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CHAPTER 7 MECHANISM OF ACTIONS OF ADAPTOGENS Introduction Chemical elucidation and proposed mechanisms of action are absent for many

adaptogenic plant remedies despite active scientific research in Russia and in China. However, in some cases, there is growing evidence to support the presence of specific compounds and to strengthen some hypotheses. The study of adaptogens is complex because there are usually several to many pharmacological properties in evidence (Evans et al., 2002; Bhattacharya and Muruganandam, 2003). Mechanisms of action may be synergistic or combinatorial, as in Bacopa monniera (Stough et al., 2001). Most adaptogenic plant species are also reported to have estrogenic, tonic, antioxidant, nootropic and aphrodisiac properties. These properties can be linked, however, to the neuroendocrine systems involved in the response to stress. To reiterate, my hypothesis suggests that by determining the phylogenetic relationships of plant species with adaptogenic activity we can begin to search for other potentially adaptogenic plant species that are presently unknown chemically. In order to identify a list of these adaptogens it was necessary to discover what is presently known about their chemistry and the possible mechanisms of action for these compounds. Chapter 6 reviewed the chemical compounds found in adaptogenic species, but also included some proposed mechanisms of action. The present chapter synthesizes proposed mechanisms of action and helps to differentiate the mechanisms involved in the increased resistance to stress shown by true adaptogens. Neuroendocrine Activity The simplest hypothesis suggests that the mechanism of action of adaptogens involves the three main classes of plant compounds (triterpenes, phenylpropanes and oxylipins) (Panossian, 2003). Respectively, these compounds, shown in Figures 2-5, are similar in structure to endogenous mammalian stress mediators of the hypothalamus-pituitary adrenal (HPA) axis: catecholamines, corticosteroids, leukotrienes and lipoxines (Panossian, 2003). Thus, adaptogen compounds may function by a sparing action or by competitive binding. If this hypothesis holds true, it would explain how adaptogenic plant remedies are able to attenuate stress mediator dysfunction. Indeed, plant compounds have been shown to bind to 5HT-2 receptors, dopamine receptors, muscarine receptors and the Ca2+ channel (Zhu and Li 1999). Khanna and Bhatia (2003) suggest that the mechanism of action of Ocimum sanctum is due to modulation of noradrenaline (norepinephrine) by the compounds in Ocimum sanctum . To take Panossians basic hypothesis a step further one must include recent contributions from science. For example, other substances have been linked to the stress response such as cholecystokinin (Abelson and Young, 2003), serotonin (Lowry, 2002), dopamine (Helm et al., 2003), and the gonadal hormones (e.g., estrogen and progesterone) (McEwen and Wingfield, 2003). Science is just beginning to sort out how these plant compounds interact in the pathways of these hormones. The following research efforts suggest potential discoveries related to the study of adaptogenic plants: structurally related immunological effects of terpenes (Bernhardt et al., 2001); investigations of the mechanism of membrane activity of selected triterpenoid saponins (Melzig et al., 2001); metabolomics of plant saponins: bioprospecting triterpene glycoside diversity with respect to mammalian cell targets (Haridas et al., 2002); and plant terpenoid synthases: molecular biology and phylogenetic analysis (Bohlman et al., 1998). As discussed in Chapter 3, stress mediators may not be limited only to catecholamines and corticosteroids. Estrogen, in particular, affects cholinergic, serotonergic, dopaminergic and noradrenergic systems and appears to have protective effects on the brain (McEwen, 1999). The actual mechanism of action may be nongenomic rather than classical nuclear receptor binding (Losel et al., 2003). What are nongenomic effects? A hormone ligand binds to a nuclear receptor, resulting in a long series of subcellular processes that include mRNA production and modification, translation into proteins, protein translation and/or insertion into membranes. This process can take hours before a response is seen. Nongenomic effects result in the same response but does not involve direct ligand to receptor binding and the response is almost immediate (Wehling, 1995). For example, ecdysterone is thought to stabilize cell membranes resulting in modifications of membrane proteins, accumulation of ligands, and other membrane associated effects (Tomaschko 1991; Kholodova 2001). The bioactivity of many plant compounds has been linked to nongenomic effects (Ferguson, 2001; Dixon and Ferreira, 2002; Gohil, 2002; Orzechowski et al., 2002; Demmig-Adams and Adams, 2002). Two mediators of the stress response, neurosteroids (Reddy, 2003) and aldosterone (Losel et al., 2003) are believed to work via nongenomic effects.

