Abstract

Magnesium status is highly associated with stress levels, with both stress and hypomagnesemia potentiating each other’s negative effects. Indeed, hypomagnesemia has been associated with stressful conditions such as photosensitive headache, fibromyalgia, chronic fatigue syndrome, audiogenic stress, cold stress, and physical stress, amongst others. The role of magnesium in these conditions is unclear, although a number of potential mechanisms for magnesium’s action have been identified including via the glutamatergic, serotonergic, and adrenergic neurotransmitter systems, as well as via several neuro- hormones. The current review examines the link between magnesium deficiency and stress, focusing on the association between magnesium and various stress pathologies, magnesium’s potential interaction with stress pathways, and magnesium’s effects on the brain.

Introduction

At the beginning of the twentieth century, Walter Cannon pioneered research concerning the importance of the sympathetic nervous system in adaptation of the body (Quick, 1994). While Claude Bernard was the first who defined the term of “milieu interieur” as being "the constancy of the internal environment" (see Cameron, 2007), it was Walter Cannon who coined the terms "homeostasis” and “fight-or- flight response" (Quick, 1994). Subsequently, Hans Selye in 1936 adapted a concept from physics describing the resistance of a body to applied pressure in order to define the concept of stress (Neylan, 1998). General adaptation syndrome, as he called it, is the non-specific response of the body to any demand for change. It consists of three stages of adaptation: an initial brief alarm reaction, a prolonged period of resistance, and finally, the stage of exhaustion and death. Although there is no generally accepted definition, stress can be understood to be a complex adaptive biochemical, physiological, psychological and gene expression change of the organism (stress response) triggered by a stimulus (stressor) that was interpreted by the brain as being dangerous (McEwen, 2008b; Kantorovich et al., 2008).

The neuroendocrine response to stress initiates hyperventilation, elevated blood pressure, increased heart rate, a sudomotor response (sweating), increased blood flow to skeletal muscles, and perturbations of gut function (the 'fight or flight' defence reaction) in order to enable body survival. More, the amygdala activates neurons in the hippocampus and neocortex, where threatening stimuli are associated with fear, in order to adapt future behaviour to avoid danger (Rupniak, 2005).

To further refine the stress concept, Sterling and Eyer (1981) proposed the term allostasis to describe the process of achieving stability through change. As compared to homeostatic values (blood oxygen, blood pH, and body temperature), which have to be kept within a narrow range, the allostatic mediators (hormones of the hypothalamic-pituitary-adrenal axis, catechol- amines, and cytokines) may vary during daily and seasonal routines (McEwen, 2008b; Ablin and Buskila, 2010; Billard, 2006).

Nowadays, the profound implications of stress in human pathology are unanimously recognized and represent a dynamic field of research. There is a continued interest in identifying new possibilities to alleviate stress and improve quality of life in a fast-changing, modern world.

The idea that magnesium (Mg) supplementation modifies the effect of chronic stress dates back to 1981 (Classen, 1981). This hypothesis is certainly feasible given the cation’s ubiquitous distribution and role throughout the body. Indeed, Mg is the fourth most abundant cation in the body and the second most abundant intracellular cation. It is involved in a wide variety of cellular processes including aerobic and anaerobic metabolism, all bioenergetic reactions, regulation of metabolic pathways, signal transduction, ion channels activity, cell proliferation, differentiation, apoptosis, angio- genesis, and membrane stabilization (Nishizawa et al., 2007; Szewczyk et al., 2008; Turner and Vink 2007; Wolf et al., 2007). At a biochemical level, more than 325 enzymes are Mg dependent, many of which are nervous system enzymes, thus reflecting the important role potentially played by Mg in CNS physiological and pathological function (Eby and Eby, 2006).

Magnesium interaction with stress pathways

Acute stress has been shown to be associated with increased plasma Mg levels and increased urinary Mg excretion (Murck, 2002; Whyte et al., 1987). The shift of Mg from the intracellular to the extracellular space initially plays a protective role in order to diminish the adverse effects of stress, but extended periods of stress result in progressive Mg deficit and deleterious conseq- uences for health (Seelig, 1994). Moreover, stress and hypomagnesemia potentiate each other’s negative effects in a veritable pathogenic vicious circle. Low Mg/Ca ratios augment the release of catecholamines in response to stress (Caddell et al., 1986; Seelig, 1994). Fatty acids resulting from adrenergic-induced lipolysis form undissociated Mg soaps which further exacerbates Mg depletion (Seelig, 1994). Mg deficiency also favours the release of vaso- constrictive and platelet aggregating factors (derived from fatty acid metabolism and endothelium), increases the thromboxane B2 to prostaglandin I2 (TxB₂/PgI₂) ratio and enhances intravascular blood coagulation (Ceremuzynski et al., 1978; Franz 2004; Dong et al., 2008; Soma et al., 1988; Sontia and Touyz, 2007). Most interestingly, Mg deficiency itself doesn’t induce specific pathology but reduces the tolerance to secondary stress (Tejero-Taldo et al., 2006).

