title: Increased extracellular magnesium modulates proliferation in fetal neural cells in culture.
abstract: Retrospective studies have shown that antenatal magnesium may decrease the risk of cerebral injury in preterm infants, leading to several ongoing trials of tocolytic magnesium as a neuroprotective agent. However, other studies have indicated that antenatal magnesium actually increases neonatal mortality, leaving it unclear if magnesium is protective or dangerous to preterm infants. This controversy may be secondary to our limited understanding about the mechanisms of magnesium's action on the fetal brain. We therefore investigated the effect of increasing extracellular magnesium on cultures of neurons from embryonic day 6 telencephalon. Conversion of MTT (3-(4,5-dimethyl, 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. Exposure of cultures for 24 h to a 4-fold increase in magnesium (3.3 mM) increased both overall cell viability (P<0.002) and proliferation (P<0.02) by approximately 50%. Proliferating cells showed characteristics of glial cell precursors but magnesium had no effect on mature astrocyte proliferation. Increased 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 with the phosphatidylinositol-3-kinase inhibitor wortmannin, magnesium significantly enhanced cell death. Thus under normal conditions in the fetus, magnesium may be a positive factor but during stress it may exacerbate cell injury. This is the first time increased extracellular magnesium has been shown to increase cell proliferation in neural cells in culture or suggested to induce Akt activation.
authors.affiliation: Department of Pediatric, University of Chicago, MC 5058, 5825 South Maryland Avenue, Chicago, IL 60637, USA. richard..krueger@cshs.org
authors.forename: R C
authors.initials: RC
authors.lastname: Krueger
authors.forename: M T
authors.initials: MT
authors.lastname: Santore
authors.forename: G
authors.initials: G
authors.lastname: Dawson
authors.forename: N B
authors.initials: NB
authors.lastname: Schwartz
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002642:Chick Embryo; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D005333:Fetus / Q000166:cytology / Q000201:enzymology; D008274:Magnesium / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology* / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D004791:Enzyme Inhibitors; D008274:Magnesium; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin