Neurogenic Inflammation and Cardiac Dysfunction due to Hypomagnesemia

Beskriver hvordan magnesium mangel bidrar til økt utskillelse av Substans P i nociceptorer, som gir økt tilbøyelighet for smertetilstander. Den sier at det ikke holder meg bare magnesiumtilskudd, man må kombinere med antioksidanter også fordi magnesium mangel spiser opp antioksidantforsvaret. Den nevner at graden av magnesium mangel er nesten lineær med graden av Substans P aktivitet og antioksidant nedgang.

This review has highlighted some key observations which helped formulate the hypothesis that release of substance P (SP) during experimental dietary Mg deficiency (MgD) may initiate a cascade of deleterious inflammatory, oxidative, and nitrosative events, which ultimately promote cardiomyopathy, in situ cardiac dysfunction, and myocardial intolerance to secondary stresses.

Significant protection against most of these MgD-mediated events has been observed with interventions that modulate neuronal SP release or its bioactivity, and with several antioxidants (vitamin E, probucol, epicaptopril, d-propranolol). In view of the clinical prevalence of hypomagnesemia, new treatments, beyond magnesium repletion, may be needed to diminish deleterious neurogenic and prooxidative components described in this article.

Animals placed on Mg-restricted diets also displayed progressive cardiovascular lesion formation, heightened cardiac inflammatory cell infiltration,15 decreased levels of endogenous antioxidants (glutathione, vitamin E, ascorbate) 16,17 and higher plasma levels of pro-oxidant metals 18 and lipid peroxidation (LPO) products.19,20 Antioxidant treatment attenuated the severity of both cardiovascular inflammation in vivo21 and postischemic reperfusion injury in vitro,22 suggesting that dietary Mg-deficiency progresses into a pro-oxidant condition.

The gut is rich in neuropeptides 53 and may contribute to the early rise in plasma SP during MgD. During week 1 of MgD, intestinal inflammation was evident and pronounced PMN infiltration occurred by week 3, when significant decreases in mucosal barrier function were observed.

Varying dietary Mg-intake in rats directly influenced plasma SP levels,58 the associated severity of systemic oxidative/nitrosative stress,59,60 and loss of myocardial tolerance to I/R stress. 58 We demonstrated that SP release also occurred in rats fed moderate MgD diets (MgD20 =20 % RDA; MgD40 = 40% RDA) 58 and the literature suggests that many of the same pathological characteristics observed in the severe MgD9 animal also occurred in these animals. 59,60

Moreover, the decline in RBC glutathione was also directly proportional to the extent of Mg-restriction: levels from MgD40, MgD20, and MgD9 rats fell 20.6%, 29.4%, and 50% compared to the Mg100 group.



Noen studier om hvordan Substans P forholder seg til mat

Denne nevner at en 10% reduksjon av anbefalt daglig magnesium inntakt øker sjangsen for osteoporose og Substans P

Bone Loss Induced by Dietary Magnesium Reduction to 10% of the Nutrient Requirement in Rats Is Associated with Increased Release of Substance P and Tumor Necrosis Factor-α1

These data demonstrated that a Mg intake of 10% of NR in rats causes bone loss that may be secondary to the increased release of substance P and TNF-α.

Denne nevner hvordan tiltak som reduserer SP bidrar til å redusere de negative virkningene av magnesiummangel.

Neurogenic Inflammation and Cardiac Dysfunction due to Hypomagnesemia.

Significant protection against most of these MgD-mediated events has been observed with interventions that modulate neuronal SP release or its bioactivity, and with several antioxidants (vitamin E, probucol, epicaptopril, d-propranolol). In view of the clinical prevalence of hypomagnesemia, new treatments, beyond magnesium repletion, may be needed to diminish deleterious neurogenic and prooxidative components described in this article.

Denne nevner hvordan SP er involvert i insulin regulering og diabetes.

Role of Substance P in the Regulation of Glucose Metabolism via Insulin Signaling-Associated Pathways

Our results demonstrate an important role for SP in adipose tissue responses and obesity-associated pathologies. These novel SP effects on molecules that enhance insulin resistance at the adipocyte level may reflect an important role for this peptide in the pathophysiology of type 2 diabetes.

