action, which was linked with the hypothalamic-pituitary- adrenal axis and the regulation of key mediators of stress response, such as molecular chaperons (e.g., HSP70), stress-activated c-Jun N-terminal protein kinase 1 (JNK1), Forkhead box O (FOXO) transcription factor DAF-16, cortisol and nitric oxide.

Introduction

The idea that a pill could improve mental and physical performance in healthy people was devised during World War II with various stimulants given to pilots and members of submarine crews [1,2,3,4,5,6]. For instance, the first studies on the stimulating and tonic effects of Schisandra chinensis were published in Soviet Union WWII military journals [5,6]. The Russian interest in S. chinensis arises from ethnopharmacological investigations by Komarov (1895) and Arsenyev (1903-1907) in the Far East regions. It was discovered that the berries and seeds were used by Nanai (Goldes or Samagir) hunters as a tonic, to reduce thirst, hunger and exhaustion, and to improve night vision [7,8,9,10]. During the period 1950-60, the idea of using herbal medicinal plants to increase stamina and survival in harmful environment was developed, and a new concept of "adaptogens" was introduced by the toxicologist Lazarev to describe compounds which could increase "the state of non-specific resistance" in stress [11,12]. This concept was based on Hans Selye's theory of stress and general adaptation syndrome, which have three phases: alarm phase, phase of resistance and phase of exhaustion [13], Figure 1.

At the end of the 1960s Brekhman and Dardimov proposed that adaptogens are innocuous agents, nonspecifically increasing resistance against physically, chemically, biologically and psychologically noxious factors ("stressors"), normalizing effect independent of the nature of pathologic state [14]. In the early 1960's, the study of adaptogens developed into a field of biomedicinal research in its own right in the USSR. This was due to a major targeted project or direction of research, such as mapping or screening of biologically active substances from the plant kingdom. The aim of the stress research was to develop drugs and methods able to stimulate the intrinsic adaptive mechanisms of the organism to help it survive in situations of intense or prolonged stress, whilst preferably maintaining the capability for physical and mental work [15]. The extent of the research carried out was enormous with 1009 studies (primarily pharmacological and clinical) published in Russia up until 1982 and most of them concerned extracts or isolates prepared from Eleutherococcus senticosus [16].

Today, research into adaptogens comprises the following four areas: (a) phytochemistry: isolation and structure elucidation of active constituents of adaptogenic plants; (b) biochemistry and molecular biology: mechanisms of stress protective activity of adaptogens on the molecular and cellular levels; (c) experimental and clinical pharmacology: efficacy and safety of adaptogens in stress related disorders on animals and humans; (d) pharmaceutical development of herbal preparations/products that have well established medicinal use in evidence based medicine. Some of the most interesting developments are studies that clearly indicate that certain adaptogenic substances can activate the protective mechanisms of cells, which is linked to an increase in survival rate both in vitro and in vivo [17,18,19,20]. These studies have so far been directed at the regulation of molecular chaperons (Heat Shock Proteins), such as Hsp70 and other key stress mediators [21,22,23].

As a pharmacotherapeutic group adaptogens were recently defined as herbal preparations that increased attention and endurance in fatigue, and reduced stress-induced impairments and disorders related to the neuro-endocrine and immune systems [23,24]. This definition was based on evidence obtained from clinical trials, which we evaluated in accordance with the European Medicines Agency Assessment Scale [25] and US Natural Standards Evidence- based Validated Grading Rationale [http://www.naturalstandard.com/grading.html].

The term adaptogen is often applied to plants, even when the criteria of an adaptogen is not met with, such as the important and significant general adaptive effect on stress involving the whole organism and its main organ and functions. In this review article, we will focus our attention on some of the most extensively studied adaptogens: Rhodiola rosea, Schisandra chinensis and Eleutherococcus senticosus [26,27,28,29,30,31,32,33,34,35,36,37,38] and discuss the results of pharmacological and clinical studies, which are relevant to the main topic of discussion.

