CHAPTER 3 STRESS PHYSIOLOGY AND PATHOLOGY The Stress Response The ability of an organism to manage stress successfully is critical

to the health of the organism. The failure to do so can lead to pathologies which adaptogens are specifically employed to remedy (Wagner et al., 1994). It is the endogenous mediators of the stress response which are thought to be involved in the mechanism of action of adaptogen plant remedies (Panossian, 2003). An understanding of the stress response and how it can go awry is vital to the definition of an adaptogen and to potential mechanisms of action of these plant remedies. Stress can be defined as environmental (i.e., severe temperature change), physical (i.e., severe illness), psychological (i.e., mental trauma or shock), and even spiritual (i.e, loss of meaning in ones life). The processes involved in the human response to stress can help to elucidate possible mechanisms of actions of adaptogens. Therefore, it is important to examine what is currently understood about the stress response process and how this response can become dysfunctional and lead to pathological conditions. In particular, excessive or continued stress has been shown to be a crucial factor in a multitude of acute and chronic pathologies such as chronic anxiety disorder, depression, fatigue states, sleep disorders, addictive behavior, neurodegeneration, gastrointestinal diseases and pre-term labor (Grammatopoulos and Chrousos, 2002). Stress has been associated with the progression of chronic gastritis, progression of HIV, trauma, allergies, tumor growth, and the common cold (Elenkov and Chrousos, 1999). Stress is also linked to many chronic diseases such as syndrome X, diabetes, and many autoimmune conditions. 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 still 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; McEwen, 2003). 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 theorists continued developing the idea that organisms attempt to maintain homeostasis and respond to unexpected challenges. Hans Seyle (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, that is, 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 but prolonged stress can diminish or wear out this ability, which can lead to maladaptation and disease. Homeostasis and Allostasis 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 (Selye, 1936; Sterling and Eyer, 1988; McEwen and Wingfield, 2003; Schulkin, 2003). Homeostasis regulates set points in the body such as glucose or oxygen in the blood and blood pH (Schulkin, 2003). 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 (McEwen and Wingfield, 2003). That is, adaptation to a normal flux of set body points is one process, while adaptation to unexpected or prolonged changes requires yet another related system of physiological processes. This realization prompted the need to explain physiological and behavioral processes that fell outside normal daily homeostatic 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. The 1980s produced many such theories, in particular, the theory of allostasis and allostatic overload (Sterling and Eyer, 1988). Allostasis was first introduced by Sterling and Eyer 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 (Sterling and Eyer, 1988). 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 sudden reaction to an accident. 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 biological organisms to reestablish homeostasis when exposed to extreme or prolonged challenge (Sterling and Eyer, 1988; McEwen and Wingfield, 2003; Schulkin, 2003). 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. Allostasis helps to explain differences in individual response to stress. Why, for instance, do some humans survive a pathogenic disease while others do not? It is the healthy regulation of allostasis that makes the difference. Researchers are now in 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). The central nervous system, endocrine system and immune system interact in a predictable way to maintain homeostasis while under severe or chronic stress. The theory of allostasis provides an explanation for how exposure to unexpected or severe stressors can result in wear and tear on tissues and organs (termed allostatic overload), which can then cause a predictable dysfunctional regulation of neurotransmitters and hormones, leading to a wide range of pathological conditions (McEwen and Wingfield, 2003). The theory of allostasis and allostatic overload is especially intriguing to this project because the roles of the neurotransmitters and hormones involved in resistance to stress parallel the proposed mechanisms of action of adaptogens. These mechanisms can suggest novel strategies for treating pathological conditions linked to the dysfunctional response to stress. Regulation of Stress Regulation of the stress response 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 neurotransmitters and hormones 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 hormone (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; Agarwal, 1999; Habib et al., 2001; Mann 2003). 