Allostasis Theory and Adaptogenic Plant Remedies Robyn Klein, 2004 Introduction The role of stress in disease has

only recently been appreciated by medicine. Stress has been associated with the progression of chronic gastritis, HIV, trauma, allergies, tumor growth, many chronic diseases such as syndrome X, diabetes, and the common cold (Elenkov and Chrousos, 1999). Stress hormones such as catecholamines have been shown to enhance bacterial growth in vitro and play a role in the infection of a host (Belay et al., 2003). Treatment of stress pathologies is of great concern today because of their increasing incidence in the United States (McEwen, 2003). Medicine is in need of novel remedies that can treat conditions resulting from dysfunctional stress response despite recent developments of new drugs to treat stress (Dubowchik et al., 2003). The central nervous system, endocrine system and immune system interact in a predictable way to maintain homeostasis while under severe or chronic stress. Researchers are in general agreement that humans and other mammals exploit a separate cascade of physiological processes in order to adapt to stress beyond everyday life homeostasis (McEwen, 2002; Schulkin, 2003). This second system is explained by the theory of allostasis, which suggests a process to protect organisms from unexpected or severe stressors. Such chronic or continued types of stressors can result in wear and tear on tissues and organs, termed allostatic overload. This overloading causes a predictable dysfunction of regulation of stress neurotransmitters and hormones, leading to a wide range of pathological conditions (McEwen and Wingfield, 2003). The contribution of plant compounds to pharmacology has been estimated in the billions of dollars, though the interest in plants as sources of novel medicines has diminished mainly because of political and technological reasons (Newman et al, 2003). Yet many scientists feel 1

that billions of dollars worth of natural products still remain undiscovered and unexplored (Verpoorte, 1998; Raskin et al., 2002; Carlini, 2003; Wu et al., 2003b). With respect to prevention and treatment of stress, plant remedies used by other countries have not been thoroughly explored by scientists in the United States. A case in point is the stress-reducing health products made from plants that have been researched since the 1940s in Russia (Panossian, 2003). These plant remedies were accepted into medical practice in Russia as adaptogen tonics after they were found to increase resistance to stress in mammals and humans, with little to no side effects (Russian National Pharmacopoeia, 1983). While practically

unknown to western conventional medicine, adaptogen remedies have nonetheless been marketed and sold in the United States since the 1970s to treat stress and fatigue (Seifert, 1976). The theory of allostasis and allostatic overload is especially intriguing to this discussion because the concepts provide additional evidence for the mechanism of action of adaptogenic plant remedies. The aim of this paper is to suggest that the theory of allostasis supports the proposed mechanism of action of adaptogen remedies and this mechanism may be useful in developing new strategies to treat stress dysfunctions. I will first discuss the physiologic mechanisms of the stress response, review the theory of allostasis, and then introduce some plant remedies possessing adaptogenic activity. Lastly, I will show that the theory of allostasis can be linked to hypothesized mechanisms of the adaptogenic effect.

The stress response Pathologic conditions related to stress have been a subject of science since 1911 when Walter B. Cannon (1911) applied the engineering concept of stress to a physiologic context, suggesting that emotional stimuli were capable of causing physical damage to the body. Other 2

theorists continued developing this idea that organisms attempt to maintain homeostasis and respond to unexpected challenges. Hans Selye (1936) proposed the general adaptation

syndrome that examined the actions and consequences of stressors on the healthy organism. His reasoning suggested that every organism must be able to adapt to environmental and social conditions that are stressful and potentially life threatening. These adaptive responses must be nonspecific because they must be able to respond to a myriad of stressful conditions, whether it is extremes of heat, cold, lack of food, injury, disease, or psychological conditions such as fear. The limiting factor of this ability, according to Seyle, was the adaptations energy of the organism. That is, the body is able to adapt to stressors up to a point. But prolonged stress can diminish or wear out this capability, and when this happens we are at risk for maladaptation and disease. Throughout the progression of stress theories emerged the idea that the ability to maintain internal viability despite extreme or unexpected stress events could not be produced by homeostasis alone (Sterling and Eyer, 1988). Homeostasis regulates set points in the body such as glucose or oxygen in the blood and blood pH. For example, homeostasis can adjust body temperature in response to slowly evolving environmental changes such as summer or winter temperature conditions. However, when the organism is exposed to harsh or unexpected events such as a sudden drop in temperature or prolonged severe temperatures, it must react and even predict these events in order to adapt and survive. The process of homeostasis can only adjust set points in the body within the realm of a normal continuum. Events that are severe or prolonged shift the organism from a homeostatic response to an auxiliary set of adaptation processes (Sterling and Eyer, 1988). That is, adaptation to a normal flux of set body points is one process, while adaptation to unexpected or prolonged changes induced yet another related system of physiological processes that works in concert with homeostasis. This realization 3

