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

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.