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The dynamic of stress.

Emotions consist of behavioural, endocrine and autonomic responses which are generally maintained in balance by the stress response system. Walter Cannon introduced the phrase "fight-or-flight response" to refer to the physiological reactions required by either fighting or avoiding the stressor. (1) As long as the response is brief, physiological responses may be bearable. However, when stress becomes chronic with an ongoing physiological arousal, it adversely affects the immune, cardiovascular, neuroendocrine and central nervous systems. The wear and tear on the body, also referred to as the allostatic load, results from either too much stress or inefficient management of stress. This load is a significant predictor of all-cause mortality, cognitive decline, physical functioning and cardiovascular disease. (2)

Perception of stress elicits adrenal release of adrenaline, noradrenaline, and cortisol, which feed back negatively to the pituitary and hypothalamus, reducing and normalizing the stress response mediated by the hypothalamic corticotrophin releasing hormone (CHR) and pituitary adrenocorticotropic hormone. (3) Adrenalin and noradrenalin affect glucose metabolism, mobilizing nutrients stored in the muscle to become available and provide energy. They also affect blood flow to the muscles by increasing cardiac blood output and consequently causing high blood pressure. (4) Additionally, norepinephrine is secreted in the brain as a neurotransmitter and in times of stress, release of norepinephrine is particularly high in the hypothalamus, frontal cortex and lateral basal forebrain. (5)

The other stress hormone is cortisol, a steroid hormone secreted in the adrenal cortex. Cortisol helps to break down protein and convert it to glucose (hence the name glucocorticoid), helps make fats available for energy, increases blood flow and stimulates behavioural responsiveness by stimulating the brain. Cortisol also decreases the sensitivity of the gonads to the luteinizing hormone (LH), which suppresses secretion of the sex steroid hormones. In a study conducted by Mulchahey et al. (6) it was found that the blood testosterone of male doctors was severely depressed presumably due to their stressful work schedule. Cortisol also stimulates the dorsal raphae nucleus to produce an increased amount of calming serotonin as well as the release of opioids, which inhibits noradrenalin release, bringing the initial stress-induced response back to normal. Almost every cell in the body has glucocorticoid receptors and consequently almost every cell in the body is affected by the stress hormone. (7)

A stressor always elicits physiological changes that are put in motion to enable the individual to cope with the event. The autonomic and endocrine responses work catabolically by mobilizing the body's energy resources. The stress response is intended to be of limited duration. In this way, its catabolic and immunosuppressive effects are homeostatic and without serious consequences. (8)

The principal role of glucocorticoids during the stress response is thought to be restraint of the effects of the stress response. When a stressor is perceived, the secretion of glucocorticoids is stimulated by the neuronal brain located in the paraventricular nucleus of the hypothalamus. From here, it secretes the corticotropin-releasing-hormone (CRH) that stimulates the anterior lobe of the pituitary gland to produce the adrenocorticotropin-releasing hormone (ACTH), which then enters the blood stream and provokes the adrenal cortex to secrete glucocorticoids. The CRH system activates the stress response and is subject to modulation by cytokines, hormones, and neurotransmitters. The interactions among these organs constitute the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis has major interactions with the hypothalamic-pituitary-gonadal (HPG) and reproductive axes, the thyroid axis and the growth hormone axis, glucoregulation, insulin resistance and Th1/Th2 balance. (7,9)

Glucocorticoids inhibit the functions of virtually all inflammatory cells. Cortisol works effectively by increasing the intracellular synthesis of IKK-B, which binds to NFkB, thereby blocking the inflammatory cascade at its starting point. Glucocorticoids modulate the stress response at a molecular level by altering gene expression, transcription, and translation, among other pathways. Glucocorticoids receptors, which are expressed in a variety of immune cells, bind cortisol and interfere with the function of NF-kB and its regulation of the activity of cytokine-producing immune cells. (3) The effect is the inhibition of the functions of inflammatory cells, predominantly mediated through inhibition of cytokines, such as IL-1, IL-6, and TNF- alpha. (3,10)

The chronic activation of the hypothalamic-pituitary-adrenal axis (HPA) from chronic stress results in the increase in adrenal glucocorticoids with well documented inhibitory effects on the inflammatory process and in the inflammatory cytokines release. This stimulation not only often results in the disruption of the central nervous system, but also adversely influences the immune system causing stress, depression and suppression of specific immunity. Circulating levels of pro-inflammatory mediators are widely accepted as a marker of systemic levels of inflammation. (3)