prompted the need to explain physiological and behavioral processes that fell outside normal daily fluctuations. This not only required a description of the process that occurred beyond homeostasis, but also an explanation for how such a process could become dysfunctional and lead to disease. In the 1980s many researchers developed theories to better explain the dysfunction associated with maladaptation stress, in particular, the theory of allostasis.

Theory of allostasis Allostasis was first introduced by Sterling and Eye in 1988 to describe an additional process of reestablishing homeostasis, but one that responds to a challenge instead of to daily ebb and flow. This theory suggests that both homeostasis and allostasis are endogenous systems responsible for maintaining the internal stability of an organism. Homeostasis, from the Greek homeo, means same, while stasis means stable; thus, remaining stable by staying the same. Allostasis was coined similarly, from the Greek allo, which means variable; thus, remaining stable by being variable. Homeostasis functions to set daily body points such as temperature or raising cortisol levels in preparation for waking. The allostatic mechanism responds to unexpected challenges such as severe temperature drop or running to protect your child from an accident. This

allostatic response to stress is what is traditionally known as the fight or flight response. During the fight or flight response the body mobilizes energy. Respiration accelerates, heart speeds up, blood vessels near the skin constrict, stored carbohydrates are released into the bloodstream, and the immune response is awakened. But what sets off this response today is not usually a grizzly bear or competition for food. It is our demanding boss, our insistent children, or our hectic schedule. These stressors are different in that they tend to be chronic, rather than short-term episodes. This kind of stress does not involve the normal physical response of running 4

or fighting to use up all that extra glucose and lipid released into the bloodstream. Additionally, a consistent lack of blood circulation to non-fight or flight organs produces deficiency and weakness in these organs. Chronic stress of this nature can lead to depression, diabetes and heart disease. Continually calling on the fight or flight mechanism creates an abnormal situation that homeostasis is not able to protect us from. Allostasis, like homeostasis, helps the organism remain stable in the face of change. But allostasis does so by varying the hormonal and neurotransmitter mediators of stress. The

mechanisms involved in homeostasis resist change, while allostasis responds to both change and the anticipatory needs of the organism. The regulatory system of allostasis does not set clear physiological points as in homeostasis. Allostasis responds to challenges an organism is not expecting, as in exposure to a pathogen or to a challenge the organism is anticipating, as in anticipation of fight or flight in the case of being stalked by a predator. This regulatory system elicits behavioral and physiological responses in order to anticipate and respond effectively to challenges. Allostasis then, is a process used by organisms to reestablish homeostasis when exposed to extreme or prolonged challenge. The goal of both homeostasis and allostasis is to meet the nutrient and energy needs of the organism, but they are uniquely designed to meet different kinds of change. The theory of allostasis attempts to explain differences in individual responses to stress. Why, for instance, do some humans survive a pathogenic disease while others do not? One explanation is that allostasis is vulnerable to severe or unrelenting stress events. Allostasis works well when needed and then shut off when not needed. However, chronic stimulation of the allostatic regulatory system causes wear and tear on tissues and it is this damage that accelerates dysfunctional responses and leads to pathologic conditions such as panic disorder, heart disease and memory deficit. This wear and tear is referred to as allostatic 5

overload. It occurs when allostatic systems remain active even though they are no longer needed. The origin of allostatic overload is thought to be due to the dysfunction of the

neurotransmitters and hormones of the organs responsible for regulation of allostasis. What are these allostatic systems and which neurotransmitters and hormones are involved?

