19. Rayssiguier Y, Malpuech C, Nowacki W, et al: Evaluation of the inflammatory state during Mg deficiency in the rat (abst.). Magnesium Res., 1994; 7 (Supp. 1): 51.
Smooth muscle cells are the next layer. Smooth muscle cells (SMC’s) provide integrity and control dilation of the arterial cavity. Endothelial cells respond to pressure by releasing agents that cause SMC’s to expand and contract. This controls blood pressure and flow in the artery. One of the earliest signs of magnesium deficiency is degeneration of the subendothelium. Animals with low magnesium diets have been shown to lose the elasticity of their arterial system. Coronary arteries require more elasticity than other arteries because the heart expands and contracts as it beats. Since these arteries are on the heart muscle itself, they too must stretch and flex as the heart beats. Continuing loss of elasticity results in inflammation of the endothelial and subendothelial layers at points that are most mechanically challenged by stretching. Imagine a small rubber-band like tube shaped to form the letter "Y". In your mind's eye grasp the two legs of the Y in one hand. With your other hand, grip the single leg. Begin pulling them apart just as though they were stretching on the surface of the heart. Stretch it as far as you can. Where is the shape weakest? If we left the rubber tube out in the sun for a week or so, what would happen if you slowly stretched it again? Where might you expect the first crack to appear? Maybe not always, but most of the time I believe it would happen at or near where one tube becomes two… at the bifurcation. If your artery loses elasticity does it make sense that the problem might show up at or near the bifurcation?
Pharmacological Mg excess causes some systemic reactions which are not the opposite of physiological effects of Mg. For example pharmacological load of Mg increases release of calcitonin and nitric oxide (NO).9,10 In contrast, physiological Mg supplementation, far from acting similarly, reduces high levels of calcitonin1 (as well as of calcitonin gene-related peptide11and of NO12 released in the case of Mg deficiency.
The great stability of brain Mg during Mg deficiency particularly disagrees with the very notion of extrapolating from in vitro or in situ, extra- or intracellular Mg data1,5 to in vivo physiological data. This leads to suggesting an updated scheme of the factors which cause NHE5: Mg deficiency would induce a diffuse NHE through a neuronal depolarization which derives from the sum of its direct cellular effects in the neural cells and from several mediated reactions.5
Mg deficiency results in three basic effects: disturbances in cellular Ca distribution, decreased second messenger nucleotidic ratio,5 and increased susceptibility to peroxydation.12-14 Through membranous and postmembranous alterations, Mg deficiency brings about a cellular Ca load with subcellular distribution modifications.5 Mg deficiency reduces 3',5'-cyclic adenosine monophosphate (cAMP) concentration and increases 3',5'-cyclic guanosine monophosphate (cGMP) concentration, perhaps through inhibition of adenylate cyclase and activation of guanylate cyclase.5 Mg-deficient animals show an increased susceptibility to in vivo oxydative stress and the tissues of these animals are more susceptible to in vitro peroxydation, affecting lipid particularly.12-14 Protein oxydation in Mg-deficient rat brains occurs early. A significant increase of protein carbonyls is observed within 2 to 3 weeks of a Mg-deficient diet. These changes take place prior to any detectable tissue damage, dysfunction, or changes in cellular glutathione.15
Extrapolating from data observed in vitro, in situ, or in other pharmacological manipulations to the physiological basis of an Mg deficiency simply due to insufficient intake1 remains a methodological error.
Biological plausibility is an important criterion for the establishment of cause and effect relationships. It is necessary to know, for example, whether a postulated association makes biological sense; that is, whether it is possible to elaborate the biochemical and biological links between the suspected causal variable(s) and the illness.15,16 In the postulated association under discussion, the question to be answered must be “is it possible to identify biological mechanisms by which a deficiency of selenium might cause the psychiatric symptoms seen in schizophrenia?” Indeed, several mechanisms linking schizophrenia to selenium deficiency appear feasible.
To illustrate, past theories of schizophrenia suggested that the biological defect in schizophrenia may be related to an excess of dopamine activity, to the production of an abnormal opioid, or excessive levels of a normal opioid, or to hypersensitivity to wheat proteins. It has been hypothesized further that the illness might be linked to an allergic phenomenon, to an inability to metabolize zinc effectively, or to pineal deficiency. Horrobin24 proposed that such hypotheses are not mutually exclusive, but may simply be different dimensions of the same problem. He further suggested that the ultimate common path in schizophrenia is a failure of the formation and action of prostaglandins, particularly those of Series Prostaglandins are short-lived, hormone-like compounds (fat soluble lipids) which regulate cellular activities on a moment to moment basis. They are formed as the result of the controlled oxidation of highly unsaturated fatty acids. Some 30 distinct prostaglandins are known, each with a specific function in the human body, being involved, for example, in the regulation of heart beat, blood flow and the action of the immune system.23 They also occur in the brain in large quantities. Experimental research demonstrated that selenium status has a significant impact on the production and activity of several prostaglandins.25-27 If so, the postulated selenium deficiency-schizophrenia relationship is biologically plausible.
Dr. Jean Durlach has performed many experiments and written papers and books on magnesium deficit and magnesium deficiency. Dr. Burton Altura is also a very well respected expert on this subject with many years of experience. These doctors have worked with credible universities and medical research facilities around the world.
There are, however, other feasible biological mechanisms for such an association. To illustrate, glutathione peroxidase is a selenoenzyme that detoxifies free radicals, which may themselves be important in the pathogenesis of schizophrenia.28 Alternatively, glutathione peroxidase is involved in the arachidonic acid cascade. Selenium supplementation in humans has been shown to allow the reduction of the lipoxygenase-derived 12-hydroperoxy-5, 8, 11, 14 eicosatetraenoic acid (12-HPETE)29 to 12-hydroxy-5, 8, 11, 14 eicosatetraenoic acid (12-HETE). 12-HPETE, therefore, accumulates in selenium deficient individuals.30 This may be highly significant since the arachidonic acid cascade, including 12-HPETE and 12-HETE, is being investigated for its role in modulating N-methyl-D-aspartate-sensitive glutamate receptors, which are thought to be involved in certain neurodegenerative diseases.31 In addition, Schoene and co-workers32 argued that selenium deficiency, and hence decreased glutathione peroxidase activity, impairs platelet activation, thus permitting increased injury from inflammatory agents. Finally, Suttle and Jones33 showed that in selenium-deficient ruminants, inadequate glutathione peroxidase is associated with immune cell dysfunction. Even if such a dysfunction does not directly result in reduced resistance to infection,33 urban crowding and selenium deficiency might promote a viral etiology for schizophrenia, particularly if such a deficiency encouraged continued inflammation and brain damage.13
While viral theories are reviewed elsewhere,34 recent research indicates links between selenium deficiency and enhanced virulence or evolution of several viruses. Beck et al35 demonstrated that while Coxsackie B3 virus was harmless in mice fed normal diets, it quickly produced serious heart damage in selenium deficient rodents. Viruses from affected mice could then cause heart damage even in mice on diets containing adequate selenium. Sequence analysis of the viral genome revealed that mutation to a more virulent form was driven by selenium deficiency.