The active transport systems between plasma and cerebrospinal fluid enable elevated and relatively constant Mg concentrations in the CSF (typically 1.1 mmol/l in CSF compared to 0.8 mmol/l in plasma) (Oppelt et al., 1963; Murck 2002). There are reports that parenteral administration of magnesium sulphate augments cerebrospinal fluid Mg concentration by 20–25% in approximately 4 hours (Ko et al., 2001; Muir, 2002), although recent reports suggest that Mg may not readily cross the intact blood brain barrier (McKee et al., 2005; see Chapter 3).

With respect to mechanisms of action, Mg affects a number of neurotransmitter systems. It inhibits the release of excitatory neuro- transmitters and also acts as a voltage-gated antagonist at the glutamate, N-methyl-D- aspartate (NMDA) receptor. Mg also antagonizes calcium entry via voltage-gated channels of all types. In addition to exhibiting agonist properties at γ-aminobutyric acid A receptors, it is an angiotensin II receptor antagonist. Mg inhibits calcium/protein kinase C related neurotransmission, increases reuptake of glutamate via stimulation of the Na⁺/K⁺ ATPase, and is involved in mitochondrial ATP-dependent potassium channel activity (Bednarczyk et al., 2005; Eby and Eby, 2006; Muir 2002; Murck , 2002). Furthermore, Mg inhibits the phos- phorylation activity of glycogen synthase kinase- 3 (GSK-3), increases brain-derived neurotrophic factor (BDNF) expression and enhances the cAMP response element-binding (CREB)/BDNF pathway via the serotonergic system, all mechanisms related to the antidepressant-like activity of this ion (Szewczyk et al., 2008).

There is also an increasing body of evidence indicating that psychological stress promotes oxidative stress, mainly by auto-oxidation of catecholamines. Several studies have shown that psychological stress exacerbates lipid peroxidation, increases production of markers of oxidative damage of DNA (8-oxo-7,8- dihydroguanine), and decreases plasma anti- oxidant activity (Seelig, 1994; Sivonova et al., 2004). Many of these processes are antagonized by Mg (Cernak et al., 2000; Muir, 2002; Nishizawa et al., 2007).

A stressor (either physical or psychological) initially activates the hypothalamic-pituitary- adrenal (HPA) axis and the autonomic nervous system. Activating these systems leads torelease of catecholamines from sympathetic nerves and the adrenal medulla, and of corticotropin-releasing factor (CRF) and vasopressin (AVP) from parvocellular neurons. Seconds later, adrenocorticotropic hormone (ACTH) is secreted from the anterior pituitary gland and stimulates release of glucocorticoids from the adrenal cortex (Rupniak, 2005; Carrasco and Van de Kar, 2003). CRF is a neurotransmitter involved in the coordination of the endocrine, autonomic, behavioural and immune responses to stress, and whose administration elicits stress-like effects (De Souza et al., 1991; Carrasco and Van de Kar, 2003; Cratty and Birkle, 1999). Magnesium interacts either directly or indirectly with the activity of a number of these neurotransmitters and neurohormones. For example, Cratty and Birkle (1999) showed that glutamate-stimulated CRF release is antagonized by the addition of MgCl₂ to the incubation medium. Mg stabilizes CRF receptor binding and is directly correlated to the number of CRF binding sites (Perrin et al., 1986). On the other hand, Mg stimulates the Na⁺/K⁺ATPase, which decreases CRF-receptor sensitivity (De Souza, 1995).

Mg also decreases the release of ACTH and modulates adrenocortical sensitivity to this hormone. As intracerebroventricular admin- istration of angiotensin II (ATII) increases the secretion of ACTH and AVP via CRF, it is presumed that Mg induces a suppression of HPA-axis activity, at least partially, through antagonism of ATII effects (Murck, 2002). Intracerebroventricular administration of artificial CSF with low Mg concentration induces an increase in cortisol secretion in cats (Garcy and Marotta, 1978). In stressful circumstances, MgSO₄ administration reduces the release of AVP (Jee et al., 2009), a neuropeptide that plays an important role in the generation of emotions, social behaviour (aggression), and learning and memory (Neumann et al., 2010; Ebner et al., 2000).

Low blood Mg levels have been associated with raised brain noradrenaline (NA) content in mice selectively bred for hypomagnesemia (Amyard et al., 1995). Such low Mg levels in blood have also been associated with increased catecholamine release in response to noise stress in rats, and with significantly increased urinary excretion (+200%) of NA (Caddell et al., 1986; Henrotte, 1997). Also, it has been proven that Mg exerts a direct suppressive effect on locus coeruleus activity and that poor Mg status increases sensitivity to stress (Henrotte et al., 1997).

