Magnesium ions and ionic channels: activation, inhibition or block--a hypothesis.

The interactions between magnesium ions and ionic membrane channels are complicated and may be classified in three categories: activation, reduction and inhibition of the ionic fluxes across the channels, corresponding to three mechanisms: open-block-close. The interactions between magnesium ions and various ionic channels are reviewed and the explanations of the three mechanisms are analyzed in term of screening/binding effects on the membrane surface polar head groups.

Headache due to photosensitive magnesium depletion.

Clinical and paraclinical data (visual stress tests, electroencephalographic and cerebrovascular photic driving, visual evoked potentials) demonstrate that the concept of photosensitive headache is fully justified. The interictal hallmark of photosensitive cephalalgic patients is potentiation (or sensitization) instead of habituation. The aetiopathogenic mechanisms of photosensitive headache associate hypofunction of the biological clock and magnesium depletion. The new concept of headache due to photosensitive magnesium depletion seems justified. It appears logical to add the treatments of magnesium depletion and of photosensitivity to classical treatment of headache. Prophylactic magnesium treatment relies on atoxic nutritional magnesium supplementation in case of primary magnesium deficiency. Pharmacological doses of parenteral magnesium may be used but may induce toxicity. Therefore it is necessary to know the therapeutic index of magnesium compound used: the larger its value, the greater the safety margin. Treatment of photosensitivity uses various types of <>: darkness therapy through physiologic, psychotherapic, physiotherapic, pharmacologic stimulating techniques and substitutive darkness therapy through palliative treatment. Melatonin is only a partial substitutive treatment of photosensitivity. A new model of photosensitive magnesium depletion with potentiation should be a useful tool for discriminating the most efficient gent.

New data on the importance of gestational Mg deficiency.

Chronic primary Mg deficiency is frequent. Around 20% of the population consumes less than two-thirds of the RDA for Mg, in both genders and in women particularly: for example, in France, 23% of women and 18% of men. Primary Mg deficiency may occur in fertile women. Gestational Mg deficiency is able to induce maternal, fetal, and pediatric consequences which might last throughout life. Experimental studies of gestational Mg deficiency show that Mg deficiency during pregnancy may have marked effects on the processes of parturition and of postuterine involution. It may interfere with fetal growth and development from teratogenic effects to morbidity: i.e. hematological effects and disturbances in temperature regulation. Clinical studies on the consequences of maternal primary Mg deficiency in women have been insufficiently investigated. To check the validity of the role of this frequent gestational Mg deficiency, the protocol of a long term multicentric placebo controlled prospective study on the effects of maternal nutritional Mg supplementation on lethality and morbidity in fetus, neonates, infants, children and adults should be carried out not only during pregnancy and the first year of life, but throughout life. Two clinical forms of chronic gestational Mg deficiency in women have been stressed: Premature labor when chronic maternal Mg deficiency is involved in uterine hyperexcitability, Sudden Infant Death Syndrome (SIDS) when it is caused by either simple Mg deficiency or various forms of Mg depletion. Nutritional Mg treatment of premature labor. If gestational Mg deficiency is the only cause for uterine overactivity, nutritional Mg supplementation constitutes the etiopathogenic atoxic tocolytic treatment. But although it is an adjuvant factor in premature labor, it is only a useful accessory treatment, devoid of toxicity but which increases the effectiveness and safety of the associated tocolytic drugs such as beta-2 mimetics. SIDS due to gestational Mg deficit: Mg deficiency or various forms of Mg depletion. SIDS may be caused by the fetal consequences of maternal Mg deficiency through an impaired control of Brown Adipose Tissue (BAT) thermoregulation, mechanisms leading to a modified temperature set point. SIDS may result from dysthermias: hypo- or hyperthermic forms. A possible prevention could rest on simple maternal nutritional Mg supplementation. Various stresses in pregnant women or in the infant may transform a simple Mg deficiency into Mg depletion: stress in baby care such as bedding in prone position, environmental factors such as parental smoking, but the role of chronopathological stress particularly appears to be too often neglected as it constitutes a clinical form of primary hypofunction of the biological clock [with its anatomical and clinical stigma such as reduced production of melatonin (MT) and of its urinary metabolite: 6 Sulfatoxy-Melatonin (6 SMT)]. SIDS might be linked to an impaired maturation of both the photoneuroendocrine system and BAT. A preventive treatment of this form of SIDS should associate atoxic nutritional Mg therapy for pregnant women with total light deprivation at night for the infant. The place of Mg therapy for the infant and of MT, L Tryptophan and taurine is uncertain for the moment.

Magnesium research: from the beginnings to today.