Pro-inflammatory cytokines can penetrate the blood-brain barrier and affect those microglial cells located in specific areas of the brain involved in mood regulation and reward process.11 Recent human studies have employed randomized double-blind trials, exposing subjects to either immune stimulants (usually endotoxin) that generate low-grade systemic inflammatory responses or saline placebo and then comparing patterns of brain activation across the groups using functional magnetic resonance imagery. Using these methods, peripheral inflammation has been associated with negative mood states that are accompanied by increased activation of the subgenual anterior cingulate cortex (sgACC) and decreased connectivity of the sgACC with the amygdala, prefrontal cortex, nucleus accumbens, dorsal raphae nucleus (DNR) and locus caeruleus (LC). Research with animals has shown that a long term exposure to glucocorticoids destroys the neurons located in the hippocampal formation by decreasing the entry of glucose and decreasing the reuptake of glutamate. (12) This effect makes the neurons more susceptible to harmful events. For example, the increased amount of extracellular glutamate allows calcium to enter the brain through NMDA receptors, the predominant molecular device for controlling synaptic plasticity and memory function. Studies conducted by Brenneman et al. (13) confirm that stress early in life can cause problems in the hippocampal function. Several studies have confirmed that the stress of chronic pain has deleterious effect on the brain and cognitive behaviour. (9)

Consistent evidence shows that individuals with major depressive disorders have higher levels of circulating markers of inflammation than non-depressed individuals. For example, two recent meta-analyses concluded that increased plasma levels of TNF-[alpha], IL-6, IL-1, and CRP accompany major depression. (6,14)

There is ample research confirming that in the immune-to-brain pathways, sickness symptoms mediated by increases in circulating pro-inflammatory cytokines, are consistent with symptoms of depression including fatigue, sleep disturbances, anxiety, negative mood, anhedonia, and loss of appetite. (11) A direct relationship between stress and the immune system was demonstrated by Keicolt-Glaser et al. (3) who found that caregivers of family members with Alzheimer's disease showed weaker immune systems. Grief and bereavement have been found to severely suppress the immune system. In another study, the clinical administration of cytokines or endotoxins resulted in a range of symptoms of depression. (15) It is also a well-known factor that the clinical administration of the pro-inflammatory cytokine interferon (IFN)-[alpha] in the treatment of cancer or chronic infection induces symptoms of major depressive disorder in 23% to 45% of all patients, with the degree of depression being positively related to dose and duration of treatment. (16) Epidemiologic evidence also shows that systemic inflammation predicts future risk for depressive symptoms and clinical episodes of depression in some studies. (8,17,18)

Conditions associated with increased and prolonged activation of the HPA axis include anorexia nervosa, obsessive-compulsive disorder and panic disorder (10,12,7) and increased susceptibility to infection and tumours. In contrast, hypo-activation of the stress system/HPA axis, resulting in chronically reduced CRH secretion, may cause pathological hypo-arousal, leading to susceptibility to inflammatory, autoimmune disease, abnormal behavioural response, (19,20) seasonal affective disorder, chronic fatigue syndrome and weight gain. Repeated and prolonged exposure to glucocorticoids causes hippocampal neurons to atrophy, it increases activation of the sympathetic and decreased activation of the parasympathetic branches of the autonomic nervous system. (3) Abnormalities of stress system activation have been shown in inflammatory diseases such as rheumatoid arthritis, as well as behavioural syndromes such as melancholic depression. Thus, the stress response is central to resistance to chronic inflammation and mood disorders.

Cytokines found within the central nervous system play an important part in neuronal cell death. (4) The human central nervous system contains neuronal pathways and receptors for cytokines (e.g. IL-1) in areas that control the acute-phase response. (21) Most cytokines are large molecules, and would not be expected to cross the blood-brain barrier with ease. However, IL-1 stimulates the production of endothelial cell prostaglandins (PGE2, PGI2), which in turn stimulate the secretion of CRH from nerve terminals in the median eminence, which lies outside the blood brain barrier. (9) IL-1 may cross the blood-brain barrier at relatively leaky parts, such as the organum vasculosum of the lamina terminalis, or during disease states such as infection or inflammation which may impair the barrier. IL-1 may also signal centrally via secondary messengers such as nitric oxide and prostaglandins, or via the vagus and other nerves. (22) The chronic production of cytokines can induce glucocorticoids resistance and impair this process.