Another pathway influenced by Mg is the serotoninergic system. Mg acts like a cofactor for tryptophan hydroxylase, intervenes in serotonin receptor binding in vitro and exhibits a direct enhancing effect on 5-HT_1A serotonin receptor transmission (Szewczyk et al., 2008; Mizoguchi et al., 2008; Abaamrane et al., 2009). Microdialysis studies showed that stressors can change the extracellular levels of serotonin in different brain areas including the hypo- thalamus, amygdala, frontal cortex and raphe nuclei (Fujino et al., 2002; Funada and Hara, 2001). Serotonin is involved in neuroendocrine regulation of stress through actions on prolactin, oxytocin, AVP, CRF and ACTH activity (Jorgensen, 2007). HPA axis dysregulation and sensitization of 5-HT₂ receptor-mediated signalling induced by CRF implicates chronic stress in the aetiology of depression and anxiety (Szewczyk et al., 2008; Magalhaes et al., 2010).

It is also tempting to speculate that the protective effect of the oestrogens in stress are partially mediated by Mg (Carrasco and Van de Kar, 2003). For example, It is known that oestrogens mediate the shift of Mg from plasma to cells and increases intracellular levels of Mg (Galland, 1991; Seelig, 1993; Seelig et al., 2004). Likewise, serum levels of Mg²⁺ and total magnesium were inversely correlated with oestrogen concentration level (Muneyyirci- Delale et al., 1999). In postmenopausal women oestrogen replacement therapy suppresses HPA axis responses to an emotional stressor (Dayas et al., 2000).

Besides cortisol, prolactin, is regarded as a measurable marker of a coping strategy to "psychological stress" (Sobrinho, 2003). Confirming that Mg levels can modulate prolactin secretion during stress, pretreatment with Mg-aspartate significantly decreased, in a dose-dependent manner, the prolactin plasma concentration of turkey pullets exposed to immobilization stress compared to non-treated birds (Ali et al., 1987). In addition, Mg acts like a positive allosteric modulator for oxytocin binding to the receptor, and in this way facilitates the neuropeptide’s action to alleviate stress (Gimpl et al., 2008; Labuschagne et al., 2010; Uvnas-Moberg and Petersson, 2005).

Magnesium deficiency, stress and miscellaneous pathologies

Clinical manifestations of hypomagnesemia include neuromuscular irritability and weakness (tremors, fasciculations, tetany and positive Chvostek’s and Trousseau’s signs, although some of these features may be due to concomitant hypocalcemia), headaches, focal seizures, hyper- emotionality, generalized anxiety, panic attack disorders, insomnia, fatigue, and asthenia (Touyz, 2004; Wacker and Parisi, 1968; Eby and Eby, 2006; Rayssiguieret al., 1990; Durlach et al., 1997). For symptomatic patients, plasma magnesium, erythrocyte magnesium, plasma calcium and daily magnesiuria, calciuria and magnesium retention test should be evaluated (Durlach et al., 1997; Cundy, 2008). The alleviation of clinical manifestations by oral supplementation with 5 mg of magnesium/kg/day confirms the diagnosis (Durlach et al., 1997).

Experimental data indicate that Mg-deficient rats exhibit slightly increased plasma cortico- sterone levels, increased irritability and aggressive behaviour, and higher mortality compared to controls (Caddell, 2001; Henrotte et al., 1997). Recent data also indicate that genetic polymorphism of Na⁺/Mg²⁺ exchanger activity influences Mg²⁺ efflux from erythrocytes (Feillet-Coudray et al., 2004). Extensive work regarding the genetic predisposition for Mg deficiency has been carried out by Henrotte et al., (1990) who showed that both major histo- compatibility complex (MHC) associated genes (HLA and H-2) and non-MHC genes are important contributing factors for Mg status. In humans, Henrotte and Levy-Leboyer (1985) also found an interesting link between HLA-B35, type A personality and low Mg²⁺ status. HLA-B35 individuals are more frequently found among stress-sensitive type A behaviour subjects and exhibit lower red blood cell Mg levels than non- carriers. Moreover, these individuals show impaired cytotoxicity and higher titres to antibodies after anti-influenza vaccination, data that establish a connection between genetic background, Mg deficiency, stress and autoimmunity. It is generally accepted that, in response to a psychological stressor, type A persons exhibit increased release of catecholamines and cortisol, which consequently lowers Mg levels and increases cardiovascular risk as compared to type B behaviour (Henrotte et al., 1985; Matthews, 1982).

Experimental Mg deficiency has also been associated with disrupted sleep patterns. In rats, Mg deficiency is associated with an increased amplitude in daily variation of sleep and slow- wave sleep delta power, and has been noted to shorten life span and lower reproductive ability (Chollet et al., 2001; Motta et al., 1998). In humans, chronic sleep deprivation is associated with progressively decreasing levels of intra- cellular Mg, reduced duration of cardio- pulmonary exercise and increased hyper- sensitivity of the chronotropic response to sympathetic nervous stimulation (Omiya et al., 2009). Intriguingly, Mg depletion is associated with decreased melatonin and its supple- mentation alleviates the symptoms (Billyard et al., 2006; Depoortere et al., 1993; Held et al., 2002). In elderly subjects, Mg administration (10 mmol and 20 mmol each for 3 days followed by 30 mmol for 14 days) significantly increased slow wave sleep, renin levels during the total night, and aldosterone levels in the second half of the night, but decreased cortisol levels in the first part of the night (Held et al., 2002).

Photosensitive headache is another condition that is exacerbated by stress and Mg deficiency. Even wearing of tinted spectacles indoors is considered to be a valid indicator of psychological distress. Patients most susceptible to develop this condition include photophobic individuals that experience ophthalmological discomfort during visual stress tests. Sarchielli et al., (1992) showed that sufferers of migraine with and without aura, and tension-type headaches, exhibit significantly lower levels of serum and salivary Mg concentrations. Hypomagnesaemia raises the sensitivity of cerebral arteries to CO₂ which in turn favours cerebral vasospasm and headache (Thomas et al., 1994). Despite being controversial, some authors recommend intravenous administration of 1 gram of MgSO₄ for the treatment of migraine headache (Durlach et al., 2005).

Fibromyalgia is considered a stress–related disorder, with both the onset and the exacerbation of the syndrome associated with intensely stressful periods. Patients with fibromyalgia frequently exhibit chronic, widespread pain caused by the increase in the processing and handling of pain by the CNS (Ablin and Buskila, 2010). It has been shown that there is an inverse correlation between Mg levels and clinical parameters in patients with fibromyalgia (Sendur et al., 2008). The beneficial role of Mg in this pathology is presumably based on its antagonistic effect upon NMDA receptors, receptors that are significantly involved in the process of central sensitization (Galland, 1991). Various studies have also shown that patients with a chronic fatigue condition closely linked to fibromyalgia exhibit low Mg levels that are correlated with total antioxidant capacity of blood and GSH concentrations, but not with lipid peroxidation in vitro (Galland, 1991; Manuel y Keenoy et al., 2000). In these patients, weekly intramuscular injections of 1 gram of MgSO₄ resulted in a significant improvement in energy levels, pain, and emotional reactions as measured by the Nottingham health profile score (Cox et al., 1991; Murck, 2002). Durlach et al., (2002) suggest that fibromyalgia and chronic fatigue syndrome are clinical forms of magnesium depletion associated with dysfunction of the biological clock.

An interesting correlation has been reported between Mg deficiency and attention-deficit/ hyperactivity disorder (ADHD). Elevated subjective stress levels and stress intolerance is often mentioned as part of the clinical presentation of ADHD, and often these patients present high post-stress cortisol concentrations (Hirvikoski et al., 2009). In a study examining 116 children, 95% of children with this pathology exhibited Mg deficiency (Kozielec and Starobrat- Hermelin, 1997). Although evidence regarding the improvement of ADHD symptoms by Mg supplementation is mixed, some studies indicate that a Mg-B6 regimen over at least two months significantly alleviated hyperactivity and hyperemotivity/aggressiveness and improved attention at school (Mousain-Bosc et al., 2006; Rucklidge et al., 2009). Interestingly, ADHD symptoms reappear in a few weeks after the cessation of the treatment, together with a decrease in erythrocyte Mg values (Mousain-Bosc et al., 2006). A Mg-B6 regimen has also been shown to be effective in the treatment of Tourette’s syndrome. Tourette’s syndrome is associated with increased vulnerability to stress, and Mg deficit is considered to be a central precipitating event (Carrasco and Van de Kar, 2003; Grimaldi, 2002). Hypomagnesemia is linked with exacerbated neural excitability, increased anxiety, orofacial tardive dyskinesia, and migraine, symptoms that are alleviated by the administration of a combination of 0.5 mEq/kg Mg and 2mg/kg vitamin B6 (Garcia- Lopez et al., 2009; Stendig-Lindberg et al., 1998).

