Increased extracellular magnesium modulates proliferation in fetal neural cells in culture

Retrospective studies have shown that antenatal magnesium may decrease the risk of cerebral injury in preterm infants, leading to several ongoing tria ls of tocolytic magnesium as a neuroprotective agent. However, other studie s have indicated that antenatal magnesium actually increases neonatal morta lity, leaving it unclear if magnesium is protective or dangerous to preterm infants. This controversy may be secondary to our limited understanding ab out the mechanisms of magnesium's action on the fetal brain. We therefore i nvestigated the effect of increasing extracellular magnesium on cultures of neurons from embryonic day 6 telencephalon. Conversion of MTT (3-(4,5-dime thyl, thiazol-2-yl)-2,5-diphenyltetrazolium bromide) by intact mitochondria was taken as a measure of cell viability. Nuclear incorporation of BrdU (5 -bromo-2'-deoxyuridine) was taken as a measure of cell proliferation. Expos ure of cultures for 24 h to a 4-fold increase iu magnesium (3.3 mM) increas ed both overall cell viability (P<0.002) and proliferation (P<0.02) by appr oximately 50%. Proliferating cells showed characteristics of glial cell pre cursors but magnesium had no effect on mature astrocyte proliferation. Incr eased Akt activation was observed following magnesium treatment, comparable to that observed with the growth factor insulin, suggesting one mechanism for proliferation. However, when apoptosis was induced in these cultures wi th the phosphatidylinositol-3-kinase inhibitor wortmannin, magnesium signif icantly enhanced cell death. Thus under normal conditions in the fetus, mag nesium may be a positive factor but during stress it may exacerbate cell in jury. This is the first time increased extracellular magnesium has been sho wn to increase cell proliferation in neural cells in culture or suggested t o induce Akt activation. (C) 2001 Elsevier Science B.V. All rights reserved .