Mechanisms of allostasis Regulation of allostasis involves three systems of the body: the central nervous system (particularly, the autonomic nervous system), the endocrine system, and the immune system Carrasco and Van de Kar, 2003). These systems utilize neurotransmitters and hormones for communication and regulation in allostasis. Central to the adaptive response is the

hypothalamic-pituitary adrenal (HPA) axis formed by the hypothalamus and pituitary in the brain together with the adrenal glands. These organs, in concert with the autonomic nervous system and the immune system, communicate via hormonal substances that travel through the tissues and the bloodstream, and form what is known as the stress system (Chrousos and Gold, 1992). The primary chemical mediators of the HPA axis are corticotropin-releasing factor (CRF) from the hypothalamus, glucocorticoids (e.g., cortisol and aldosterone) from the adrenal cortex, catecholamines (e.g., epinephrine and norephinephrin) from the adrenal medulla, and cytokines (e.g., interleukins) from macrophages and leukocytes (Chrousos, 1998; Habib et al., 2001; Mann 2003). Other chemical mediators that also have a role in stress are: vasopressin, serotonin, vasoactive intestinal polypeptide, neuropeptide Y, substance P, cholecystokinin, and estrogen (Carrasco and Van de Kar, 2003). The mediators and effectors of the stress response system profoundly influence reproduction, growth and immunity (Chrousos and Gold, 1992). Within the complex systems involved in allostasis are a myriad of other endocrine, neuronal and immune cascades. New players in the role of stress adaptation that have been proposed include 6

serotonin (Lowry, 2002), dopamine (Helm et al., 2003), nitric oxide (Masood et al., 2003; Albrecht et al., 2003), cholecystokinin (Abelson and Young, 2003), and gonadal hormones (e.g., estrogen and progesterone) (McEwen and Wingfield, 2002). The stress regulation system can be thought of as on and off switches where the release of a hormone sets off a cascade of other communicator chemicals along with a feedback system to shut off their continued release (Panossian et al., 1999). An additional regulatory feature is the protective suppression of systems, such as the suppression of the immune system in response to excess cortisol (Carrasco and Van de Kar, 2003). When an organism perceives a severe change requiring a response, the first system to respond is the autonomic nervous system, which sends a message to the hypothalamus. The hypothalamus in turn, releases corticotropin-releasing factor (CRF), which is picked up by the nearby pituitary. This neuropeptide stimulates the pituitary to release adrenocorticotropin hormone (ACTH) into the bloodstream. ACTH

stimulates the production and release of norepinephrine (adrenaline) and glucocorticoids such as cortisol from the adrenal glands. Norepinephrine and cortisol stimulate the release of glucose from body stores, which provides energy to the body to fight off the danger or to run away from it. Once the threat is over, the mediators return to baseline levels due to negative feedback on the HPA axis (McEwen, 2002; Carrasco and Van de Kar, 2003). Thus, neurotransmitter and

hormone mediators protect the organism and provide an allostatic process, which is accompanied by the homeostatic process to maintain balance (Schulkin, 2003). As mentioned, release of stress hormones involves a negative feedback system in order to inhibit continued release. Cortisol and cytokines cause inflammation, which alerts the immune system and stimulates it to action. However, chronic inflammation damages tissues. Thus, the negative feedback system will temporarily suppress the immune system to protect the organism. The downside is that the immune system is then vulnerable to pathogen attack. While short-term 7

protective mechanisms are favorable, continued stress, and the resulting release of neurotransmitters and hormones are thought to cause these mechanisms to fail, causing a dysregulation of these mediators (McEwen and Wingfield, 2002; McEwen, 2003). When this dysregulation continues it can lead to the development of various pathologies, including autoimmune conditions (Sapolsky, 1986; Grammatopoulos and Chrousos 2002).