An inverse correlation between audiogenic stress and erythrocyte Mg levels has been observed (Galland, 1991), and low Mg status has been linked to self-reported noise sensitivity, noise-induced emotional lability and noise- induced feelings of tenseness (Galland, 1991). Notably, exposure to long-term road traffic noise in both children and adults leads to elevated night time secretion of noradrenaline and cortisol when compared to controls (Ising and Braun, 2000). Mg administration is effective in diminishing ototoxicity (Abaamrane et al., 2009; Ehrenberger and Felix, 1995) as well as in alleviating transportation stress (Tang et al., 2008; Peeters et al., 2005). Cold stress also induces a decrease in Mg levels in CSF and raises the incidence of clinical manifestations (Matsui, 2007). Interestingly, a correlation has been described between Mg levels (in serum and peritoneal fluid) and stress perception (Jung et al., 2010; Garalejic et al., 2010) in relatively healthy, adult women unable to conceive but without identified organic causes of sterility.

It is now well known that Mg deficiency facilitates epileptiform discharges in hippo- campal slices (Gutierrez et al., 1999) and in audiogenic seizures (Bac et al., 1998). Hippocampal neurons are more sensitive to low Mg than neurons from other brain regions and their responses to Mg deficiency differ depending on the developmental period (Furukawa et al., 2009). Human studies show that stress augments seizure frequency and severity in epileptic patients (Sawyer and Escayg, 2010).

Data from a second examination of the Copenhagen City Heart Study showed that self- reported high stress intensity and weekly stresswere associated with almost a doubled risk of fatal stroke (Truelsen et al., 2003). In ischemic or hypoxic tissue, Mg antagonizes calcium’s effects and decreases reactive oxygen species production through phopholipases, lipoxygenase and cyclooxygenase pathways. Likewise, in conditions associated with cerebral ischemia, Mg deficiency promotes vasoconstriction of cerebral and coronary arteries, as well as anoxic depolarizations and cortical spreading depression. Accordingly, Mg supplementation potentially plays a neuroprotective role (Turner et al., 2004). Mechanical stress such as membrane stretch or osmotic cell swelling can activate TRPM7-like channels (Numata et al., 2007), which are involved in Mg transport. These channels are members of the ubiquitously expressed melastatin-related subfamily of transient receptor potential (TRP) channels, and represent essential mediators of anoxic neuronal death (Aarts and Tymianski, 2005; Penner and Fleig, 2007). Low intracellular levels of Mg, a process that exacerbates the effects of stress on the organism, also activate TRPM7 channels.

Conscious, critically ill patients experience unprecedented levels of stress, both physical and psychological. However, even unconscious, comatose or sedated patients can exhibit stress initiated by peripheral stimuli that directly activate limbic structures prior to cortical involvement. These patients exhibit multiple organ dysfunction and veritable endocrine chaos (Papathanassoglou et al., 2010). In these patients, hypomagnesemia is often associated with hypokalemia and is considered to aggravate the prognosis. Under these conditions, prolongation of QT interval constitutes a useful biomarker of electrolyte imbalance and the requirement for replacement therapy (Whitted et al., 2010). It is noteworthy that hypo- magnesemia has been linked with a decrease in insulin sensitivity which can also affect the neurological outcome of critically ill patients (Polderman et al., 2003). In critically ill patients, a daily Mg supplementation index higher than 1 gram/day is associated with a lower mortality rate. Mg supplementation is also recommended for patients exposed to therapeutic hypothermia who often exhibit hypomagnesemia due to polyuresis (Dabbagh et al., 2006; Polderman et al., 2003).

In a model of intraperitoneal sepsis, MgSO₄ administration (750 µmol/kg) attenuated increased blood–brain barrier permeability and caused a reduction in brain edema formation (Esen et al., 2005). Similar results have been observed in experimental traumatic brain injury (Turner and Vink, 2007) where intravenous administration of MgSO₄ (250 µmol/kg) also significantly decreased the incidence of post- traumatic depression/anxiety as compared to non-treated animals (Fromm et al., 2004).

Stress also influences the susceptibility to neurodegenerative disorders such as multiple sclerosis and Alzheimer’s disease (Brown et al., 2006a; 2006b; Esch et al., 2002a). Pro- inflammatory effects associated with stress are exacerbated and exert deleterious actions upon the neurons, including increased IL6 levels that initiate microglial activation. Increased iNos levels are also expressed during critical periods and the elevated stress hormones themselves impair hippocampal neurogenesis and memory (Esch et al., 2002a; 2002b). Moreover, Mg deficiency increases neuronal calcium influx and consequently augments NO production that is associated with cytotoxic effects (Eby and Eby, 2006). Recent data also indicate a possible link between acute and sudden psychological stress and the appearance of malignant primitive brain tumours (Cabaniols et al., 2010). Furthermore, long-term survivors of brain cancer continue to experience elevated levels of stress as the fear of recurrence increases with time (Keir et al., 2007). Epidemiological data have described an inverse relationship between Mg content in drinking water and incidence of some types of cancers (Maier et al., 2007). A protective effect of fresh vegetable and fruit intake has also been noted. Although the role of Mg in carcinogenesis is yet to be established, it’s involvement in DNA stabilization has been described (Anastassopoulou and Theophanides, 2002; Anghileri, 2009; Wolf et al., 2009).