The normal paradigm one drug for one disease is not appropriate for adaptogens as they can have numerous pharmacological effects and indications. Table 1 and Table 2 show their pharmacological profiles, which are different but similar in terms of their stress-protective action. Therefore, all these pharmacological effects can be combined into the groups associated with stimulating and stress-protective effects in CNS and vegetative nervous systems, endocrine system and immune system, comprising by definition the parts of neuroendocrine-immune complex - stress-system, Table 3 [26].

The adaptogens Eleutherococcus senticosus, Rhodiola rosea and Schisandra chinensis were reported to be safe in acute and subacute toxicity studies. Moreover, adaptogen induced state of non-specific resistance to highly toxic chemicals (e.g., chlorophos, phosphorus, cyclophosphane, strychnine, aniline, sodium nitrite, narcotics like sodium barbital, hexenal, chloralhydrate, benzene, acetone, ether, etc.) and microbes demonstrated in many pharmacological/toxicological studies [28], actually implies that they have an anti-toxic activity. For example, it was demonstrated that repeated administration of Rhodiola rosea extract during 10 consecutive days decreased LD50 of 40% ethanol in mice from 24.1 ml/kg to 55.2 ml/kg. It was also shown that salidroside shortened (from 100% to 19%) the duration of benzene induced sleep in rats [28].

Active Compounds

Chemically, the adaptogens are typically either complex phenolics or tetracyclic triterpenoids/ steroids (Figure 2). The phenolic compounds include phenylpropanoids and phenylethane derivatives, such as salidroside (rhodioloside), rosavin, syringin, triandrin, tyrosol, [28,35,38,39,40,41,42,43] and lignans, such as eleutherosid E [44,45,46,47,48] and schisandrin B [49,50,51,52,53,54,55,56,57,58,59,60]. They are structurally similar to the catecholamines -the mediators of the sympathoadrenal system (SAS) involved in activation of the stress system in the early stages of stress response. The tetracyclic triterpenoids, such as cucurbitacin R diglucoside [61,62], ginsenosides [63,64,65,66,67,68] and phytosterol-glycosides (e.g, SG, eleutheroside A, sitoindosides, daucosterol) [27,69,70,71] structurally resemble the corticosteroids that act as stress hormones involved in protective inactivation of the stress system [72,73,74]. In addition, the monoterpene glucoside rosiridin, which is isolated from Rhodiola rosea, was found to inhibit monoamine oxidases A and B in vitro implying its potential beneficial effect in depression and senile dementia [75].

Salidroside - the active principles of R. rosea extracts - was found to have neuro-protective activity, which reduced stress induced impairments and disorders related to the neuro-endocrine and immune system through: Stimulation of CNS system [28,39,76,77,78].Protection of cultured neuronal cells from sodium azide and glutamate induced injuries [79,80].Attenuation of glutamate-induced apoptotic cell death in primary cultured hippocampal neurons of rats [81].Blockage of H2O2-induced apoptosis in rat neuronal PCl2 cells [82].The effect of anti-neuronal apoptosis related to its function of decreasing intracellular free calcium concentration [83,84].Protection of rat neuronal PCl2 cells against amyloid beta-peptide (A beta)-induced cytotoxicity reduced accumulation of reactive oxygen species and malondialdehyde (MDA) [85].Stimulation of glucose uptake in skeletal muscle cells by activating phosphorylation of AMP-activated protein kinase [86].Protection from oxidative damage during fatigue [87].Reduction of the degree of cerebral edema in rats with global cerebral ischemia-reperfusion injury, relieves the metabolism abnormity of free radical and improves the function of cognition [88].

A number of these findings might raise the possibility of potential therapeutic applications of salidroside in preventing and treating cerebral ischemic and neurodegenerative diseases [89].