triterpenes

phytosterols flavonoids

phytoecdysteroids

oxylipins
Figure 2. Classes of compounds found in adaptogenic plants.

lignans

ginsenoside triterpene beta -sitosterol phytosterol

cortisol
leuzeasterone phytoecdysteroid

Figure 3. Comparison of triterpenoids and cortisol.

Structure of flavonoids and lignans similar to adrenaline


flavonoid

adrenaline

lignan

Figure 4. Comparison of phenylpropanoids and catecholamines.

Plant oxylipins

Human oxylipin

Figure 5. Comparison of plant oxylipins and human leukotrienes.

Adrenal and sex steroids act in many tissues not usually thought of as classical target tissues (Baker, 2003). For example, cortisol regulates gene transcription in the brain, heart, kidney and liver as well as other tissues. Thus, evidence is still mounting, plant compounds that have a similar structure to hormone ligands may be able to interact with human receptors and enzymes. Baker (2003) has hypothesized that the enzyme-mediated regulation of steroid response arose in a primitive vertebrate. Enzymes that reversibly activated and deactivated steroids may have been an important mechanism for controlling steroid access to a receptor (Baker, 1992; Baker, 1995; Baker, 1998a; Baker, 1998b; Baker, 2001a; Baker, 2001b; Baker, 2003). Antioxidant Activity The mechanism of reactive oxidation species (ROS) is virtually identical in animals and plants (Grassmann et al., 2002). Many compounds have been shown to bind to ROS and detoxify them, especially phenylpropane and terpene compounds (Havsteen, 2002). Dietary chlorophylls may also have an antioxidant property, while their metabolized derivatives could potentially have cell-signaling roles through the retinoid X receptor (Ma and Dolphin, 1999). Flavonoids (Havsteen, 2002), stilbenes (Ryu et al., 2002), anthocyanins (Butterfield et al., 2002), lignans and anthraquinones (Chiu et al., 2002) have all been suggested to have antioxidant properties. Antioxidant flavonoids are believed to stimulate the immune system through inhibition of inflammatory prostaglandins that suppress the immune response (Havsteen, 2002). Many adaptogenic plants have been shown to have strong antioxidant and free radical quenching properties such as Schizandra chinensis (Chiu et al., 2003), Serratula strangulata (Cai et al., 2002), Panax ginseng (Liu et al., 2003), and Withania somnifera (Parihar and Hemnani, 2003). While the importance of phenolic O-H groups has been identified for antioxidant properties of flavonoids (Priyadarsini et al., 2003), other antioxidant mechanisms for adaptogenic species have been suggested, such as inducement of glutathione and heat shock proteins by Schizandra chinensis (Chiu et al., 2003). Reduced glutathione (GSH) does not just detoxify reactive oxygen species. GSH has also been shown to play a role in DNA synthesis and in