Individuals with cardiovascular pathology are most susceptible to the concerted effects of stress and Mg deficiency. The inotropic and chronotropic response induced by catechol- amine release produces an oxygen debt in the myocardium. In a hypoxic tissue, Mg shifts from the intracellular to the extracellular space, and calcium enters into cells, leading to increased risk of arrhythmias and cardiac deterioration (Seelig, 1989). Interestingly, MgSO₄ is successfully used in the treatment of pheochromocytoma, a condition associated with excessive release of catecholamine. In this situation, Mg exhibits simultaneous beta-agonist effects and alpha-adrenergic antagonist actions, improves diastolic dysfunction and reduces episodes of arrhythmia (James, 2009). Encouraging results have also been obtained using Mg therapy in two newly described cardiomyopathic syndromes: Irukandji syndrome and stress cardiomyopathy. Irukandji syndrome is caused by envenomisation from a jelly- fish (Carukia barnesi), which induces excessive release of endogenous catecholamines. Administration of MgSO₄ alleviates pain and the cardiovascular response in Irukandji syndrome but there is still a need for evidence-based guidelines in the management of this condition (Tiong, 2009; Nickson et al., 2009; Barnett et al., 2005; Corkeron et al., 2004). Stress cardio- myopathy (also referred as Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome) is an acute reversible apical ventricular dysfunction provoked by elevated levels of catecholamines. These stress hormones enable the shift of β2-adrenoceptor transducing signal from Gs protein to Gi protein causing negative inotropic effects (Lyon et al., 2008). While there is no specific treatment for this condition, some authors reported beneficial results with Mg administration (Akashi et al., 2008).

Considerable evidence now supports the fact that Mg presents beneficial effects in different types of surgical stress, including induction and maintenance of pneumoperitoneum, endotracheal intubation, cardiopulmonary bypass, occlusion- reperfusion surgery and middle ear surgery (James 2009; Jee et al., 2009; Puri et al., 1998; Ashton et al., 1991; Delhumeau et al., 1995; Manrique et al., 2010; Dorman et al., 2000; Kurian and Paddikkala 2010; Ryu et al., 2009). Considering the fact that pain induces the release of stress mediators, the blockade of neuronal NMDA receptors by Mg provides additional positive effects. Even if Mg is not a potent analgesic per se, several authors have shown that Mg potentates the analgesic effect of traditionally used pain relievers, reduces their requirements and decreases the incidence of postoperative shivering (Dabbagh et al., 2009; Lysakowski et al., 2007). Following carotid endarterectomy or cardiac surgery, Mg therapy improves cognitive outcome and prevents postoperative arrhythmias, especially in patients with contraindications for beta-blockers (Mack et al., 2009; Dabrowski et al., 2008; Davis et al.,).

In athletes who are subjected to severe physical stress, Mg favourably stabilizes the membrane integrity by binding with phosphate groups of phospholipids located in cell and organelle membranes (Golf et al., 1998). In these subjects, 17 mmol magnesium supplementation per day lowered serum cortisol levels and augmented venous O₂ partial pressure leading to better performance. Recent studies indicated that magnesium intake should be at least 260 mg/day for male and 220 mg/day for female athletes (Nielsen and Lukaski, 2006). According to Couzy and colleagues (1990), Mg overdosage in professional sportsmen may lead to hypo- zincemia. The overtraining syndrome described in athletes is also a stress-related condition that designates the exhaustion stage of Selye's general adaptation syndrome. This syndrome is characterized by impairment of psychological processing, systemic inflammatory response, and HPA dysfunction (Angeli et al., 2004). Magnesium deficiency has been reported in this condition.

Stress and the brain

The brain is very susceptible to stress, largely because corticosterone binds at this level to high affinity mineralocorticoid receptors (Abaamrane et al., 2009) and to glucocorticoid receptors (GR), albeit with 10-fold lower affinity. The CA1 and dentate gyrus neurons of the hippocampus express high amounts of both receptor types, whereas CA3 pyramidal neurons primarily express mineralocorticoid receptors (Karst and Joels, 2003). A stress-induced rise in corticosteroid levels modulates short-term memory, generally by promoting storage of information that is emotionally related to the stressful event, but by suppressing information that is not associated with it (Lupien and Maheu, 2007). Glucocorticoids contribute to the consolidation of contextual fear conditioning, but can also lead to memory impairments (Kolber et al., 2008; Leon-Carrion et al., 2009). The inability to remember important data worsens the individual’s stress and makes the subject even more vulnerable. Animal studies also show that stress-induced increases in NA levels modulates declarative memory according to an inverted-U- shaped function by enhancing the memory for information unrelated to the source of stress (Lupien and Maheu, 2007). A strong link between noradrenergic activation, glucocorticoid effects and basolateral amygdala function has been described (McGaugh and Roozendaal, 2002; Baldi and Bucherelli, 2005).

