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.