Allostatic overload and pathogenesis Catecholamines, glucocorticoids and cytokines all respond at first to help the body adapt when stressors activate the hypothalamic-pituitary-adrenal axis. Short term effects of these mediators is protective and their release induces a negative feedback process on these systems. In fact, acute stress can enhance immunity while chronic stress suppresses the immune response (Carrasco and and Van de Kar, 2003). However, continued release of these mediators results in prolonged effects on target cells and this can lead to receptor desensitization, tissue damage (McEwen, 2003) and hypofunctioning or suppression of immune responses (McEwen and Wingfield, 2002). Chronic release of stress hormones under excessive or long-term stress leads to a cumulative allostatic load on the body or cost of adaptation (McEwen, 2003). Normally, a built-in feedback system is in place that protects the organism from oversecretion by turning off these mediators. The abnormal continued release of stress mediators has been shown to lead to three kinds of overload (Shulkin, 2003): 1) overstimulation by frequent stress, resulting in excessive stress hormone exposure; 2) failure to inhibit allostatic responses when they are not needed or an inability to habituate to the same stressor, both of which result in overexposure to stress hormones; and

3) inability to stimulate allostatic responses when needed, in which case other systems (e.g., inflammatory cytokines) become hyperactive and produce other types of wear and tear Corticotropin releasing factor (CRF) has been shown to induce negative effects such as motor activation, anxiety-like behavior, anorexia, decreased sexual behavior and altered cognitive performance (Zorrilla et al., 2002). Chronic release of cortisol has been linked to a pathological suppression of the immune system. Similarly, hyposecretion of stress mediators has also been linked to pathological conditions such as autoimmune diseases (Chrousos and Gold, 1992). Dysfunctional release of stress mediators, characterized by both excess and deficiency, have been linked to pathological conditions such as loss of libido (Zorrilla et al., 2002), bone demineralization, atrophy of the amygdala and hippocampus, abdominal obesity, long-term depression, memory deficits and free radical damage, high cholesterol and cardiovascular diseases (McEwen, 1999). In general, excessive and continued stress has been shown to be a crucial factor in chronic anxiety disorder, depression, fatigue states, sleep disorders, addictive behavior, neurodegeneration, allergic and autoimmune disorders, metabolic syndrome, gastrointestinal diseases and pre-term labor (Grammatopoulos and Chrousos, 2002). Thus, the hallmark of pathologies that seem to be caused by a wide variety of stressors is the dysregulation of stress mediators, specific neurotransmitters and hormones. When regulated appropriately, these endogenous chemicals are responsible for protecting the organism from continued and severe stressors. It is these substances, then, that are involved in the mechanism of action of adaptogenic plant remedies.

Remedies of allostatic overload: the adaptogens The concept of treating stress-related conditions with medicinal plants is familiar to most traditional healing models throughout the world (Anonymous, 2002). Two of the oldest models, 9

traditional Chinese medicine and the Ayurveda model from India, both employ remedies to counteract stress, fatigue, loss of memory and to rejuvenate both those who are recovering from illness and those who are aging. Qi tonics such as Panax ginseng and Astragalus

membranaceous have been used for over 2,000 years in China to raise the qi or vital energy (Huan and Rose, 2001). In India, rasayana remedies such as Withania somnifera are believed to nourish and strengthen the primordial tissue or rasa in order to delay old age, promote vital energy and improve the mental intellect (Puri, 2003). Though conventional medicine does not use these remedies, citing lack of research, the popular health market has been touting their benefits and providing these herbal products for many decades in the United States and elsewhere. In 1943, the Peoples Commissars Council of the Union of the Soviet Socialist Republics charged its scientists with the task of finding tonic substances to strengthen the health of workers in the Russian defense industry during World War II (Panossian, 2003). Thus began the effort to find remedial substances that would increase the protective state of resistance during conditions of stress. N.V. Lazarev (1946; 1962) showed that ingestion of certain plant extracts could improve stress markers in laboratory animals. By 1958 he had coined these plant remedies adaptogens and suggested three criteria that described their remedial action (Brekhman and Dardymov, 1969). An adaptogen 1) should be innocuous and cause minimal disturbance to the normal physiological function of an organism, 2) its action should be nonspecific (i.e., should increase resistance to a wide range of stressors), and 3) it should have a normalizing action irrespective of the direction of the preceding pathological changes (i.e., be able to normalize either high and low physiological responses to stressors). Continued research on adaptogenic plants in Russia and other countries resulted in the production of dozens of over the counter remedies. Two of these remedies are Bryonia alba 10

tablets which are now registered in Armenia as an adaptogen medicine (Panossian et al., 1997), and the standardized extract of Rhodiola rosea (SHR-5), registered as an herbal medicinal product in Sweden (Swedish Herbal Institute, 2003). Further investigation of adaptogenic compounds in other Slavic countries including Czechoslovakia, led to the discovery that plants synthesize steroidal compounds, called phytoecdysteroids, for plant defense. These compounds mimic insect steroids and inhibit The discovery that these compounds

developmental molting, which then kills the insect.