Study of magnesium bioavailability from ten organic and inorganic Mg salts in Mg-depleted rats using a stable isotope approach

Nevner alt om hvordan magnesium taes opp og biotilgjengeligheten i forskjellige magnesium produkter. Sier at den viktigste måten det taes opp på er passiv overgang fra tynntarm til blod som følge av at blodet har mindre magnesium enn tarmen. Sier også at opptaket er bedre jo surere miljøet i tarmen er. Tabell 3 viser at de fikk i seg 13mg/d (magnesiumcitrat) og at 48% ble tatt opp. Maten de spiste innehold 600mg magnesium pr kg mat.

The target Mg level in these diets was 600 mg Mg/Kg diet.

It is essentially a passive intercellular process mediated by electrochemical gradients and solvent drag, and active transport occurs only for extremely low dietary Mg intake and its regulation is unknown [11].

In conclusion, the present study demonstrated that all ten organic and inorganic Mg salts were equally efficient in restoring blood Mg levels in plasma and red blood cells in rats. Because of the importance of the passive process, the quantity of Mg in the digestive tract is the major factor controlling the amount of Mg absorbed. However, the organic forms of Mg, in particular Mg gluconate, seem more absorbable than inorganic salts as assessed by intestinal absorption and urinary excretion.

Magnesium: Novel Applications in Cardiovascular Disease – A Review of the Literature

En review studie fra 2012 som inneholder det meste om Magnesium, spesielt rettet mot betennelser i hjerte/kar og nervesystemet.

Magnesium L-lactate and L-aspartate are the oral magnesium compounds that have the greatest bioavailability, are the most water-soluble and have the greatest serum and plasma concentrations [8].

After a mean follow-up of 9.8 years and adjusting for confounders, the authors concluded that women in the highest quintile (an intake of 400 mg/day of magnesium) had a decreased HTN (hypertension) risk (p < 0.0001) versus those in the lowest quintile (approx. 200 mg/day of magnesium) [20].

Because of magnesium’s anti-inflammatory, statin-like and anti-mineralizing effects, a role for it is emerging in cardiovascular and neurological medicine.

The potential impact of magnesium in cardiovascular and neurological health, the abundance and low cost of the supplement, the relatively low side effect profile and the paucity of information in the literature about this common mineral suggest that more studies should be conducted to determine its safety and efficacy. The majority of human trials with magnesium thus far have not been interventional, but based on food questionnaires which may not be accurate and are subject to a recall bias. Further work is also needed to determine the mechanism of action by which magnesium modulates the mineralization and inflammation of the cardiovascular and nervous systems.

Magnesium attenuates chronic hypersensitivity and spinal cord NMDA receptor phosphorylation in a rat model of diabetic neuropathic pain

Magnesium gjør at nervesystemet blir mindre sensitivt i studie på rotter med nevropati. Dosen er beregnet til å være ca 147 mg pr dag (24t), som er veldig mye relativt til kroppsvekten på en mus på 10-20g. Om vi regner det om til menneskevekt blir det megadoser.

Neuropathic pain is a common diabetic complication affecting 8–16% of diabetic patients. It is characterized by aberrant symptoms of spontaneous and stimulus-evoked pain including hyperalgesia and allodynia. Magnesium (Mg) deficiency has been proposed as a factor in the pathogenesis of diabetes-related complications, including neuropathy. In the central nervous system, Mg is also a voltage-dependant blocker of the N-methyl-d-aspartate receptor channels involved in abnormal processing of sensory information. We hypothesized that Mg deficiency might contribute to the development of neuropathic pain and the worsening of clinical and biological signs of diabetes and consequently, that Mg administration could prevent or improve its complications. We examined the effects of oral Mg supplementation (296 mg l−1 in drinking water for 3 weeks) on the development of neuropathic pain and on biological and clinical parameters of diabetes in streptozocin (STZ)-induced diabetic rats. STZ administration induced typical symptoms of type 1 diabetes. The diabetic rats also displayed mechanical hypersensitivity and tactile and thermal allodynia. The level of phosphorylated NMDA receptor NR1 subunit (pNR1) was higher in the spinal dorsal horn of diabetic hyperalgesic/allodynic rats. Magnesium supplementation failed to reduce hyperglycaemia, polyphagia and hypermagnesiuria, or to restore intracellular Mg levels and body growth, but increased insulinaemia and reduced polydipsia. Moreover, it abolished thermal and tactile allodynia, delayed the development of mechanical hypersensitivity, and prevented the increase in spinal cord dorsal horn pNR1. Thus, neuropathic pain symptoms can be attenuated by targeting the Mg-mediated blockade of NMDA receptors, offering new therapeutic opportunities for the management of chronic neuropathic pain.