homeostasis of cytosolic Ca2+. It is therefore possible that the mechanism of action involving antioxidant activities in adaptogen remedies may account for modulation of other cellular functions, not simply direct quenching of free radicals. These signaling mechanisms offer a more lucid hypothesis for the adaptogenic activity of increasing resistance to stress. This idea is supported by research that suggests that antioxidant plant compounds are in too low of an amount to have any direct effect on ROS (Orzechowski et al., 2002). However, in low doses, plant compounds such as phytosterols, isoflavonoids, and lignans could affect regulation of gene expression (Orzechowski et al., 2002), and possibly by a nongenomic mechanism (Ferguson, 2001; Gohil, 2002; Orzechowski et al., 2002; Demmig-Adams and Adams, 2002). For example, recent research has now focused on nongenomic mechanisms of affecting estrogen receptors (Luconi et al., 2002). Perhaps plant compounds can mimic steroid hormones using these nongenomic mechanisms (Rahman and Sarkar, 2002). The antioxidant activity of phenylpropanoid compounds does not explain remedying of neurotransmitter and hormonal dysregulation, whereas nongenomic activity on these stress mediators is more likely. Flavonoids exhibit hormonal activity (Baker, 1998a; Baker et al., 1998b) and thus, may influence the dysfunctional stress response process. Many phenylpropanoid compounds have also been shown to form chelates with other compounds changing the biochemical properties of the compound (Mors et al., 2000). Antioxidant activity is strongly related to both radioprotective effects (Shobi and Goel, 2001) and beneficial effects on learning, both properties of adaptogens. The ability to learn involves the formation of new protein molecules (Bhatia and Jain, 2003). Insults to the central nervous system, such as radiation, decrease protein content by either reducing protein synthesis or increasing protein consumption or both. Thus, increase in protein concentration as a result of ingestion of plants or their extracts high in antioxidant compounds may simply be providing a compensatory effect (Bhatia and Jain, 2003). Such compensation may not, however, be a primary adaptogenic effect. That is, while antioxidants may ameliorate excessive allostatic load in terms of energy directed towards neutralization of free radicals, detoxification and tissue repair, antioxidants may not directly ameliorate the primary dysfunctional response of modulating excessive or deficient cortisol and adrenaline. Any effect relating to antioxidant activities should perhaps be treated as secondary, including beneficial nootropic and aphrodisiac effects due to antioxidant activity. To suggest otherwise implies that all plants with strong antioxidant properties are adaptogens, which may not be the case.