While acute stress affects memory in a reversible way, chronic stress results in deleterious changes in the hippocampus, especially an atrophy of dendrites of pyramidal neurons in the CA3 region of the hippocampus, and in other brain regions (prefrontal cortex, amygdala, brain stem and pons). By antagonising NMDA receptors, Mg prevents acute glucocorticoid effects on neurogenesis (McEwen, 2008a; Slutsky et al., 2010). Mg removal from the extracellular medium produces hyperexcitability and cellular death in cultured hippocampal neurons through a mechanism based on NMDA receptor activation and Raf-MEK-MSK1 signalling pathway (Hughes et al., 2003). Moreover, through the effects upon P-glycoprotein, Mg modulates the access of corticosteroids to the brain (Murck, 2002). Consistent with these data, Mg deficiency represents an important factor in the pathogenesis of aging defined by decreased adaptability to stress, alteration of hippocampus functioning, failure to turn off the hypothalamo- pituitary-adrenal axis and hyperadreno- glucocorticism (Durlach et al., 1993; Steptoe, 2007).

Stress exposure results in a long-lasting sensitization of the HPA axis to subsequent novel stressors. Exposure to a single stressor induces CRF-dependent depression of postsynaptic NMDA receptors that allows glutamate synapses in the paraventricular nucleus of the hypothalamus to undergo a short-term potentiation (STP) (Kuzmiski et al., 2010). There is a growing body of evidence that Mg plays an important role in synaptic plasticity and is involved in long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission (Billard, 2006). LTP is induced by cortical stimulation in Mg-free solutions and it is associated with massive calcium influx through NMDA-type receptors (Nakano et al., 2010). Diamond et al., (2007) suggested that complex interactions between LTP and LTD processes in the hippocampus contribute to the storage of emotional memories and stress-induced amnesia. Whether Mg can modulate effects of stress on LTP in the hippocampus, amygdala and prefrontal cortex remains to be established. Magnesium-L- threonate administration in rats increases the density of synaptophysin-/synaptobrevin-positive puncta in DG and CA1 subregions of the hippocampus, which contributes to improvement of cognitive functions (learning abilities, working memory, short- and long-term memory in rats) (Slutsky et al., 2010). Mg also acts synergistically with the NMDA antagonist memantine on hippocampal LTP, and there are data that indicate that Mg leads to an improvement of cognitive function in dementia (Danysz et al., 2000; Frankiewicz et al., 1996).

Mg is also involved in long-term memory formation through NA activated pathways. Saturation by free Mg increases the affinity of adenylate cyclase for adrenaline and excessive stress affects the stability of this enzyme and produces loss of activity. Moreover, by activating adenylate cyclase in fat tissues, stress increases the production of chelating metabolites like ATP⁴⁻ or citrate⁻, which reduce the level of free Mg²⁺ (Bennun, 2010).

Magnesium during the developmental period

A number of studies have now suggested that magnesium and stress may play an important regulatory role in the early developmental period. For example, in rhesus monkeys, stressful pregnancy reduced the hippocampal volume and impaired neurogenesis in the dentate gyrus of the offspring (Bac et al., 1995; Coe et al., 2003). An acoustic startle protocol applied during the 24-weeks gestation time was associated with increased levels of cortisol and reduced exploratory behaviour in the 3-year-old descendants. Another study examining the newborn’s response to moderate surgical trauma showed that neonates are more susceptible to stress than infants (Okur et al., 1995). Although there were not significant differences between infants and neonates regarding the elevations of cortisol and growth hormones after surgical stress, Mg concentrations declined more in newborns compared to the other group.

Both experimental and clinical data also suggest that fetal Mg depletion (as a consequence of maternal deficiency) and stress during critical developmental periods are involved in the pathogeny of sudden infant death syndrome (Caddell, 2001; Durlach et al., 2004). Durlach et al., (2002) also emphasize the importance of chrono-pathological stress due to primary hypofunction of the biological clock and the pineal dysfunction. Among the exogenous stressors that may lead to this syndrome, it is worth mentioning parental smoking, maternal alcoholism, environmental pollutants, bottle feeding, sleeping position, bedding, wrapping and ambient temperature (Durlach et al., 2004).

In fetal guinea pig brain, maternal MgSO₄ administration during hypoxic stress exhibits neuroprotective effects by ameliorating nuclear membrane peroxidation and nuclear DNA fragmentation (Maulik et al., 2001). Additionally, maternal MgSO₄ treatment before anticipated early preterm birth has proven to reduce the risk of cerebral palsy in surviving infants (Marlow, 2009). Given the “anti-stress” properties of Mg, this discovery once more emphasizes the importance of maternal Mg status on the neural, hormonal and behavioural outcome of the progenitors.

