2. Stress.
Making a brief synopsis (see Figure 1), the classical stress pathways initially involve the Hypothalamus that integrates the information from the sensory and visceral pathways, the Hypothalamus would activate two parallel routes: the SAM axis (Sympathetic-Adreno-Medullary) and the HPA axis (Hypothalamic-Pituitary-Adrenal) (Sirera et al, 2006).
Figure 1
The SAM axis begins when the sympathetic preganglionic neurons of the spinal cord receive information from the hypothalamus by activating the Sympathetic Branch and inhibiting the Parasympathetic Branch, this activation generates changes aimed at preparing the body for sustained physical exertion and decision making. The activation of sympathetic postganglionic neurons produces the release of Noradrenaline that is secreted at the level of the adrenal medulla and in brain structures: hypothalamus, limbic system, hippocampus and cerebral cortex. On the other hand, the sympathetic preganglionic neurons activate the marrow of the adrenal glands, releasing the adrenaline circulation and, to a lesser extent, norepinephrine, generating an increase in the plasma glucose and fatty acid levels, the production of thyroxine is also increased, while It produces a decrease in insulin, estrogen and testosterone levels, and inhibition of prolactin secretion.
In parallel, the HPA Axis starts from the activation of the Paraventricular Nucleus of the Hypothalamus and aims to maintain the parameters of effort and attention. The neurons of the paraventricular nucleus secrete through the portal vessels to the adenohypophysis the Corticotropin-Releasing Hormone (CRH). CRH and other related hormones enter the circulatory system that joins the hypothalamus with the anterior pituitary, and by activating the pituitary, corticotropin (ACTH) is released and to a lesser extent β-endorphin.
On the other hand, the activation of the Neurohypophysis by the magnocellular neurons of the hypothalamus generates the segregation of Vasopressin and Oxytocin that will enhance the effect of CRH. Once Corticotropin is secreted in the bloodstream, it stimulates the production and release of Glucocorticoids (cortisol and corticosterone) and mineralocorticoids by the Adrenal Glands. The effects of high levels of glucorticoids (especially cortisol) in the medium / long term on health are really harmful: increase in blood pressure, damage to muscle tissue ... so there are feedback circuits that try to maintain their levels blood within defined parameters.
Immune system activation (Hansen-Grant et al, 1998; Reiche et al, 2004) by the SAM and HPA axes occurs through two different mechanisms, on the one hand the binding of hormones to their cognitive receptors and on the other indirectly through the deregulation of the balance that has to prevail in the production of pro-inflammatory cytokines (Sirera et al, 2006b; Maes et al, 1998). Proinflammatory cytokines are soluble mediators that promote and mediate inflammatory processes, the following stand out: interleukin 1 (IL-1) is involved in the regulation of the immune process and inflammation; interleukin 6 (IL-6) which also serves as a link between the endocrine system and the immune system; and Tumor Necrosis Factor (TNF) that has the ability to destroy certain cell lines and initiates the cascade of proinflammatory cytokines and other mediators. There are data that in addition to the endocrine system, the cytokines IL-1, IL-6 and TNFα interact with the Noradrenergic, Serotonergic, and Dopaminergic systems (Kronfol & Remick, 2000
Inflammation
Inflammation is a biochemical process that can be caused by numerous endogenous or exogenous factors, in fact any immunological phenomenon capable of affecting the stability of the system can be considered as a stressor and the process may be referred to as inflammatory stress. The Immune System has the function of recognizing and destroying both external and internal pathogens. To do this, it has two intercommunicated systems: innate or nonspecific immunity and acquired or specific immunity that is usually subdivided into two complementary groups: cellular immunity and humoral immunity. It is the nonspecific system cells (neutrophils, macrophages and dendritic) that initiate the immune response through phagocytosis and inflammation. Non-specific immunity induces specific immunity, and as a result a specialized response is generated and we could say with memory. The intensity, duration and peculiar characteristics of the inflammations will depend on the affected area, the previous state and the cause that causes it.