Nootropic Activity Agents that have a selective facilitatory effect on intellectual performance, learning and memory are classed as nootropic drugs. Cholinergic neurotransmitters are partly responsible for healthy functioning of learning and memory (Sarter and Bruno, 1994). A healthy ratio of neurosteroids such as dehydroepiandrosterone (DHEA) and the HPA neurotransmitters, such as corticotrophin releasing hormone (CRH), and hormones, such as cortisol, are important in the pathophysiology of dementia disorders (Rupprecht, 2003). For an overview, see Rupprecht (2003). Many adaptogen species ameliorate learning and memory problems. Saponin compounds are thought to be responsible for the nootropic properties in Bacopa monniera (Vohora et al., 2000), Albizzia lebbeck (Chintawar et al., 2002), Pfaffia paniculata (de-Paris et al., 2000), Withania somnifera (Dev, 1999), Panax ginseng (Attele et al., 1999), and several species of Rhodiola (Mook-Jung et al., 2002). Both estrogen and phytoestrogens have been shown to influence cognition and memory (Lephart et al., 2002; Duffy et al., 2003). The phytoestrogenic property of Panax ginseng may be responsible for nootropic effects. Memory and learning enhancement is also thought to be due to phenylpropanoids and other flavonol derivatives as in the adaptogens Rhodiola rosea (Wagner et al.,1994; Brown et al., 2002) and Ocimum sanctum (Dev, 1999). Many plants other than those with adaptogenic property have been found to enhance learning and memory such as Rehmannia (Watanabe, 1997), Hypericum perforatum (Khalifa, 2001), Salvia miltiorrhiza (Howes and Houghton, 2003) and Huperzia serrata (Zhang and Tang, 2003). Alkaloids from Huperzia serrata are thought to cause reversible and selective acetylcholinesterase (AChE) inhibition attenuating cognitive deficits (Zhou et al., 2001; Zhang and Tang, 2003). Both flavonoids and terpenoid compounds have also been shown to have beneficial cognitive activities (Howes and Houghton, 2003). Nootropic activities are therefore not relegated to adaptogenic species alone. Nitric Oxide Activity In plants, nitric oxide (NO) serves as a signal in hormonal and defense responses (Guo et al., 2003). Though no gene or protein with sequence similarity to known mammalian-type NOS has been found in plants, plant NOS activity has properties similar to mammalian eNOS and nNOS (Guo et al., 2003). In humans, nitric oxide (NO) also play a role as a signaling molecule in physiological processes such as host defense, immunological reactions, neuronal communication and the regulation of vascular tone. NO is a two-edged sword that has been linked to tissue damage and chronic pathologies via inducible nitric oxide synthase (iNOS), yet also to beneficial properties such as relaxation of vascular and muscle tone via endothelial nitric oxide synthase (eNOS). The many effects of nitric oxide produced by endothelial nitric oxide synthase (eNOS) are regulation of vascular tone/tissue plasticity in blood vessels, endothelium, lungs, heart and corpus cavernosum, inhibition of vascular smooth muscle cell proliferation, protection during inflammatory process and inflammatory diseases, protection against arteriosclerosis and beneficial effects on ischaemia/reperfusion injury in cardiac tissue, regulation of leukocyte adhesion to the endothelium, inhibition of platelet aggregation and neutrophil adhesion, regulation of bone mass and bone turnover, regulation of renal oxygen consumption and protection against glomerulonephritis, and antitumor activity of macrophages. Nitric oxide is likely an important neurotransmitter/neuromodulator in pathologies involving allostatic load. However, most research on medicinal plants has focused on release of the damaging iNOS rather than the beneficial eNOS (Wang et al., 2000). This laboratory bias is likely due to lack of a specific, selective inhibitor for eNOS, and until recently, eNOS has been regarded as static, producing a constant amount of NO in both physiological and pathological conditions (Cirino, et al., 2003). However, this concept is now changing, though the role of NO in stress and stress-induced changes is, unfortunately, not well documented (Masood et al., 2003). In one rat study, restraint stress and NO modulators (L-arginine) consistently reversed stress-induced suppression in both elevated plus maze and open field tests (Masood et al., 2003). These effects are highly suggestive of an antistress/adaptogenic profile for NO. Indeed, nitric oxide has been shown to be involved in the stress response (Masood et al., 2003; Albrecht et al., 2003). Endothelial nitric oxide synthase can be induced by a variety of factors and circumstances, one of which is exercise training. The attendant shear stress increases several-fold the expression of mRNA that encodes eNOS. Athletes have been shown to exhibit a heightened non-specific adaptive response to stress. Panossian et al., (1999) found that high levels of nitric oxide are increased after heavy physical exercise in the saliva of beginner athletes, but not in experienced athletes. It is believed that nitric oxide is involved in adaptation to heavy physical exercise. When extracts of Bryonia alba and Schizandra chinensis were given to beginner athletes it had the same effect as heavy physical exercise: elevation of both NO and cortisol levels in plasma and saliva (Panossian et al., 1999). When Bryonia alba

