Magnesium sulfate treatment alters fetal cerebellar gene expression responses to hypoxia.

Prenatal perturbation of brain circulation and oxygenation is a leading cause of perinatal brain damage affecting about 0.3-0.9% of births. Hypoxia-ischemia (HI) in preterm human infants at gestational week 23-32 results in neurodevelopmental abnormalities in childhood, presenting as learning disability, seizure activity, motor impairment and in the most severe cases, death. Here, we examined the potential of MgSO4 treatment, prior to foetal hypoxia, to attenuate hypoxia induced damage in a murine model of maternal hypoxia. We studied the time course of maternal hypoxia and MgSO4 pre-treatment effects on cerebellar tissue by means of DNA microarray analyses. Mild hypoxia induced minor expression changes in most genes. However, there were 5 gene sets which were down-regulated by maternal hypoxia. MgSO4 pre-treatment abrogated these decreases in gene. A cell cycle gene set which responded immediately (2 h) to hypoxia, showed a delayed response (24 h) when MgSO4 pre-treatment was given. Similar proportions of cell death were observed in all groups before P7, where combined hypoxia and MgSO4 treatment increased cell death in the internal granule layer. There were a higher number of BrdU positive cells at the end of hypoxic episodes and a down-regulation of Reelin signaling, compared to control. MgSO4 pre-treatment prevented the enhancement of cell proliferation due to hypoxia and increased Reelin levels. Altogether, MgSO4 pre-treatment both reduced the number of genes differentially affected by hypoxia and delayed the responses to hypoxia. In addition, MgSO4 pre-treatment modified the nature of the transcriptional response; while hypoxia induced down-regulation of gene sets, MgSO4 pre-treatment mostly up-regulated them. The dual reaction to the MgSO4 treatment may be the source of the ambiguity in observations reported for affected newborns.

Impaired migration signaling in the hippocampus following prenatal hypoxia.

Prenatal hypoxia ischemia is a major cause of neurodevelopmental impairment in the newborn, associated with risk for motor, behavioral and cognitive impaired outcomes. We used an established mouse model of maternal hypoxia to examine the immediate molecular responses of signaling pathways associated with both cell death and neurogenesis. We also characterized responses to maternal pre-treatment with MgSO(4). Maternal hypoxia at embryonic day 17 (E17) failed to trigger inflammation or cell death in fetal brain at 24 h after hypoxia. However, maternal hypoxia decreased levels of neuronal migration signaling: Reelin (53% of control), Disabled 1 (Dab1, 77% of control), and amyloid precursor protein (APP, 64% of control) 2 h after the insult. These changes persisted for 24 h. At later times, Reelin levels in hippocampi of newborns in the maternal hypoxia-treated group increased compared to controls. Full protection from maternal hypoxia effects on hippocampal Reelin levels resulted from maternal pre-treatment with MgSO(4). Hypoxia and MgSO(4) increased radial and lateral migration distance in the CA1 four days after the insult, while in the DG the hypoxia treatment alone increased migration. Maternal hypoxia and MgSO(4) pre-treatment also stimulated hippocampal expression of genes related to neurogenesis, such as BDNF and NeuroD4. Taken together, the long-term neurodevelopmental outcome of prenatal and perinatal hypoxia may depend on perturbation of developmental signals that affect neuronal migration.