Diabetes is also the most common pathological state in which secondary magnesium (Mg) deficiency occurs. Indeed, Mg deficiency has been described in 25–30% and 13.5–47.7% of type 1 and type 2 diabetic patients, respectively (Garland, 1992Tossielo, 1996Corsonelloet al. 2000Engelen et al. 2000Rodriguez-Moran & Guerrero-Romero, 2003Pham et al.2007) and its incidence is correlated to diabetes complications (De Leeuw, 2001). Mg is an ATPase allosteric effector involved in inositol transport (Grafton et al. 1992) and the impaired Na+/K+-ATPase activity in peripheral nerves of diabetic animals (Garland, 1992) plays a role in the pathophysiology of diabetic neuropathy (Li et al. 2005).

In the central nervous system, Mg has voltage-dependent blocking properties that play an important role in pain processing at the N-methyl-d-aspartate (NMDA) receptor channel complex (Mayer et al. 1984Xiao & Bennett, 1994Begon et al. 2000). In vitro, this blockade operates at extracellular Mg concentrations of less than 1 mm (Mayer et al. 1984), i.e. within the ranges found in human and animal cerebrospinal fluid and plasma (Morris, 1992). The excess release of glutamate from central nociceptor terminals due to nerve damage releases Mg blockade and activates NMDA receptors known to trigger painful sensations (hyperalgesia, allodynia) and alter the sensitivity of postsynaptic cells, resulting in central sensitization (Bennett, 2000). This central sensitization involving the NMDA receptor can be induced in rats in vivo by Mg depletion (Alloui et al. 2003). Several studies suggest that phosphorylation of the NMDA receptor NR1 subunit is correlated to the presence of signs of neuropathy and to persistent pain following nerve injury (Gao et al.2005Ultenius et al. 2006Gao et al. 2007Roh et al. 2008).

One week after STZ or distilled water injection, the animals were assigned to the following three experimental groups:

  • MgSO4-supplemented STZ-D group: STZ-D rats receiving MgSO4 (296 mg l−1 of Mg) in drinking water for 3 weeks,
  • Non-supplemented STZ-D group: STZ-D rats given tap water,
  • Control non-diabetic group: rats given tap water.

Water intake was 10-fold and sixfold higher in non-supplemented and MgSO4-supplemented STZ-D rats, respectively, compared with non-diabetic rats. Water intake was significantly lower in MgSO4-supplemented STZ-D rats than non-supplemented STZ-D rats (Table 1). Consequently, urine excretion was 24-fold higher in non-supplemented STZ-D rats than non-diabetic rats. The MgSO4-supplemented STZ-D rats also developed polyuria corresponding to a 15-fold increase in urine excretion compared with non-diabetic rats, but which was nevertheless lower than the increase in non-supplemented STZ-D rats (Table 1). Polyuria in STZ-D rats was significantly correlated to water intake (P < 0.001).

Parameter Non-diabetic Non-suppl. STZ-D MgSO4-suppl. STZ-D
Water intake (ml (24 h)−1) 35.22 ± 2.36 376.6 ± 32.87*** 214.4 ± 30.87***,###
Urine excretion (ml (24 h)−1) 12.45 ± 1.51 300.1 ± 24.16*** 184.4 ± 25.23***,##
Food intake (g (24 h)−1) 30.7 ± 1.83 54.66 ± 3.67** 42.06 ± 6.21
Total Mg intake (mg (24 h)−1) 61.40 ± 3.66 109.32 ± 7.34*** 147.58 ± 1.58***,###

Figure 4: Time course of mechanical sensitivity measured by paw pressure-induced vocalization threshold (VT) variations in non-diabetic (Non-D), non-supplemented STZ-diabetic (Non-suppl. STZ-D) and MgSO4-supplemented (MgSO4-suppl. STZ-D) rats

Parameter Non-diabetic Non-suppl. STZ-D MgSO4-suppl. STZ-D
Tactile hypersensitivity
Week 2 0/10 3/10 0/10#
Week 4 0/10 6/10* 0/10#
Thermal hypersensitivity
Week 2 0/10 6/10* 0/10#
Week 4 0/10 6/10* 0/10#

This study clearly showed that Mg supplementation prevents tactile and thermal allodynia and attenuates and delays mechanical hyperalgesia in STZ-D rats. This effect was mediated, at least in part, by the prevention of NMDA receptor NR1 subunit phosphorylation in STZ-D rats. However, the study also showed that Mg supplementation did not improve most of the biological and clinical signs of diabetes despite restoration of normal insulin secretion.