and Schizandra chinensis were administered to experienced athletes both extracts decreased salivary cortisol but increased salivary NO. After physical exercise, NO and cortisol levels decreased. This fits with the concept that NO activates the neuroendocrine system under stress, while cortisol suppresses it as a protective mechanism. Adaptogens increase production of both the activators and deactivating messengers of the stress system (Panossian et al., 1999). Extracts of Gynostemma pentaphyllum have also been shown to elicit the production and release of nitric oxide from vascular endothelium, resulting in a vasorelaxant effect (Tanner et al., 1999). The suspected active compounds are gypenosides. Similarly, other triterpenoid saponins such as ginsenosides from Panax ginseng have shown vasorelaxant effects as well as nitric oxide release from endothelial tissues (Tanner et al., 1999). Thus, an important mechanism of action of adaptogenic herbs may be the support of the endothelial and vascular integrity through inducing eNOS. Nitric oxide has also been linked to the immunomodulating activities of Panax ginseng (Park et al., 2001), nutritional effects of dietary polyphenol and phenylpropane compounds (Janero, 2001), and antiinflammatory properties of Scutellaria baicalensis (Kim et al., 1999). Other reported adaptogenic herbs have been shown to inhibit iNOS such as Withania somniferum (Iuvone et al., 2003) and Uncaria rhynchophylla (Suk et al., 2002). One possible mechanism for inhibition of iNOS is via mimicking cortisol as cortisol inhibits the activation of iNOS via nuclear factor !B (Ma et al., 2003). Ursodeoxycholic acid, an endogenous lignan, has been shown to activate the glucocorticoid receptor in human hepatoma cell line. Thus, a similar mechanism may be involved in the effect of ursodeoxycholic acid on iNOS (Ma et al., 2003). Aphrodisiac Activity The pathogenesis of the dysfunctional stress response includes loss of libido and infertility, and like many plant remedies, adaptogens have been touted to remedy these problems. This practice, however, is not a new one and may date back thousands of years. The subject of aphrodisiacs is complex because many foods and spices have also been used as aphrodisiacs (Lev et al., 2000; Drewes, 2003). Most of these types of remedies contain vasodilating and pungent essential oils, which might be interpreted as stimulating, yet, are not truly ameliorating allostatic load. Still other herbs employed as aphrodisiacs also have nerve strengthening properties as in the case of the adaptogen, Withania somnifera. While an aphrodisiac property could suggest adaptogenic activity, a concomitant amelioration of stress and/or relaxation could relieve sexual dysfunction without adaptogenic activity. Thus, investigation of aphrodisiac remedies could easily lead to false positives unless a clear mechanism of action is elucidated. Unfortunately, this is the case for the majority of remedies used as aphrodisiacs. Thus, aphrodisiac remedies lacking adaptogenic properties do not provide strong leads. It is unresolved how the gonadal system interacts with the hypothalamic-pituitary systems and affects the regulation of stress-related HPA function. However, it is thought that testosterone plays a key role (Viau, 2002). The aphrodisiac property of some plant remedies may in fact mitigate faulty stress adaptation. Cells throughout the hypothalamus coordinate the slow, rhythmic pulses of gonadotropinreleasing hormone that is essential for maintaining a healthy reproductive cycle. When these pulses are inhibited by the action of stress hormones, fertility can be reduced. Activation of the sympathetic nervous system due to stressful experiences shunts blood away from the reproductive organs to skeletal muscles (Chrousos and Gold, 1992). Thus, there are probably many ways in which dysfunctional adaptation to stress can lead to impotence and infertility. Sexual stimulation requires the release of nitric oxide (NO) from the parasympathetic nerves into the smooth muscle cells that line the arteries of the erectile tissue and activates guanylate cyclase. This enzyme converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP), which in turn causes the smooth muscles around the penis to relax, leading to dilation and increased influx of blood into the penile tissue. This results in an erection and is how the erectile-dysfunction drug, sidenafil has been shown to work (Drewes et al., 2003). Both release and inhibition of nitric oxide has shown to have vasorelaxant effects on various tissues in the body (Albrecht, 2003; Matsuda et al., 2003). It is now suspected that nitric oxide may act as an anti-stress agent/adaptogen (Masood et al., 2003). Ginsenosides in the adaptogen, Panax ginseng, have been shown to relax rabbit corpus cavernosum through release of nitric oxide from endothelial or neural cells (Gillis, 1997; Nocerino et al., 2000). Many herbs employed as aphrodisiacs have shown to have a normalizing effect on the reproductive organs and hormones (Cicero et al., 2001; Galvao et al., 2002). Species of Saussurea (Asteraceae) have been used in traditional Chinese medicine as aphrodisiacs, and as such, appear to regulate uterine functions through vascular relaxation and thus decongest the uterus (Holmes, 1996). So while this class of remedy is problematic, it is tied to increasing resistance to stress.