Tyrosol - another active principle of Rhodiola extract - increases phosphorylation of eNOS and FOXO3a, which are key molecular targets involved in this mechanism. Furthermore, it has recently been shown that tyrosol induces the expression of the longevity protein SIRT1 [90].

It is noteworthy that administration of the amino acid tyrosine, which is a common precursor of biosynthesis of tyrosol, salidroside and catecholamines (Figure 2), alleviates both stress-induced depletion of brain catecholamines (norepynephrine and dopamine in the alarm phase of stress syndrome) and reduces fatigue, as noted in animal task performances [91]. A number of clinical studies suggest that supplementation of tyrosine might improve stress- induced (e.g., cold, noise, anxiety and fatigue) accuracy of mental performance [92].

Indeed, schisandrin B has a similar pharmacological profile associated with stress-protective activity. Apparently the neuroprotective effect of schisandrin B [54,55,59,93,94] is associated with the expression of heat shock proteins Hsp70. It has been demonstrated that schisandrin B stimulate the expression of Hsp70 in normal cells [95, 96,97,98,99,100,101], which is associated with the enhancement of mitochondrial glutathione status [95,97,100, 101,102,103], antioxidant activity [59,96,104,105,106,107,108,109], ATP generation [110], mitigation of age- related impairments in mitochondrial antioxidant status and functional ability in various tissues, enhancement in cognitive functions and an increase in the survival of aging in rodents [56,97,112].

Antistress and Stimulating Activity of Adaptogens in Animal Model Systems

A typical pharmacological assessment of adaptogens includes the evaluation of stimulating, tonic and stress- protective activities in model animal systems, which were subjected to various stress conditions [112,113].

Anti-Stress Effect of Adaptogens

The stress protective effect of adaptogens has been demonstrated on simple organisms and on isolated cells [17,18, 114,115]. Thus, there may be an association with regulation and homeostasis of the neuro-endocrine-immune complex. In addition, there may also be a connection with more evolutionary older congential mechanisms of regulation in cellular homeostasis and the adaptive/defense response to external stressors. We hipothezise that this type of defence system is apparently common for all cells and living organisms and probably includes heat shock proteins among the number of key mediators of innate nonspecific resistance to stressors.

It has been shown that the same mechanism can be found in stress tolerance and lifespan extension, which makes them parallel phenomenon Therefore, it is not surprising that adaptogens prolong the lifespan of the nematode Caenorhabditis elegans [18] and Drosophila melanogaster in a dose dependent manner [19], e.g., see Figure 3, where effect of ADAPT-232-a fixed combination of Rhodiola rosea, Schisandra chinensis and Eleutherococcus senticosus extracts-on the life splan of C.elegance is demonstrated.

Molecular Mechanisms behind Anti-Stress Effect of Adaptogens

It has been demonstrated that the beneficial stress-protective activity of adaptogens was associated with the hypothalamic-pituitary-adrenal axis and the regulation of key mediators of the stress response common to all cells, of such as: Heat shock proteins Hsp70 and Hsp16 [17,22,23,95,96,97,98,99,100,101,116,117,118,119,120], which are molecular chaperons involved in stress-induced cytoprotection and in adaptation of repeated exposure to an initial stressor.Stress- activated c-Jun N-terminal protein kinase 1 (JNK1) [21,121].Forkhead box O (FOXO) transcription factor DAF-16 [17,90].HPA- axis, including cortisol and glucocorticoid receptors [21,123,124].Beta- endorphin [125,126,127].Nitric oxide [21,128,129,130,131].The biosynthesis of ATP, thus inducing an alteration in energy source [23,131], Figure 4.

Typically, a cell is either in: balance (dynamic equilibrium - homeostasis), orfunctioning under stressful conditions (threatened homeostasis-imbalance),.the state of adaptation (tolerance) to stress (i.e., state of non-specific resistance to stress; heterostasis or homeostasis with a higher level of equilibrium),the state of apoptosis (dying).