The beginnings of magnesium research, from the 18th century to the first quarter of the twentieth century, consists mainly of the development of chemical and pharmacological knowledge. The modern period began in 1926 when the essential character of magnesium was acknowledged. The early part of the modern period, up to the 1960s, saw the foundation of our knowledge of the basic physiological, epidemiological and clinical aspects. The present modern period began in 1971 with the First International Symposium on Magnesium and the subsequent creation of SDRM (the international Society for the Development of Research on Magnesium), an international coordinating structure, which promotes the publication of magnesium books (volumes of proceedings and monographs) and of journals: Magnesium Research the international official organ of SDRM and several national journals: the Journal of Japanese Society for Magnesium Research (Japan), the Buletin informativ al societatii romane de cercetare a magneziului (Romania), the Journal of Elementology (Poland) and which regularly organizes national and international meetings. The next great international meeting will be held on October 23-26, 2006 in Osaka (Japan). We will discuss the latest research findings on magnesium in health and disease. The subject shows that today magnesium research remains active in basic sciences and embraces all the facets of pathology.

Elemental maps in human allantochorial placental vessels cells: 2. MgCl2 and MgSO4 effects.

Extracellular magnesium salts are known to interfere with ionic channels in the cellular membranes. The membrane potential, a regulator of vascular tone, is a function of the physiological activities of ionic channels (particularly, K+ and Ca2+ channels in these cells). These channels regulate the ionic distribution into these cells. Micro-Particule Induced X-ray Emission (PIXE) analysis was applied to determine the ionic composition of vascular smooth muscle cells (VSMC) and of vascular endothelial cells (VEC) in the placental human allantochorial vessels in a physiological medium (Hanks' solution) modified by the addition of 2 mM MgCl2 or 2 mM MgSO4 which block the calcium-sensitive K+ channels (K(Ca)), the ATP-sensitive K+ channels (K(ATP)) and the voltage-sensitive K+ (K(df)) and Ca2+ channels. In VSMC (media layer), the addition of MgCl2 induced no modification of the K, Cl, P, S and Ca concentrations but increased the Na and Mg concentrations and the addition of MgSO4 only significantly increased the Mg concentration, the other ion concentrations remaining constant. In endothelium (VEC), MgCl2 or MgSO4 addition implicated the same observations as in VSMC. These results confirmed the blockage of K(df), K(Ca), K(ATP) and Ca channels in VSMC and VEC by magnesium salts, the relationship between Mg2+ ions and internal Na and demonstrated the possible intervention of a Na+/Mg2+ exchanger.

Beta-2 mimetics and magnesium: true or false friends?

Physiological beta stimulation may be involved in the regulation of magnesium status namely by homeostatic increase of magnesemia during magnesium deficiency. But conversely excessive beta stimulation namely by use of pharmacological high doses of beta mimetics may induce a decrease of magnesemia. Two different types of magnesium therapy ought to be distinguished. Nutritional magnesium therapy which may physiologically palliate a magnesium deficiency due to an insufficient magnesium intake. It is devoid of any toxicity. Pharmacological magnesium therapy, whatever the magnesium status, causes a iatrogenic magnesium load. It may induce magnesium toxicity. Tocolysis is the one common obstetrical indication for beta mimetics and magnesium. Beta-2 mimetics are the reference tocolytic drugs in most countries. But high doses of beta-2 mimetics for suppression of premature labor are associated to a high incidence of maternal, fetal and neonatal side effects. Tocolysis must then be discontinued or limited to shorter treatments with the lowest possible doses. Nutritional magnesium therapy which palliates gestational magnesium deficiency is efficient and atoxic. Conversely, high doses of intravenous MgSO4 for tocolysis are less efficient and unsafe. Because of its maternal and above all pediatric side effects, this maternal pharmacological magnesium therapy should be abandoned for tocolysis. Investigation of the therapeutic ratio of various magnesium salts before their clinical use could help to determine if other anions different from sulfate could decrease the toxicity. Beta-2 agonists are first line asthma therapy, but their safety is debated. Asthma and Chronic Obstructive Pulmonary Disease (COPD) per se may induce magnesium depletion related to a dysregulation of the control mechanisms of magnesium status. It requires a correction of its causal regulation, but nutritional magnesium supplementation is ineffective. When chronic primary magnesium deficiency coexists with obstructive bronchial disorders, it constitutes a decompensatory factor. Atoxic nutritional magnesium therapy may palliate this coexistent magnesium deficiency. Pharmacological magnesium treatment for obstructive pulmonary diseases is not very efficient with low safety. Combination of palliating nutritional magnesium therapy and of beta-2 mimetics for tocolysis or pulmonary obstructive indications may be beneficial and remain atoxic. Conversely combination of intravenous tocolytic high doses of magnesium and of beta-2 mimetics is contra-indicated because of its dubious efficiency and its possible toxicity. The possible role of SO4- as regards toxicity must be discussed. Contra-indications of lower intravenous or inhaled Mg doses for pulmonary bronchial obstruction are less imperative than for tocolysis. The selection of a particular magnesium salt among others should take into account reliable plasmacological and toxicological data. It seems necessary to determine the therapeutic ratio (LD50/ED50) of the various available magnesium salts before pharmacological use.

Physiological importance of the connective tissue in the human amnion. Role of magnesium.