Cortisol resistance has been associated with insulin resistance. The similarities rest on reduced cellular expression of receptors, compromised receptors pathways through micronutrients deficiency and energy depletion. Long term exposure to glucocorticoids as also been linked to negatively affect the hippocampal formation by decreasing the entry of glucose and decreasing the reuptake of glutamate, thus destroying the neurons. (15,16) High levels of cortisol accelerate the process of adrenal exhaustion and lead to cortisol resistance. This phenomenon is characterized by increased plasma cortisol concentration and high urinary free cortisol. Cortisol resistance has a variety of different effects including increased blood pressure, damage to muscle tissue, steroidal diabetes, infertility, inhibition of growth, inhibition of the inflammatory responses and suppression of the immune system. (23,24)

Depending on the duration of the stressors, the pattern of the adrenal

axis dysfunction will differ. Early in the stress response, there might be elevated cortisol and catecholamines, but with chronic stress the system's ability to produce cortisol and other adrenal steroids maybe reduced and reserve of catecholamines depleted. (25) The consequence is fatigue, exhaustion and the inability to mount an adequate stress response on and hour-to-hour basis.

By helping the body cope with stress, adaptogenic herbs literally help to produce an adequate stress response. Traditionally, the focus has been directed to remedies that help maintain and improve adrenal stress response. Amongst others, they include Siberian Ginseng, Dong Quai and Gotu Kola. In particular, Korean Ginseng acts mainly on the hypothalamus and has a sparing action on the adrenal cortex. Response is stronger and quicker and feedback control is more active, so that when stress decreases, glucocorticoid levels fall more rapidly to normal. (26) During chronic stress, glucocorticoid production is reduced by Korean Ginseng (a sparing effect), while at the same time adrenal capacity is increased (trophic effect). Ginseng also raises plasma ACTH (27) and cortisone in the relaxed state, thereby generating a sense of alertness and well-being. Recommended dosage: 0.5 to 3g/day of the dried main or lateral root or 1 to 6ml of the 1:2 liquid extract. Preparations from the root hairs are therapeutically inferior and should be avoided.


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(14.) Ridker PM, Hennekens CH, Buring JE, Rifai N: C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000, 342:836-843.

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(18.) Milaneschi Y, Corsi AM, Penninx BW, Bandinelli S, Guralnik JM, Ferrucci L: Interleukin-1 receptor antagonist and incident depressive symptoms over 6 years in older persons. Biol Psychiatry 2009, 65:973-978. PubMed Abstract.

(19.) Sternberg EM, Glowa J, Smith MA, et al. Corticotrophin-releasing hormone-related behaviour and neuroendocrine response to stress in Lewis and Fischer rats. Brain Res1992; 570:54-60.

(20.) Patchev VK, Kalogeras KT, Zelazowski P, Wilder RL, Chrousos GP. Increased plasma concentration, hypothalamic content, and in vitro release of arginine vasopressin in inflammatory disease-prone, hypothalamic corticotrophin-releasing hormone-deficient Lewis rats. Endocrinology1992; 131:1453-7.

(21.) Ericsson A, Liu C, Hart RP, Sawchenko PE. Type 1 interleukin-1 receptor in the rat brain: distribution, regulation, and relationship to sites of IL-1 induced cellular activation. J Comp Neurol1995; 361:681-98.

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(23.) Maeda K, Tanimoto K, Terada T, Shinitani T, Kakigi T. Elevated urinary free cortisol in patients with dementia. Neurobiol Aging 1991; 12:161-3.

(24.) Norbiato G, Bevilacqua M, Vago T, et al. Cortisol resistance in acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1992; 74:608--13.

(25.) Joseph-Vanderpool JR, Rosenthal NE, Chrousos GP, et al. Abnormal pituitary-adrenal responses to corticotrophin-releasing hormone in patients with seasonal affective disorder: Clinical and pathophysiological implications. J Clin Endocrinol Metab1991; 72:1382-7.

(26.) Fulder, S., The Root of Being. Hutchinson &Co., London 1980.

(27.) Chang, HM., But, P., Pharmacology and Applications of Chinese Materia Medica. World Scientific, Singapore 1986 Vol 1.

Manuela Malaguti Boyle, ND
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Author:Boyle, Manuela Malaguti
Publication:Journal of the Australian Traditional-Medicine Society
Article Type:Report
Geographic Code:8AUST
Date:Jun 1, 2012
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