Hydroxylation It should be mentioned that many terpenoid metabolites in adaptogenic plants are hydroxylated such as some triterpenoid saponins and phytosterols. The number and position of hydroxy groups is thought to be important in the anabolic activity of phytoecdysteroids (Syrov et al., 2001). Oxylipins are also hydroxylated. Additionally, Manthey et al. (2002) suggest that increased degree of hydroxylation of flavones can enhance their ability to inhibit enzymes such as the reductive and oxidative activities of 17!hydroxysteroid dehydrogenase enzymes involved in the metabolism of estrogens and androgens (Manthey et al., 2002). Glycyrrhetic acid, a triterpene from the roots of licorice (Glycyrrhiza glabra) has been shown to interfere with the deactivation of cortisol by the enzyme 11!-hydroxysteroid dehydrogenase (Bruneton, 1995). Thus, hydroxylation is an important factor for bioactivity of plant compounds in mammals. Research involving the triggering of immunity by 7-hydroxysteroids could provide another possible mechanism of action for some adaptogenic compounds, especially triterpenoid saponins (Morfin, 2002). The 7-hydroxysteroids are derived from pregnenolone, dehydroepiandrosterone (DHEA) or 3-betahydroxysteroids by cytochrome P450 oxygenases in many tissues in the body. Excessive release of glucocorticoids can lead to autoimmune disease. The 7-hydroxysteroids and their derivatives can produce an anti-glucocorticoid action, thus preventing suppression of the immune system that occurs in dysregulation of cortisol (Morfin, 2002). How this is accomplished is still unclear, though a paracrine role is suspected rather than binding to glucocorticoids receptors (Morfin, 2002). Thus, one way to limit the negative effects of cortisol is to reduce cortisol receptors in cells. The 7-hydroxysteroids can do just this (Morfin, 2002). It may be that certain plant compounds may mimic these 7-hydroxysteroid derivatives, or may induce CYP450 cytochromes that produce them. Adaptogenic compounds could trigger the specific cytochromes involved in this protective process. Further research could elucidate either mimicry of adaptogenic compounds and/or binding to cytochrome species involved in protection against immune suppression. Cell Membrane Activity It is notable that many plant compounds, such as triterpenoid saponins, prenylated flavonoids, and fatty acids can intercalate between the cell membrane bilayer and thus influence signaling and transport of substances in an out of cells. The ability of a molecule to associate with cell membranes can also be accomplished by attaching a terpenoid chain to molecules such as proteins that make it more lipophilic (DeWick, 2002). For example, polyprenol molecules can destabilize the phosphatidylcholine bilayer, developing conductive pores in the membrane and facilitating the transport of ions, increasing membrane permeability for chloride and sodium ions (Janas et al., 2000). These molecules have a prenylated tail and include prenylated flavonoids found in some adaptogenic plant species such as Epimedium saggitatum (Kuroda et al., 2000). The lipophilic nature of triterpene glycosides enhances their ability to transverse cell membranes by simple diffusion which may cause permeability of the cell membrane, allowing exchange of ions (Melzig et al., 2001) and potentially according them the ability bind to intracellular receptors modulating gene transcription or translation (Lee et al., 2003; Attele et al., 1999; Yuan et al., 1998; Lee et al., 2003). The stabilization of proteins and the cell plasma membrane may have a beneficial affect on pathological processes such as protein denaturation (Saso et al., 1999). For example, oxidation of polyunsaturated lipids tends to reduce membrane fluidity which is essential to proper functioning of cells which can damage membrane integrity, interfere with signal transduction, molecular recognition and transport, maintenance of membrane potential or cellular metabolism and thus impair cellular functions and initiate disease. Phytoecdysteroids may also normalize phospholipids and proteins imbedded in the membranes by affecting the structure and fluidity of cell membranes (Syrov et al., 1992; Tomaschko, 1999). Rather than induce RNA synthesis, phytoecdysteroids may accelerate the translocation process (Syrov, 1984). Ecdysterone is thought to stabilize cell membranes by modifying the structure and fluidity through changing their composition resulting in modifications in permeability, conductivity, rotation mobility of membrane proteins, accumulation of other ligands, and other membrane associated effects (Kholodova, 2001). Plant sterols serve primarily as structural components of cell and organelle membranes, regulating the fluidity and permeability of these membranes. Phytosterols are also likely involved in signaling, regulating of transcription and translation, cellular differentiation and cell proliferation (Piironen et al., 2000).