Finally, children hospitalized for respiratory pathology and who received sporadic parental visits exhibited lower serum Mg level and increased excretion of this cation compared to children who received constant parental support (Bednarek et al., 2004). There are also data that suggest Mg deficiency in children brought up in stressful orphanage conditions may lead to a lower intelligence quotient (Manrique et al., 2010; Papadopol et al., 2001).

Magnesium and self-damaging behaviour

In order to cope better with stress, individuals exhibit variable behavioural responses ranging from improving lifestyle to self-damage (e.g. smoking, drinking, overeating) or risk-taking. It is well known that susceptibility to stress among the population is diverse and there is a minority who exhibit an extreme response to stress in respect to intensity, features and extension of time. The myriad of individual differences regarding stress responses are mainly a result of genetic background, developmental processes (both prenatal and postnatal), and lifetime experiences (McEwen, 2007).

Individuals exhibiting self-damaging behaviour are more likely to present hypomagnesemia as alcohol itself depletes the organism of Mg (Romani, 2008). Depletion of Mg induced in rat astrocytes by alcohol produces disturbances in cytoplasmic and mitochondrial bioenergetic pathways leading to Ca²⁺ overload, ischemia and stroke (Altura and Altura, 1994). Eating disorders are also commonly linked to hypomagnesemia that may or may not be associated with hypokalemia, hypocalcemia and hypophosphat- emia (Laird Birmingham 2010; Touyz, 2004). This is particularly concerning where the normal western diet is already low in magnesium. For example, in most countries, the magnesium RDA for women varies from 240 to 400mg/day and for adult men varies from 310 to 420mg/day. However, Mg intake in 70% of the western population is less than 400 mg Mg²⁺ per day, and for approximately 20% of the population this cation intake is less than one-half of the recommended dose (Eby and Eby, 2006). Persons with inadequate nutrition that often accompanies chronic stressful lifestyle need Mg supplementation as increased intake of carbohydrates, fats, exaggerated consumption of coffee and sodas reduce the Mg levels in the organism (Seelig, 1994; Nishimuta, 2007).

Mg administration can provide beneficial effects by decreasing the susceptibility of stress- induced drug relapse. Mg decreases activity of central glutamatergic synapses, especially those involved in the reward system that is activated by stress (Gilman, 2007; Nechifor, 2008), and displays a modulatory effect for opioid receptor binding (Turner and Vink, 2007). Furthermore, Mg administration indirectly influences hippo- campal neurogenesis through its effect upon corticosteroid hormones, and in this way may decrease the drug-seeking behaviour in drug- addicted persons (Noonan et al., 2010).

Magnesium and substance P

Several authors have recently suggested that many of the consequences of Mg deficiency in stress may be explained by the release of substance P. Substance P is a neuropeptide that preferably activates tachykinin NK1 receptors. It is considered to be involved both in early (4-7 days) and late (3 weeks) phases of the systemic response to Mg deficiency. In the early days after the onset of a Mg-restricted diet, low concentrations of this cation diminishes the Mg- gated blockade of NMDA receptor channels, which leads to the release of substance P and calcitonin gene-related peptide from the sensory C fibres. The increased circulating levels of these neuropeptides initiate an important “neurogenic inflammation” characterized by raised levels of inflammatory cells, inflammatory cytokines and augmented production of reactive oxygen and nitrogen species (Kramer et al., 2009; Tejero- Taldo et al., 2006). Brain microinjection of substance P activates stress-processing pathways and induces defensive respiratory, cardiovascular, gastrointestinal and psychological changes, as well as stimulating corticosterone secretion by the adrenal glands (Rupniak, 2005). Furthermore, in a model of chronic psychosocial stress in shrews, the NK1 receptor antagonist SLV-323 alleviated dentate cytogenesis and diminished the decrease of hippocampal volume induced by stress (Czeh et al., 2005). Thus, substance P is now widely considered to be involved in the clinical expression of stress.

Conclusion

Mg still represents an emerging research field despite being entered into medicine in the XVII^th century as a constituent of Epsom salts (Durlach 2007). Although much has been discovered, many aspects of magnesium still remain unclear and await discovery. Undoubtedly, the future will uncover new Mg compounds of medicinal value, will further characterize Mg as a common factor in more stress-related pathologies, and will result in the discovery of more Mg transporters, while better methods for the determination of intracellular levels of the cation will pave the way for an improvement in simple diagnosis of true Mg²⁺ deficiency.

Acknowledgements

Magdalena Cuciureanu was a recipient of a 2010 Australian Go8 European Fellowship.

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