The elemental ionic distribution in the epithelial layer (EL) and in connective tissue (CT = compact layer + fibroblast layer) of the human amniotic membrane has been studied in reference samples, after conservation in a physiological fluid (Hanks' solution) and after addition of 2 mM MgCl2 in Hanks' solution. Particle induced X-ray emission and Rutherford backscattering spectrometry techniques were used to provide quantitative measurements. In physiological fluid, with regard to reference samples, the monovalent ions (Na+, K +, Cl-) concentrations were identical on both layers. This data indicates that the connective tissue, in particular the compact layer, acts as a buffer which fix minerals. Mg2+ and Ca2+ levels were higher in EL than in CT. The addition of MgCl2 in Hanks' solution induced a decrease of the monovalent ion concentrations in both layers except Na+ level in EL which remained constant, an increase of the Mg2+ level in both layers, while the Ca2+ remained constant. These data indicate the possible role of connective tissue in pregnancies complicated by poly or oligohydramnios.

Biorhythms and possible central regulation of magnesium status, phototherapy, darkness therapy and chronopathological forms of magnesium depletion.

Biological clock and magnesium status are linked. Central magnesium regulation may be hypothetized. Balanced magnesium status is requested to obtain efficiency of suprachiasmatic nuclei and of pineal gland. Conventional bright light therapy appears as a speedy and efficient antidepressant medication useful for the treatment of various types of depression, and of non migrainous headaches also. Although decrease in melatonin production seems accessory, increases of serotonergy and perhaps of Reactive Oxygen Species constitute the main mechanisms of action. Chromatotherapy emphazizes the effects of short exposure to specific colors. Although the increased production of melatonin constitutes the best marker of darkness, it is only an accessory mechanism of its action. The psycholeptic sedative effects of darkness, like those of magnesium, rely on direct membraneous and oxidant actions, neural mediated effects (i.e. stimulation of inhibitory neuromodulators such as GABA and taurine), and on antagonism of neuroactive gases (CO and NO). Darkness therapyper se, partial substitutive therapy with melatonin and with their mimicking agents (Mg, L-Tryptophan,Taurine) apply to all the chronopathological forms of magnesium depletion with decreased production of melatonin: sleep disorders, migraine, chronic fatigue syndrome, fibromyalgia, some forms of asthma and of sudden infant death syndrome. Further research should assess the importance of the chronopathological forms of magnesium depletion in the physiopathology of these disorders.

Metal pollutants and bioelements: retrospective of interactions between magnesium and toxic metals.

Protection from heavy metals is a problem that has not been solved in a satisfactory manner so far. Usage of complexing agents in therapy of exposed workers results in both favorable outcome and recognized adverse effects. In the field of environmental protection, they cannot be used in practice, meaning that the risk of escape of metal pollutant from factory premises and their attack on the environnement remains present. The age of chemistry ('Chemistry, key to better living') has led to potent development of industry producing, at the same time, major problems induced by diffusion of metal pollutants, the nightmare of our times, like Camus' 'Plague'. According to the available results, it remains to be answered whether magnesium may influence this important problem, i.e. is this approaches the issue justifiable?

Magnesium deficit and sudden infant death syndrome (SIDS): SIDS due to magnesium deficiency and SIDS due to various forms of magnesium depletion: possible importance of the chronopathological form.

Sudden Infant Death Syndrome (SIDS) might be due to the fetal consequences of a Mg maternal deficiency, which might be prevented by simple atoxic nutritional Mg intake by the mother. Various stresses in the pregnant women or in the infant may transform a simple Mg deficiency into Mg depletion which may not be cured by nutritional Mg supplement, but requires a correction of its causal dysregulation. Beside the well established risk factors in baby care and in the environment, it is important to stress the possible role of a primary hypofunction of the biological clock. This may be treated by darkness therapy: total light deprivation at night for the infant and atoxic nutritional Mg supplement for the pregnant women. The place in the prevention of SIDS of Mg therapy for the infant and of the use of melatonin, L-tryptophan and taurine is now uncertain yet.

Evidence of K and Ca channels in endothelial cells of human allantochorial placental vessels.

Presence of ionic channels was evaluated in human endothelial cells (ECs) from allantochorial placental vessels by the measure of the membrane potential, the main factor of the excitation-contraction coupling. To characterize endothelial cell channels, vasoactive and vasorelaxant agents and channels blockers were used. In predepolarized cells by high-K+ concentration, the voltage-dependent K+ channels (Kdf) were blocked. Acetylcholine, sodium nitroprusside and isoproterenol hyperpolarized the predepolarized-high K+ ECs. This hyperpolarization was inibited by charybdotoxin (a blocker of big Ca(2+)-activated K+ channels) or/and by tetraethylammonium and was insensitive to glibenclamide (a blocker of ATP-sensitive K+ channels). Serotonin depolarized ECs and the depolarization was inibited by nifedipine, a blocker of voltage-gated Ca2+ channels. These results indicated that membrane potential of human placental allantochorial ECs was regulated by voltage-gated, C(2+)-sensitive K+ channels and by voltage-gated Ca2+ channels.