Chronic inflammation occurs as a result of the presence of an infectious agent, antigen or for a long time due to an immune system disorder. More and more data are available that suggest that inflammation may contribute to the development of diseases such as Alzheimer's (Tan et al, 2007), cancer (Pikarsky et al, 2004), atherosclerosis (Pi?on & Kaski, 2006), and diabetes (Rosado and Mendoza, 2007), in addition to those where inflammatory processes are the same basis of the disease as Crohn or rheumatoid arthritis. Chronic inflammation is characterized by the formation of fibrous tissue and that the cell infiltrate is mainly composed of macrophages, lymphocytes and plasma cells. Among the mediators of inflammation we must highlight the role of cytokines, especially IL-1β and TNFα, capable of activating numerous humoral cascades of mediators that perpetuate the activation of the system. Cytokines (see Table 1) form an important group of proteins that act as mediators of communication between living cells. In order to understand the role of cytokines, it is necessary to understand their mechanisms of action that are both local and general, several non-exclusive ones have been postulated: passive transport to the circumventricular zone, union to the vascular endothelium and subsequent release by other agents (prostaglandins, nitric oxide) inside the brain, active transport across the blood brain barrier and peripheral activation of nerve endings where release has occurred (Watkins al, 1995
IL-1β and TNFα are present from the beginning in the sequence of activities that seek the release and use of glucose for tissue repair or elevation of body temperature, inducing the production of a second wave of cytokines, IL -1, IL-6, IL-8 and Macrophage Chemotactic Protein, derivatives of arachidonic acid or eicosanoids, platelet activating factor (PAF), free radical release and nitric oxide (NO) production, also anti-inflammatory cytokines (IL-4 and IL-10) and the release of other inflammatory mediators (Nonaka, 2001) such as bradykinins, histamine ... IL-1 and IL-6 act on the HPA axis (Chrousos, 1995) increasing ACTH and cortisol secretion. The regulatory-suppressive function of the immune response will then depend on the balance between the synthesis of different cytokines with different actions. If the inflammation is prolonged, other systems will be activated: the Endocrine, the Noradrenergic, the Serotonergic and the Dopaminergic (Kronfol & Remick, 2000).
Inflammatory stress is immunomodulator, in this sense the existence of a possible pattern of inhibition of cellular immune response (Th1) has been hypothesized while increasing humoral immunity (Th2) or vice versa (Singh et al, 1999; Agarwal & Marshall, 1998). Th1 produce (IFN-γ, TNF-β) macrophage activators, in contrast Th2 produce IL-4, IL-5, IL-10, and IL-13 activators of antibody response, other models could also exist . However, the results observed in clinical processes such as systemic Lupus erythomatous (Chang et al, 2002) or in prostate cancer (Filella et al, 2000) have been described as ambiguous. We accumulate data that suggest that proinflammatory cytokines are capable of: activating both the HPA Axis and the Locus Coeruleus - Norepinephrine system of the SAM Axis. Stimulate plasma glucocorticoid concentrations, altering the activity of hypothalamic noradrenergic neurons, reducing norepinephrine in the spleen. Glucocorticoids in turn inhibit the secretion of IL-2, IFNγ and IL-12 while increasing the secretion of IL-4 and IL-10. The chronic or intermittent inflammation that is generated by the presence of an infectious focus can thus be associated with stress, being able to initiate the cascade of biochemical processes that make it formally indistinguishable from the psychobiological process itself.