Hormesis As mentioned in Chapter 6, it may be possible that in low doses, plant compounds such as phytosterols, isoflavonoids, and lignans can affect regulation of gene expression (Orzechowski et al., 2002). In fact, a growing hypothesis suggests just this (Ferguson, 2001; Gohil, 2002; Orzechowski et al., 2002; Demmig-Adams and Adams, 2002). The idea of low doses causing responses is not new. Hormesis, also known as reverse effect, sufficient challenge and the Arndt-Schultz Law, is a once discarded theory now being re-visited with enthusiasm by many scientists in the field of toxicology and pharmacology (Calabrese and Baldwin, 2003; Trewavas and Stewart, 2003). The definition is given by Calabrese and Baldwin (2002): Hormesis is the adaptive response characterized by biphasic dose responses of generally similar quantitative features with respect to amplitude and range of the stimulatory response that are either directly induced [i.e., direct stimulation hormesis] or the result of compensatory biological processes following an initial disruption in homeostasis [i.e., overcompensation stimulation hormesis]. The hormetic dose response can be described as the unanticipated or paradoxical effect of a toxic chemical(s), which is characterized by biphasic dose responses that form a U-shaped dose-response curve (Trewavas and Stewart, 2003) (See Figure 6).

Figure 6. The general form of U-shaped dose-response curve showing response relative to a reference level, with a region of apparent improvement (e.g., reduction in dysfunction) as well as a region of toxic or adverse effects. From Davis & Svendsgaard, 1992. Hormesis attempts to explain the mechanism of action of low doses of toxic chemicals having beneficial effects on growth, reproduction, longevity and potentiation of immune responses. There are many examples of substances that produce a U- or J-shaped curve when organisms are exposed to low to high doses. Alcohol in small doses protects the cardiovascular system. Selenium in high doses is toxic but necessary in small doses for health and can promote tumor growth when deficient in the body. Hormesis is more than simple overcompensation. There are a number of exceptions which have now been developed into a broad family of U-shaped dose-response relationships with hormetic responses (Calabrese et al., 1999). More interestingly, hormesis has recently been described as an adaptive response that is the result of a compensatory biological process following an initial disruption in homeostasis (Calabrese and Baldwin, 2002a). Stressors can initially be stimulatory and enhance hippocampal-dependent cognition, while

prolonged or severe exposure is disruptive, thus indicating a U-shaped pattern (Sapolsky, 2003). One particular hormetic link to dysfunction of stress mediators and adaptogens can be seen with epinephrine and memory. Epinephrine has been shown to be able to enhance memory in rats, whereas, the chronic release of epinephrine can cause memory deficits. The characteristics of this dose-response are U-shaped (Calabrese and Baldwin, 2002a). Dysregulation of cortisol has also been shown to cause memory loss (McEwen, 1999). Thus, there is a link between dose of epinephrine and cortisol and memory deficit. It is intriguing to hypothesize that adaptogen compounds such as those with similar chemical structure may be providing a mechanism of action for attenuation of the dysregulation of these stress mediators. The hormesis theory provides an extremely tantalizing hypothesis for the mechanism of action of adaptogenic plant remedies. It is consistent with a systemic feedback response of the organism linked to evolutionary adaptation to low-level environmental stressors (Calabrese et al., 1999). However, the hormetic effect juxtaposes the traditional definition of adaptogen in that in certain doses some adaptogens cause serious side effects such as that seen in the ginseng abuse syndrome. Hormesis would help explain how adaptogens cause beneficial effects. This theory should be investigated as a mechanism of action for adaptogen remedies and herbal remedies in general.

