Experimental and clinical evidence of differential effects of magnesium sulfate on neuroprotection and angiogenesis in the fetal brain

Abstract

Clinical studies showed beneficial effects of magnesium sulfate regarding the risk of cerebral palsy. However, regimen protocols fluctuate worldwide and risks of adverse effects impacting the vascular system have been reported for human neonates, keeping open the question of the optimal dosing. Using clinically relevant concentrations and doses of magnesium sulfate, experiments consisted of characterizing, respectively, ex vivo and in vivo, the effects of magnesium sulfate on the nervous and vascular systems of mouse neonates by targeting neuroprotection, angiogenesis, and hemodynamic factors and in measuring, in human fetuses, the impact of a 4‐g neuroprotective loading dose of magnesium sulfate on brain hemodynamic parameters. Preclinical experiments using cultured cortical slices from mouse neonates showed that the lowest and highest tested concentrations of magnesium sulfate were equally potent to prevent excitotoxic‐induced cell death, cell edema, cell burst, and intracellular calcium increase, whereas no side effects were found regarding apoptosis. In contrast, in vivo data revealed that magnesium sulfate exerted dose‐dependent vascular effects on the fetal brain. In particular, it induced brain hypoperfusion, stabilization of Hif‐1α, long‐term upregulation of VEGF‐R2 expression, impaired endothelial viability, and altered cortical angiogenesis. Clinically, in contrast to 6‐g loading doses used in some protocols, a 4‐g bolus of magnesium sulfate did not altered fetal brain hemodynamic parameters. In conclusion, these data provide the first mechanistic evidence of double‐sword and dose‐dependent actions of magnesium sulfate on nervous and vascular systems. They strongly support the clinical use of neuroprotection protocols validated for the lowest (4‐g) loading dose of magnesium sulfate.

Protection of brain development by antenatal magnesium sulphate for infants born preterm

“…Indeed, high doses of magnesium sulphate were implicated in the excess of mortality observed in the infants exposed to magnesium in the MAGnet trial, as well as in the occurrence of vasculopathy. Combined with the results of the preclinical study of Lecuyer et al, the individual personal data meta‐analysis results support the use of magnesium sulphate in low doses.…”

“…In cortical slices of mice pups, a dose‐dependent deleterious effect of magnesium sulphate on cerebral angiogenesis was noted. An elevated dosage of magnesium sulphate (not achieved using human protocols) induced brain hypoperfusion, and affected cortical angiogenesis and endothelial cell survival …”

“…An elevated dosage of magnesium sulphate (not achieved using human protocols) induced brain hypoperfusion, and affected cortical angiogenesis and endothelial cell survival. 19 Thus, although the full effects of magnesium sulphate are not yet well understood, magnesium clearly exerts antiinflammatory and anti-excitotoxic effects that could underlie its neuroprotective properties. However, the sex-specific actions and deleterious impact when used at high dosage need to be confirmed with other experimental studies.…”

The Effect of Antenatal Neuroprotective Magnesium Sulfate Treatment on Cerebral Oxygenation in Preterm Infants

“…MgSO 4 was shown to have multiple direct effects on the nervous tissue, such as blockade of NMDA (N-Methyl-d-aspartate) receptors and increasing angiogenesis. 29 Again, one of the significant assumptions is the maintenance of cerebral circulation with a more constant CBF with fewer fluctuations in blood pressure during the early postnatal vulnerable period. 24,25 Additionally, CBF might be augmented by diminishing constriction of cerebral arteries.…”

Description of Hemoproteins and Elemental Homeostasis in Brain Tumors

“…Inositol-3-phosphate signaling system is dominant for maintaining the proliferative activity of embryonic cells, so the increase of calcium concentration, which is a secondary messenger, leads to the activation of this system [12]. In malignant brain tumors magnesium level was reduced, but increased magnesium level has been shown to stabilize and activate hypoxia-inducible factor 1α (HIF-1α), which, in turn, reduces hypoxia-induced effects in the cell [13] [14]. HIF-1α has been shown as a master regulator of hypoxic response [13].…”