produced an adaptogenic response when ingested by mammals has led to over 200 products made from various plants high in phytoecdysteroids and sold in health food stores around the world (Kholodova, 2001; Oberdorster et al., 2001; Bthori, 2002). These phytoecdysteroid compounds meet the three criteria of an adaptogen: innocuous, nonspecific and normalizing in action. Additionally, adaptogenic activity has recently been described for the plant sterol, !sitosterol (Bouic, 2002). Surprisingly few well-designed, randomized, placebo-controlled, double-blinded clinical studies have been conducted in the United States on adaptogenic products. However, open clinical uses of these herbs have been taking place for millennia in the indigenous practice of China and India (Wu et al., 2003a). Russia and many other countries have supported hundreds of clinical studies on adaptogens (see Table 1). Continued research on adaptogenic products from natural sources has resulted in the production of dozens of over the counter remedies. Two of these remedies are Bryonia alba tablets which are now registered in Armenia as an adaptogen medicine (Panossian et al., 1997), and the standardized extract of Rhodiola rosea (SHR-5), registered as an herbal medicinal product in Sweden (Swedish Herbal Institute, 2003).

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Table 1. Examples of some human clinical studies on adaptogens.

Aralia mandshurica The influence of Aralia mandshurica tincture, Aminalon or their combination on memorization of texts (Sedykh, 1986) On the influence of Aralia mandshurica tincture on the central nervous system (Kazakevich, 1972) Bacopa monniera The acute effects of an extract of Bacopa monniera (brahmi) on cognitive function in healthy normal subjects (Nathan et al., 2001) The chronic effects of an extract of Bacopa monniera (brahmi) on cognitive function in healthy human subjects (Stough et al., 2001) Bryonia alba and Schisandra chinensis Effects of heavy physical exercise and adaptogens on nitric oxide content in human saliva (Panossian et al., 1999) Eleutherococcus senticosus The influence of Eleutherococcus on muscle work capacity in humans (Asano et al., 1986) Eleutherococcus senticosus reduces cardiovascular stress response in healthy subjects: a randomized, placebo-controlled trial (Facchinetti, et al., 2002) Leuzea carthamoides (= Rhaponticum carthamoides) The effect of extract from Rhaponticum carthamoides Wild Iljin Leuzea on learning and memory (Mosharoff, 1987) Rhodiola rosea A randomized trial of two different doses of a SHR-5 Rhodiola rosea extract versus placebo and control of capacity for mental work (Shevtsov et al., 2003) Rhodiola rosea in stress induced fatigue a double blind crossover study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty (Darbinyan et al., 2000) A double-blind, placebo-controlled pilot study of the stimulating and adaptogenic effect of Rhodiola rosea SHR-5 extract on the fatigue of students caused by stress during an examination period with a repeated low-dose regimen (Spasov et al., 2000) Effect of Rhodaxon preparation on the psychophysiological and physical adaptations of students to learning load (Spasov et al., 1998) Clinical and experimental substantiation of asthenic conditions therapy using Rhodiola rosea extract (Mikhailova, 1983) The effect of herbal adaptogens in working capacity of sportsmen-divers (Lapaev, 1982)

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Effect of Rhodiola rosea on the human mental activity (Komar et al., 1981) A study of Rhodiola rosea extract effect using the MMPI method (Metscheryakova et al., 1975) Clinical studies on Rhodiola rosea (Saratikov, 1987) New data on the therapy of asthenic conditions (Krasik et al., 1970) About the adaptogenic and stimulating effect of Rhodiola rosea extract (Krasik et al., 1970) The effect of Eleutherococcus and Rhodiola rosea extracts upon the functional condition of the organ of hearing in those working in noisy shops of the Tomsk Electric engineering plant and in pilots of the Tomsk Airport (Oleinichenko, 1966) Schisandra chinensis The influence of Schizandra on normal and pathological visual functions (Sinovich and Akhmerova, 1958) 20-hydroxyecdysone Study of excretion of ecdysterone in human urine (Tsitsimpikou et al., 2001) Antidiabetic agents containing ecdysterone or inokosterone (Takahashi and Nishimoto, 1992) Oral antidiabetic compositions containing !-ecdysone from Cyanothis arachnoids (Yang et al., 2001)

