title: High dose magnesium sulfate exposure induces apoptotic cell death in the developing neonatal mouse brain.
abstract: BACKGROUND
  Magnesium sulfate (MgSO4) is often used as a treatment for pre-eclampsia/eclampsia and preterm labor, resulting in the exposure of a significant number of neonates to this drug despite a lack of evidence suggesting that it is safe, or effective as a tocolytic. While there is evidence that MgSO4 may be neuroprotective in perinatal brain injury, recent reviews have suggested that the effects are dependent upon dose, and that higher doses may actually increase neonatal morbidity and mortality. There is a lack of evidence investigating the neurotoxic effects of neonatal magnesium (Mg) exposure on the developing brain, specifically in terms of neurodevelopmental apoptosis, a cell-killing phenomenon known to be potentiated by other drugs with mechanisms of action at Mg-binding sites (i.e. NMDA receptor antagonists such as MK-801, ketamine, and PCP).
  
  
  OBJECTIVE
  To investigate the effects of Mg exposure on the neonatal mouse brain at different postnatal ages to determine whether MgSO4 treatment causes significant cell death in the developing mouse brain.
  
  
  METHODS
  C57Bl/6 mice were treated with four doses of MgSO4 (250 mg/kg) on postnatal days 3 (P3), 7 (P7) or 14 (P14). Caspase-3 immunohistochemistry, cupric silver staining, and electron microscopy techniques were used to examine Mg-treated brains for neurotoxic effects.
  
  
  RESULTS
  Qualitative evaluation using cupric silver staining revealed widespread damage throughout the brain in P7 animals. Results of electron microscopy confirmed that the cell death process was apoptotic in nature. Quantitative evaluation of damage to the cortex, caudate-putamen, hippocampus, thalamus, and cerebellum showed that Mg treatment caused significant brain damage in animals treated on P3 and P7, but not P14.
  
  
  CONCLUSIONS
  Administration of high doses of Mg may be detrimental to the fetal brain, particularly if exposure occurs during critical periods of neurodevelopment.
authors.affiliation: Division of Emergency Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Dribben
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Creeley
authors.forename: Hai Hui
authors.initials: HH
authors.lastname: Wang
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Smith
authors.forename: Nuri B
authors.initials: NB
authors.lastname: Farber
authors.forename: John W
authors.initials: JW
authors.lastname: Olney
mesh_terms: D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development*; D053148:Caspase 3 / Q000032:analysis; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D003300:Copper; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007150:Immunohistochemistry; D008278:Magnesium Sulfate / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D012834:Silver; D013194:Staining and Labeling; D013788:Thalamus / Q000166:cytology / Q000187:drug effects
chemical_list: D012834:Silver; D008278:Magnesium Sulfate; D003300:Copper; D053148:Caspase 3