Panel (a) shows that mitochondria generate aggressive oxygen-containing radicals that can damage native or repair proteins by distorting their 3-D structure, so that they can no longer fulfil their functions in the cell.

There are many "players' involved in the regulation of homeostasis at both the cellular level and the organism level, such as: the stress hormone cortisol (a molecule that is secreted from glands and regulates the functions of organs and systems of the organism).glucocorticoid receptors that modulate/regulate cortisol secretion (feedback regulation).NO, an intracellular signalling molecule that mediates stress response and modulates stress-induced activation of hormonal, nervous and immune systems.FoxO, a Forkhead protein that controls the synthesis of proteins involved in stress resistance, cell survival and longevity.

Panel (b) shows that under stress (e.g., infection, cold, heat, radiation, physical load, emotional stress) an external stress signal activates a cascade of "signalling" proteins/enzymes including JNK, a stress-activated enzyme that plays important roles in the regulation of a diverse array of cellular functions such as neuronal development, activation of the immune system and programmed cell death (apoptosis). The functions of JNK are as follows: To increase the formation of aggressive radicals and nitric oxide, which in turn suppresses the generation of energy providing molecules (ATP). As a result of lack of energy, many proteins cannot work, several factions are suppressed, and the first symptoms of fatigue and exhaustion are observed. ATP is also required for the normal functioning of heat shock proteins (e.g., Hsp70), which are produced as a defence response to stress and assist in the repair of misfolded and damaged proteins.To suppress glucocorticoid receptors (GR) such that the feedback inhibition of cortisol secretion ceases to function and levels of circulatory cortisol increase. The cortisol inhibits the immune system, and has anti-inflammatory effects on the body. It is also required to protect the organism from over-reaction/over-activation in response to stress. However, chronically high levels of cortisol are associated with depression, chronic fatigue and impaired cognitive function, such as decreased attention and learning ability.To activate translocation of FoxO to the nucleus and initiates the synthesises of proteins that confer stress-resistance and increased longevity.

Panel (c) shows that adaptogens such as ADAPT-232 decrease NO, cortisol and JNK under stress and stimulate/ activate the expression of Hsp70 and p-FoxO1. The stimulation of Hsp70 biosynthesis is a key point in the mechanism of action of adaptogens since the heat shock protein: enhances the repair of damaged proteins.inhibits the stress-induced expression of NO genes. ATP is increased to normal levels in the adapted cell. This is due to the inability of reduced levels of NO to suppress the formation of energy providing molecules.inhibits JNK and consequently apoptotic death and suppression of immune system via activation of GR and other mechanisms. Normal GR function and normal ATP levels are associated with the anti-fatigue and anti-depressive effects of adaptogens and with normal cognitive function (e.g., good attention, memory and learning).is probably associated with the effect of adaptogens on the phosphorylation of FoxO and its translocation into the nucleus of isolated cells (i.e., human monocytes) or simple organisms (i.e., DAF-16 in C. elegance) and, consequently, with increased resistance to stress and increased life span.

In summary, ADAPT-232 works like a stress vaccine (stress-mimetic) by activating stress-induced self-defence mechanisms in order to adapt the cell and organism to mitigate stress-induced harmful effects.

It seems that activation of Hsp70 expression is a key point in the mode of action of adaptogens [23]. We have demonstrated that adaptogens induce an increase of serum Hsp72 in animal studies [22]. This induction is considered as a defense response to stress, which increases tolerance to stress in a combination of physical and emotional stresses. Our data suggest that increased tolerance to adaptogen-induced stress is associated with its stimulation of expression of circulating serum Hsp72 [22]. In fact, Hsp72 production and release is a known mediator of the stress response involved in repairing proteins during physical load. Our working hypothesis is that adaptogens adapt (or make less sensitive) the organism to stress. Thus, adaptogens act like low molecular weight "vaccines" or stress-mimetics, which induce mild activation of the stress system in order to cope with more severe stress. The adaptogens act as challengers and mild stressors (stress-mimetics) [23]. This gives rise to adaptive and stress-protective effects, which are mainly associated with the HPA axis, a part of the stress system that also contributes to the nervous, cardiovascular, immune, gastrointestinal and endocrine systems [64,132,133].