Chemistry of plant adaptogens Plants synthesize thousands of primary and secondary plant compounds that have a dizzying array of chemical structures (Wink, 1999). For adaptogens, finding which compounds produce adaptogenic effects has been a challenging task because of the multitude of targets and activities of these plants. Adding to this challenge is that, compared to drug remedies that are usually concentrated, single substances, plant extracts have a complex synergistic action that has made the scientific investigation of adaptogen remedies a precipitous and tortuous affair. Panossian et al. (1999) and researchers before them have paved the way for identifying the primary chemical compounds thought to be responsible for adaptogenic activity. They suggest that three main classes of plant compounds are responsible for increasing resistance to stress: triterpenes, phenylpropanoids and oxylipins. Some examples of these compounds in adaptogenic plant species are given in Table 2.

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Table 2. Plant compounds believed to be responsible for adaptogenic effects and adaptogenic plants. Chemical compound Triterpenoids araloside astragaloside bacoside bidentatosides centelloside/asiaticoside cucurbitacin eleutheroside ginsenoside gypenoside/gylongiposide tanshenoside withanolide Phenylpropanoids dichotosin flavonoids rosavin, rosin, rosarin schizandrin Oxylipins hydroxylated fatty acids hydroxylated fatty acids bryonia licorice Bryonia alba Glycyrrhiza glabra Panossian et al., 1983 Panossian, 2003 hoppea holy basil rose root wu wei Hoppea dichotoma Ocimum sanctum Rhodiola rosea Schizandra chinensis Wagner et al., 1994 Wagner et al., 1994 Brown et al., 2002 Bartlova et al., 2002 spikenard huang qi brahmi oxknee root gotu kola bryonia Siberian ginseng ginseng jio gu lan bellflower ashwagandha Aralia mandshurica Astragalus membranaceus Bacopa monniera Achyranthes bidentata Centella asiatica Bryonia alba Eleutherococcus senticosus Panax ginseng Gynostemma pentaphyllum Codonopsis pilosula Withania somnifera Baranov, 1982 Bone, 1996 Vohora et al., 2000 Mitaine-Offer et al., 2001 Shobi and Goel, 2001 Panossian et al., 1999 Baranov, 1982 Rudakewich and Benishin, 2001 Tanner et al., 1999 Yuda et al., 1989 Evans, 2002 Common name Latin name Citation

It has been suggested by Panossian (2003) that these three main classes of plant compounds may be mimicking the neurotransmitter and hormones involved in allostasis and in allostatic load by providing a sparing action or competitive binding. If so, it would explain how adaptogenic plant remedies are able to attenuate stress mediator dysfunction. Some of these plant compounds have been shown to bind to serotonin, dopamine, and muscarine receptors and the Ca2+ channel (Zhu and Li, 1999). It is possible that they may reduce allostatic load by mimicry and thus, provide a sparing action or weak response. The support for such mimicry is 14

found in both the biosynthetic pathways common to both plants and humans, resulting in similar chemical structures. Cortisol, a hormone, is made in a similar biosynthetic pathway as terpenes in plants (see Figure 1) (DeWick, 2002). Triterpenes also include phytosterols and phytoecdysteroids, both of which are thought to have adaptogenic roles in mammals and in humans (Bouic, 2001; Slama, 1993; Oberdorster et al., 2001). Most adaptogen plant species contain triterpenoid saponins, in particular, Panax ginseng, Eleutherococcus senticosus and Aralia mandshurica, genera of the Araliaceae family. Phytosterols are steroid compounds that function similar to cholesterol in animals to stabilize plant cell membranes. The most common phytosterols in plants are beta-sitosterol, campestrol, and stigmasterol. Phytoecdysteroids, the third class of triterpene compounds important in

adaptogen plant species, are identical to steroids found in insects. It is believed that plants make these insect steroids for protection against insect predation. Phenylpropane compounds in plant adaptogens (e.g., flavonoids, lignans) are synthesized from tyrosine, similar to the biosynthesis of the catecholamines, norepinephrine and epinephrine (DeWick, 2002). Phenylpropane compounds particularly emphasized in Rhodiola rosea