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 vasopressin, vasoactive intestinal polypeptide, neuropeptide Y, substance P, (Carrasco and Van de Kar, 2003), serotonin (Lowry, 2002), dopamine (Helm et al., 2003), nitric oxide (Szabo, 1998; Masood et al., 2003; Albrecht et al., 2003), cholecystokinin (Abelson and Young, 2003), and gonadal hormones (e.g., estrogen and progesterone) (McEwen and Wingfield, 2003). All these mediators and effectors of the stress response system profoundly influence reproduction, growth and immunity (Chrousos and Gold, 1992; McEwen and Wingfield, 2003b). The stress regulation system can simply be thought of as on and off switches where the release of a mediator sets off a cascade of other communicator chemicals along with a feedback system to shut off their continued release (Panossian et al., 1999b). 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 adrenocorticotrophin 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 will damage tissues. Thus, the negative feedback system will temporarily suppress the immune system in order to protect the organism. The downside is that the immune system is then vulnerable to pathogen attack. While short-term 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, 2003; McEwen and Wingfield, 2003). When this dysregulation continues it can lead to the development of various pathologies, including autoimmune conditions (Sapolsky, 1986; Grammatopoulos and Chrousos, 2002). Thus, the stress response system is vulnerable to severe or unrelenting stressful events. This system 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 can lead to pathologic conditions such as panic disorder, heart disease and memory deficit (McEwen, 2003). This wear and tear is referred to as allostatic overload (McEwen, 2002; Schulkin, 2003). 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? 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, 2003). 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 The three main mediators of stress, catecholamines, glucocorticoids and cytokines, all respond when stressors activate the hypothalamic-pituitary-adrenal axis. Short term effects of these mediators is protective and their release induces a negative feedback system on these systems. Short-term stress can enhance immunity while chronic stress can suppress the immune response. 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, 2003). Normally, the feedback system protects the organism from oversecretion by turning off these mediators. But continued, abnormal release of stress mediators overwhelms the organism, resulting in pathogenesis.

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, cardiovascular diseases (McEwen, 1999), and autoimmune diseases (Chrousos and Gold, 1992). The two most critical mediators involved in the dysregulation of stress-coping mechanisms are cortisol and corticotropin releasing factor (CRF) (Sapolsky, et al., 1986; McEwen, 1998; Shulkin, 2003). 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). Cortisol has been shown to affect CRF by increasing or inhibiting its production or making CRF unresponsive to cortisol (Shulkin, 2003). Though the hypothalamus is traditionally considered the source of CRF, this neurotransmitter hormone and its receptors are also found in the gastrointestinal tract, skin, adrenal gland, testis, cardiac muscle, thymus, and spleen. 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 stress-coping mechanisms such as anorexia, diabetes, loss of libido, heart disease, and immune pathologies (Bale and Vale, 2003). CRF is negatively regulated by cortisol. Heightened stress sensitivity and dysregulation of stresscoping mechanisms appear to involve regulatory mechanisms of CRF (Bale and Vale, 2003). 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 then help ameliorate the negative effects of CRF and 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 possible. Summary Homeostasis and allostasis work in concert to regulate the human response to stress. A myriad of neurotransmitters and hormones interact like on and off switches to maintain homeostasis and allostasis. When regulated appropriately, these endogenous neurotransmitters and hormones protect the organism from a wide variety of stressors. Chronic exposure to unexpected or severe stressors can result in wear and tear on tissues and organs and cause a dysregulation of neurotransmitters and hormones, which can then lead to pathologies. Adaptogenic agents appear to increase resistance to stress, prevent exhaustion and the development of allostatic overload (Bhattacharya and Muruganandam, 2003). The nonspecific nature of the allostatic stress response and the biphasic feature of hyper- and hypo-pathologies correspond to the distinctive characteristics of plant adaptogenic remedies (Panossian et al., 1999b). Adaptogens are believed to ameliorate the very pathologies that are caused by dysregulation of allostatic mediators. Thus, the stress response theory of allostasis and allostatic overload provides a compelling hypothesis for the definition and mechanism of action of adaptogenic plant species. The roles that stress mediators (neurotransmitters and hormones) play in the response to stress can provide a mechanism of action of plant adaptogens (Panossian, 2003). Robyn Klein 2006 www.rrreading.com Phylogenetic and phytochemical characteristics of plant species with adaptogenic properties MS Thesis, 2004, Montana State University Chapter 3 of 8