4. Depression
Depression is a syndrome or mood disorder characterized by the criterial presence of a set of symptoms: sadness, anhedonia, asthenia or lassitude, decreased attention and concentration, loss of self-confidence, pessimism, ideation of death or suicide, insomnia, anorexia? In the classic model that emerged in the 1960s, the Serotonin system and the Noradrenergic System were basically involved in the development of the syndrome (Ressler & Nemeroff, 2000; Mongeau et al, 1997; Nemeroff. 2002). However, in recent years various biochemical processes capable of generating changes in mood have been studied in depth. Among them we can highlight inflammation, ischemia, necrosis, apoptosis ... Of all of them it is probably the most studied inflammation and in which we have more data that suggest the relationship between the course of depression and that of inflammation (Licinio & Wong, 1999)
The theoretical bridge to relate inflammation and depression, as well as stress (both psychological and physical), is made up of cytokines (Connor & Leonard, 1998 and more specifically by interleukins, especially proinflammatory ones. Proinflammatory interleukins interact with Endocrine, Noradrenergic, Serotonergic and Dopaminergic Systems (Kronfol & Remick, 2000) In the most current two-way models, it is considered that both stress and depression and inflammation are capable of activating and modifying the cytokine balance and vice versa. As an example, an increase in pro-inflammatory interleukins (IL-1, IL-6, TNFα) regardless of their origin can be related to increases in norepinephrine, serotonin, dopamine, cortisol, corticotropin CRH releasing hormone, and ACTH corticotropin, together with a decrease in Gonadotropin GnRH Liberating Hormone and Natural Killer activity cells (Kronfol & Remick, 2000).
The strongest evidence of the role of cytokines in depression comes from the clinical observation of animals (Felger et al, 2007) and patients treated with interferons (Asnis & La Garza, 2005). Thus the administration of interferon-α (Gleason & Yates, 1999) (in Hepatitis C or Melanoma), of interferon-β (in Multiple Sclerosis), interferon-γ (Kaposi's Sarcoma or in Chronic Granulomatous Disease) or of interleukin -2 (in Metastatic Cancer), are associated with affective and behavioral changes that include the development of depressive episodes. Other evidence that suggests the role of the immune system in the development and consolidation of depression includes observations that depressed patients show: high levels of IL-6 (Chrousos, 1995; Maes et al, 1993); high levels of acute phase reactants and activation markers of immune cells, as well as impaired immune function (Maes et al, 1993). Cytokines appear to exert a depressive effect, directly through activation of corticotropin-releasing hormone, or indirectly causing resistance to glucorticoid receptors, which causes hyperactivity of the hypothalamic-pituitary-adrenal axis, due to inhibition of the normal feedback mechanism. . Intracranial administration of proinflammatory cytokines causes the same disease effects as their systemic administration. Therefore, proinflammatory cytokines have two places where they can exert their distinct action, in the same place of inflammation and in the CNS.
Stress, whether physical or psychological, plays an important role in triggering and evolving depressive disorders. In addition, depression has shown the existence of a biochemical profile at the endocrine and immunological level similar to that observed in stress. Glucocorticoids (Burke et al, 2005) are among the main mediators of the immunosuppressive effects generated by stressors. Among the effects described in humans we find lymphocytopenia (for example after widowing), monocytopenia, and neutropenia. Also glucocorticoids seem to be involved in reducing the production of certain cytokines (IL-1, IL-2, IL-6, IL-8, TNF) or in the increments of others such as IgA, IgE, IgG or IgM . In addition, glucocorticoids also exert their action in the brain by crossing the blood brain barrier. In this sense, mineralcorticoid receptors have been found among other locations in the pyramidal and granular neurons of the hippocampus, the olfactory nucleus, the amygdala, the striatum and the septum. Glucocorticoid receptors are present in a high proportion in the hippocampus and in the hypothalamus, we also find them in the frontal, parietal and entorhinal cortex among others. Consequently glucocorticoids can modulate various processes in the central nervous system.
In recent years, the dopaminergic system is acquiring a specific weight (Dunlop & Nemeroff, 2007) in the pathophysiology of depression. The excitatory function of Dopamine in the neurons of the Paraventricular Nucleus, where the activation of the D1 and D2 dopaminergic receptors stimulates the HPA axis and promotes corticosterone secretion, establishing a positive feedback system. And also the relationships that are being found between neurons with D2 receptors and PAR-4 proteins (Gurumurthy et al, 2005; Park et al, 2005; Mattson & Gleichmann, 2005)