(Crassulaceae) are salidroside, rosavin, rosin, rosarin, and tyrosol, and the lignan, schizandrin, in Schizandra chinensis (Magnoliaceae). The flavan glycosides, dichotosin, dichotosinin and

diffutin are characteristic of Hoppea dichotoma (Gentianaceae) and the tetraoxygenated xanthones in Hoppea fastigiata (Peres et al., 2000). . Flavonoids and lignans have been the main focus of adaptogenic activity and often have attached sugars or terpene chains, being termed glucopyranosides and prenylated flavonoids. These attached structures are likely

important for bioactivity (Tziveleka et al., 2002; Galichet and Gruissem, 2003).

15

cortisol

cortisol
triterpenes

Terpene Biosynthetic Pathway in Humans (mevalonate pathway) Acetyl-CoA " isoprene " cholesterol " glucocorticoid hormones (e.g., cortisol, aldosterone, estrogen)

B
ginsenoside phytosterols beta-sitosterol

Terpene Biosynthetic Pathway in Plants (mevalonate pathway) Acetyl-CoA " isoprene " triterpenes, phytosterols, phytoecdysteroids

phytoecdysteroids

ecdysone

Figure 1. A. Cortisol; B. three types of terpene compounds: triterpene saponins, phytosterols and phytoecdysteroids. The third class of adaptogen compound, oxylipins, are plant defense compounds made in plants via the acetate pathway from polyunsaturated fatty acids in plants (Ble, 1998). Oxylipins are similar in structure to the immune compounds leukotrienes and lipoxines in mammals and have similar biological roles to those of the eicosanoid compounds in animals (see Figure 3) (Howe and Schilmiller, 2002). Oxylipins are oxygenated fatty acids. In plants, oxylipins are believed to be involved in defense strategies against pathogens and insects (Ble, 1998). The particular plant oxylipins illustrated in Figure 3 are have three hydroxyl (OH) groups attached. It is these

16

Flavonoids and Lignans Phenylpropane plant compounds found in adaptogen plants such as flavonoids and lignans are synthesized via the shikimate pathway. Precursor is tyrosine and phenylalanine.

Adrenaline Catecholamines (neurotransmitters) such as adrenaline are synthesized in humans via the amino pathway. Precursor is tyrosine.

flavonoid

adrenaline

lignan Figure 2. Phenylpropane compounds in plant adaptogens, compared to the catecholamine, adrenaline. polyhydroxylated oxylipins that are particularly thought to have an adaptogenic activity (Panossian et al., 1981). In mammals, oxylipins play an important role in stress responses to infection, allergy, and in the exposure to substances not originating from the body which may pose danger (Ble, 1998). The polyhydroxylated oxylipins from the adaptogenic species,

Bryonia alba, are proposed as the compounds responsible for adaptogenic activity (Panossian et al., 1981).

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Plant oxylipins Are synthesized via the lipoxygenase pathway Precursor is linolenic acid Plant oxylipins

Human oxylipins Are synthesized via the fatty acid pathway. Precursor is arachidonic acid (C20 fatty acid) Human oxylipin

Figure 3. The structure of plant oxylipins is similar to human oxylipins such as leukotrienes.

