Magnesium sulfate treatment alters fetal cerebellar gene expression responses to hypoxia

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.

Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies

“…The possible mechanism may be mainly due to the fact that MgSO 4 can bind to the magnesium site on N -methyl- d -aspartate (NMDA) glutamate channels, inhibiting free radical production, and stabilizing the cell membrane [72,73,74,75]. There is now evidence from meta-analyses of randomized controlled trials that antenatal administration of MgSO 4 is associated with a small but significant reduction in the risk of cerebral palsy and gross motor dysfunction after preterm birth [76,77].…”

Unraveling the ischemic brain transcriptome in a permanent middle cerebral artery occlusion mouse model by DNA microarray analysis

“…Over the last decade, and particularly within the last 3 years, researchers have begun focusing their attention on genomic approaches to investigate brain ischemia and physiological responses to it (Jin et al, 2001; Büttner et al, 2008; Meschia, 2008; Qin et al, 2008; Juul et al, 2009; Grond-Ginsbach et al, 2009; Haramati, 2009; Nakajima, 2009; Popa-Wagner et al, 2009; Yao et al, 2009; Di Pietro et al, 2010; Pruissen et al, 2009; Stamova et al, 2010; Zhan et al, 2010). These studies have shown the importance of high-throughput transcript profiling, such as the DNA microarray technique (DeRisi et al, 1997), for gaining insight into the ischemic brain.…”

Early Postnatal Exposure to Intermittent Hypercapnic Hypoxia (IHH), but Not Nicotine, Decreases Reelin in the Young Piglet Hippocampus

“…As previously mentioned, most animal studies show that exposure to hypoxia is associated with decreased reelin expression in the brain (Golan et al 2009;Haramati et al 2010;Komitova et al 2013;Pillai 2014, 2016;Nisimov et al 2018).…”