The anti-depressive effect of Rhodiola rosea [134] may be associated with parts of the stress-system (e.g., secretion of cortisol and the JNK mediated effects on the glucocorticoid receptors) [21,122,134] through its effect on mono-amine oxidase A [75].

A recent review [135] focused on the neuroprotective effects of adaptogens. The authors concluded that the adaptogens Eleutherococcus senticosus, Rhodiola rosea and Schisandra chinensis were all involved in the protection of brain neurons from various injuries, which means that they may have an influence on neurodegenerative mechanisms in Parkinson's disease [135]. 3.3. CNS Stimulatory Effect

Apparently, stimulating (acute/single dose effect) and tonic (effect of repeated/multiple administration) effects of adaptogens are actually consequences of their stress-protective activity. CNS stimulating and tonic effects of adaptogens are well documented in numerous publications and reviewed in Phytomedicine [77]. In contrast to conventional stimulants, such as sympathomimetics (e.g., ephedrine, fenfluramine, phentermine, prolintane) and general tonics, the adaptogens don't possess addiction, tolerance and abuse potentials, they don't impair mental function and lead to psychotic symptoms in long term use, Table 4. Their clinical and pharmacological effects are due to a different mode of action. Their stimulating effect is more pronounced against a background of fatigue and stress.

Clinical Studies

The most important characteristics of adaptogens, such as stress-protection and a stimulatory effect are common to all adaptogens. However, the effects may differ under various circumstances (Table 1 and Table 2) as has been documented in a number of clinical studies (Table 5) and reviews [14,23,26,28,31,32,36,37,77,78,112,113,137,138, 139,140].

The majority of the reviews focused on narrative observations of clinical studies and only a handful conducted a systematic assessment and quality scoring of the level of evidence as recommended by the Natural Standards and the EMEA [23,77].

One such review [31] focused on over 35 clinical trials on Eleutherococcus senticosus in healthy human subjects (ca. 6,000 subjects aged from 19 to 72), which were performed in normal and stressful conditions (e.g., high temperature environment, forced work periods, loud noise conditions, motion sickness, varying degrees of deafness, heavy physical burden, hypertension, mountain rescuers under forced conditions, athletes, deep sea divers, intense mental work and physical work, factory workers under extreme working condition). Farnsworth et al. observed that there was an improvement of the physical and mental work capacities in all cases. In addition, over 35 studies have focused on the effect of Eleutherococcus senticosus on more than 2,200 sick patients [31]. The studies included patients with atherosclerosis, acute pyelonephritis, diabetes, hypertension, trauma, neuroses, rheumatic heart disease, chronic bronchitis, insomnia, cancer and several other ailments. In most cases, a moderate improvement relative to the initial conditions was observed. The extracts were well tolerated and no side effects were observed [31,32].

However, the most convincing evidences of the efficacy of adaptogens were found in studies related to its neuro- protective effects, effects on cognitive functions and mental performance in fatigue, and on its efficacy in asthenia and depression [23]. The evidence points to adaptogens may be beneficial on neurodegenerative disorders [54,83, 84,89,135,141].

Adaptogens in Fatigue, Effect on Cognitive Functions

In total, more than 30 publications on the clinical efficacy of various Rhodiola rosea preparations can be found in the PubMed database. The majority of these studies are of varying methodological rigor and concern cognitive functions and mental performance under fatigue, Table 5.