Synergism Laboratory research usually focuses on single compounds, but it should be remembered that plant extracts contain tens of dozens of primary and secondary compounds. Glycyrrhiza glabra, for example, has been found to contain more than 50 triterpenoids (25%), and more than 200 phenolic compounds (36%), dozens of polysaccharides (20%), many amino acids (10%), and many lipids (3-4%) (Pavlova et al., 2003). The complexity of plant compounds cannot be understated and must be considered, though it seems an insurmountable task. Recent research suggests that primary compounds can also have secondary defense roles (Keyu, 2002) and secondary compounds can also have primary growth and development roles (Ferguson, 2001). Another focus of the mechanism of action of plant compounds has traditionally been on inhibitory or antagonistic effects on receptors and enzymes. Yet, many other mechanisms have been suggested such as nongenomic activity (Tomaschko, 1999; Luconi et al., 2002) and beneficial endogenous nitric oxide effects (Albrecht, 2003). Both these mechanisms are difficult to test for and thus there may be a bias in the scientific investigation of plant compounds (Cirino et al., 2003). An appreciation for the synergistic activity between plant compounds has become more common in the scientific literature (Verpoorte, 1998; Zhu and Li, 1999; Mors et al., 2000; Silva et al., 2002; Channa et al., 2003; Li et al., 2003; Savelev et al., 2003). Many research activities report possible synergistic activities. For example, the sedative activity of Perilla fructescens is suggested to be a combined effect of both secondary and primary compounds (perillaldehyde and stigmasterol). A recent review on snakebite remedies suggests such a concerted synergy between compounds (Mors et al., 2000). Recent papers on both Saint Johns wort (Hypericum perforatum) and black cohosh (Cimicifuga racemosa) both suggest that flavonoids play more important roles than the previously accepted active compounds (anthocyanins and triterpenes, respectively). Such implications strengthen the hypothesis that phytosterols, phytoecdysteroids and fatty acids are working synergistically with triterpenes and phenylpropanoids to create an adaptogenic activity. Summary The bioactivity of adaptogenic plant species is extensive and complex, and can include antioxidant, nootropic, nitric oxide, and aphrodisiac properties. Hydroxylation and cell membrane activity are further important to understanding how adaptogens may be working to increase resistance to stress. However, not all plant species with these properties meet the definition of a nonspecific, innocuous, normalizing agent. Therefore, it is imperative that researchers proceed carefully in the investigation of this class of medicinal plant. The two classes of compounds in adaptogenic remedies most discussed are triterpene and phenylpropane compounds. It is notable that these compounds are perhaps among the most versatile with a wide spectrum of activities in mammals. The history of the use of adaptogenic plant species that lack triterpenes and phenylpropanoid compounds, yet contain high levels of primary compounds such as phytosterols, phytoecdysteroids, oxylipins, and fatty acids suggests that these additional compounds may also be bioactive. The wealth of research on the anabolic properties of phytoecdysteroids should also be included in future elucidation of adaptogens.

Advances in psychoneuroendocrinology and natural products research have the potential to shed light on the mechanism of action of adaptogens, though they may do so with more momentum if traditional practices are appreciated. An appreciation for similar defense pathways, ligands, and enzymes between plants and animals supports the pharmacological properties of plant remedies (Hippeli et al., 1999; Leshem, 2000; Clouse 2002; Cock et al., 2002; Grassman et al., 2002; Nurnberger and Brunner, 2002; Koonin et al., 2003; Rosati et al., 2003). So perhaps, it should not be a surprise that plant remedies can prevent and ameliorate allostatic load and related pathological conditions. It is now obvious that adaptogens are a very difficult subject to investigate due to the complexity of their history of use, biological effects, chemical compounds, and potential mechanisms of actions. Yet, in light of recent discoveries and insights adaptogens offer novel advancements to many scientific disciplines, including phylogenetic analysis. Robyn Klein 2006 www.rrreading.com Phylogenetic and phytochemical characteristics of plant species with adaptogenic properties MS Thesis, 2004, Montana State University Chapter 7 of 8

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