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Magnesium sulfate treatment alters fetal cerebellar gene expression responses to hypoxia
Ofir Haramati1, Revital Mane, Gabriela Molczadzki
1Department of Developmental Genetics and Virology, Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Insights
Magnesium sulfate (MgSO4) pre-treatment may protect preterm infants from brain damage caused by hypoxia-ischemia. This study found MgSO4 reduced gene expression changes and delayed cellular responses to hypoxia in a mouse model.
Area of Science:
- Neuroscience
- Developmental Biology
- Genomics
Background:
- Prenatal hypoxia-ischemia (HI) causes perinatal brain damage, leading to neurodevelopmental issues in preterm infants.
- This condition affects 0.3-0.9% of births, with severe cases resulting in death.
Purpose of the Study:
- To investigate the neuroprotective potential of magnesium sulfate (MgSO4) pre-treatment against hypoxia-induced brain damage.
- To analyze the effects of MgSO4 on gene expression and cellular responses in a murine model of maternal hypoxia.
Main Methods:
- Utilized a murine model of maternal hypoxia to simulate prenatal oxygen deprivation.
- Employed DNA microarray analysis to examine gene expression changes in cerebellar tissue over time.
- Assessed cell death and proliferation using BrdU labeling.
Main Results:
- Maternal hypoxia induced down-regulation in 5 gene sets; MgSO4 pre-treatment abrogated these changes.
- MgSO4 pre-treatment delayed the cellular response to hypoxia and prevented hypoxia-induced increases in cell proliferation.
- While hypoxia down-regulated gene sets, MgSO4 pre-treatment predominantly up-regulated them, suggesting a complex interaction.
Conclusions:
- MgSO4 pre-treatment demonstrates potential in mitigating hypoxia-induced gene expression alterations and cellular damage in the developing brain.
- The dual transcriptional response to MgSO4 warrants further investigation to understand its impact on neurodevelopmental outcomes.
Abstract:
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.
