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3: Magnesium sulfate to prevent adverse neurological injury: providing biological evidence

      Objective

      Recent clinical trials suggest that antenatal exposure to magnesium sulfate (MG) reduces the risk of adverse neurological outcomes in ex-preterm children. About 70% of preterm infants result from spontaneous preterm birth (PTB) which is highly associated with intrauterine inflammation. Using a mouse model of intrauterine inflammation, these studies sought to assess if MG prevents brain injury.

      Study Design

      CD-1 mice on E15-16 were randomized to intrauterine infusion (IU) of LPS or saline (NS). After IU, dams were randomized to intraperitoneal (IP) treatment with MG (270mg/kg X1, then 27mg/kg q20 min for 4 hrs and 2nd dose of 270mg/kg) or equal volumes of NS. From the 4 treatment groups, (IU NS+IP NS; IU LPS+IP NS; IU LPS+IP MG; and IU NS+IP MG), fetal brains (FB) were collected and neuronal cultures were created. Immunocytochemistry and confocal microscopy were performed to assess morphology and number of dendritic processes. FB from the 4 groups were used to investigate mRNA expression of cytokines, cell death, and neuronal and glial differentiation.

      Results

      IL1 mRNA was differentially expressed between the treatment groups (P=0.009); LPS+NS and LPS+MG had increased IL1 levels compared to controls. Markers of pro-oligodendrocytes were altered by LPS+NS but not by LPS+MG (P=0.06). Caspase-1 mRNA was increased 1.3-fold in LPS and 1.6-fold in LPS+MG compared to controls (P=0.03). Neuronal cultures from LPS+NS demonstrated fragility, decreased aggregation, and a reduced number of dendritic processes; this neuronal injury was prevented by MG (*P<0.001, FIG).

      Conclusion

      Prevention of neuronal injury in inflammation-associated PTB may be a key mechanism by which MG prevents cerebral palsy. These studies provide biological plausibility for the clinical use of MG in preterm deliveries.