Amelioration of allostatic load by adaptogens Though the hypothalamus is traditionally considered the source of corticotropin-releasing factor (CRF), this neurotransmitter hormone and its receptors are also found in the gastrointestinal tract, skin, adrenal gland, testis, cardiac muscle, thymus, and spleen (Bale and Vale, 2003). It is perhaps not coincidental that these particular tissues are also involved in the development of disorders related to heightened stress sensitivity and dysregulation of stresscoping mechanisms such as anorexia, diabetes, loss of libido, heart disease, and immune pathologies (Bale and Vale, 2003). It is well established that CRF is negatively regulated by cortisol and that heightened stress sensitivity and dysregulation of stress-coping mechanisms appear to involve regulatory mechanisms of CRF (Bale and Vale, 2003). Corticotrophin-

releasing factor (CRF) is a key stimulator of the stress response and is regulated by cortisol in the following manner (Shulkin, 2003): 18

inhibition of CRF increased production of CRF unresponsiveness of CRF to cortisol CRF is decreased in the hypothalamus CRF effects in increased fear and hypervigilance

It has been shown that some herbal formulas can inactivate the secretion of CRF in rats by inhibiting CRF mRNA (mitochondrial) expression (Dai et al., 2000). Preventing the synthesis of CRF would help ameliorate the negative effects of CRF, which would mimic the regulatory role of cortisol. This is, perhaps, one of the most likely mechanisms of actions of herbs having adaptogenic properties, but it is by no means, the only mechanism evident. Thus, adaptogen remedies may be mimicking cortisol, adrenaline, or possibly ACTH or CRF, in a way that does not cause the same deleterious effects in stress dysfunction cascades, yet somehow tricks the body into thinking these endogenous substances are being supplied in a normal way. This mechanism may modulate allostasis and lower allostatic overload. The dysregulation of neurotransmitters and hormones of the stress response pathway is now accepted as the hallmark of pathologies linked to heightened stress sensitivity and failure of stress-coping mechanisms. The precursor to these pathologies is the dysregulation of various stress neurotransmitters and hormones. The definition of adaptogen requires a remedy to

produce a nonspecific increase in resistance to stress. To have this adaptogenic activity, a plant must have evidence to support its ability to increase resistance to stress, and not simply meet the definition of innocuous, nonspecific, and normalizing. Adaptogens must have physiologic evidence to support their therapeutic activity, such as amelioration of adverse effects on glucose metabolism, cognitive, immune and gonadal functions, or behavioral patterns of maladaptation (Bhattacharya and Muruganandam, 2003). 19

Remedies with an adaptogenic property must attenuate or prevent the initial dysfunction of neurotransmitters and hormones by increasing resistance to stress, and in addition, attenuate or prevent pathological conditions resulting from the dysfunction. Adaptogens increase the

organisms ability to maintain both homeostasis and allostasis. Not only does the theory of allostasis validate proposed mechanisms of action for adaptogenic plant remedies, but this theory also helps to differentiate between a true adaptogenic effect (dysregulation of neurotransmitters and hormones) and remedies that attenuate pathologies downstream from the initial dysregulation.

Discussion The HPA axis is regulated at many levels by a complex system involving many mediators, the primary ones considered to be cortisol and adrenaline. Dysregulation of this system leads to cell death, mood disorders, and other diseases. The ability of an organism to maintain stability when exposed to chronic or severe stress is a critical strategy by which organisms actively manage stress in their environment. This ability has been termed allostasis, and respectively, allostatic overload when this type of stress overwhelms the organism. Adaptogenic agents increase resistance to stress and prevent exhaustion and allostatic overload (Bhattacharya and Muruganandam, 2003). Adaptogens ameliorate the very pathologies that are caused by the dysregulation of allostatic mediators such as hypercholesteremia and loss of lean muscle mass. The effects of adaptogen remedies are subtle and biphasicthey modulate both hyper- and hypo-conditions. The mechanism of action of adaptogens is believed to be a mimicking of the on and off switches used to protect the organism from allostatic overload. This is reminiscent of the allostatic process of regulating stress mediators by varying their release and inhibition. The nonspecific nature of the allostatic response and the characteristic 20

dysregulation of stress hormones and neurotransmitters correspond to the distinctive characteristics of plant adaptogenic remedies (Singh et al., 2001). These therapeutic medicines have been missed by conventional medicine most likely because of the lack of clinical studies, their esoteric use by traditional herbal medicine practitioners, and because the therapeutic strategy of traditional medicine has not yet been fully appreciated (Bhattacharya and Muruganandam, 2003). Thus, the allostasis theory provides an excellent hypothesis for the mechanism of action of adaptogenic plant species.

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