The clinical trials using Schisandra chinensis (13 studies) and Eleutherococcus senticosus (11 studies) on mental performance in humans have been the subject of a recent review [23]. A systematic review showed that adaptogens have a significant, beneficial and specific effect on stress-induced symptoms under fatigue [23]. It was seen that Rhodiola rosea, in particular, significantly reduced symptoms of fatigue and improved attention after four weeks of repeated administration [122]. Furthermore, it was suggested that the inhibitory effect of Rhodiola rosea on the increased basal level of salivary cortisol results in an improvement of cognitive function. This is in line with other studies demonstrating that optimal corticosteroid levels are a requirement for efficient cognitive function. It has been shown that significant changes (upregulation or downregulation) of circulating levels of corticosteroids are associated with cognitive impairment [168]. Moreover, studies on healthy volunteers receiving single and repeated doses of SHR-5 extract (Rhodiola rosea) have demonstrated an anti-fatigue effect and improvement in cognitive functions during fatigue and in stressful conditions [143,144,145]. Thus, one may conclude that repeated administration of R. rosea extract (SHR-5) exerts an anti-fatigue effect on healthy subjects and burnout patients expressing fatigue syndrome. This in turn, increases the patient's mental performance and ability to concentrate.

Adaptogens in Asthenia and Psychiatric Disorders

It should be mentioned, that the majority of clinical studies cited here are the most questionable and poorly documented as standardized psychological measures were not used in the earlier studies. Indeed, some of them did not use randomization, or blinding of subjects. However, the main problem in assessment of these studies is that the Soviet diagnostic criteria were different from commonly used criteria in the rest of the world [169,170,171]. The diagnostic criteria used in the USSR prior to 1990 for schizophrenia was particularly idiosyncratic, overused, and misapplied to other conditions [169,170,171]. For example, some patients who would be diagnosed as having psychotic depression, schizotypal disorder, schizoaffective disorder, or bipolar disorder by a non-Soviet psychiatrist would have been diagnosed as schizophrenic by a Soviet psychiatrists [166,167,168]. Indeed, the term "sluggish-schizophrenia" was particularly misused [172]. The diagnoses of asthenia and neuroasthenia include a very heterogeneous group of patients with mixed psychological and physical disorders, making the studies more difficult to interpret.

Nevertheless, in spite of numerous shortcomings, which reduced the quality of evidences obtained in the early clinical studies in Russia, these scientific evidences provide important information about efficacy and safety of adaptogens in the treatment of psychiatric disorders, table 6. Some of these publications are discussed below.

Conclusions and Perspectives of Implementation

Recent pharmacological studies of some adaptogens give a rationale to their effects at the molecular level. It has been shown that the beneficial stress-protective effect of adaptogens is related to the regulation of homeostasis via several mechanisms of action, which are associated with the hypothalamic-pituitary-adrenal (HPA) axis and the regulation of key mediators of the stress response, such as molecular chaperons (e.g., Hsp70), stress-activated c- Jun N-terminal protein kinase (JNK1), Forkhead box O (FoxO) transcription factor, cortisol and nitric oxide (NO). In summary, adaptogens may be regarded as a novel pharmacological category of anti-fatigue drugs that: (i)induce increased attention and endurance in situations of decreased performance caused by fatigue and/or sensation of weakness.(ii)reduce stress-induced impairments and disorders related to the function of stress (neuro-endocrine and immune) systems.

It was suggested that adaptogens have not only specific therapeutic effects in some stress-induced and stress- related disorders, but will also have an impact on the quality of life of patients when implemented as adjuvants in the standard therapy of many chronic diseases and pathological conditions (e.g., post-surgery recovery, asthenia, congestive heart failure, chronic obstructive pulmonary disease). It may be suggested that adaptogens have potential use in age related disorders, such as neurodegenerative diseases, and cardiovascular diseases. Thus, elderly people may be able to maintain their health status on a normal level, improve their quality of life and may increase longevity. However, further research may be needed to evaluate the efficacy of adaptogens as geriatrics and to elucidate molecular mechanisms of action of these complex herbal extracts and their active principles.

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