Abstract
MgSO4 is widely used in the prevention of preterm neurological disabilities but its modes of action remain poorly established. We used a co-hybridization approach using the transcriptome in 5-day old mice treated with a single dose of MgSO4 (600 mg/kg), and/or exposed to hypoxia-ischemia (HI). The transcription of hundreds of genes was altered in all the groups. MgSO4 mainly produced repressions culminating 6 h after injection. Bio-statistical analysis revealed the repression of synaptogenesis and axonal development. The putative targets of MgSO4 were Mnk1 and Frm1. A behavioral study of adults did not detect lasting effects of neonatal MgSO4 and precluded NMDA-receptor-mediated side effects. The effects of MgSO4 plus HI exceeded the sum of the effects of separate treatments. MgSO4 prior to HI reduced inflammation and the innate immune response probably as a result of cytokine inhibition (Ccl2, Ifng, interleukins). Conversely, MgSO4 had little effect on HI-induced transcription by RNA-polymerase II. De novo MgSO4-HI affected mitochondrial function through the repression of genes of oxidative phosphorylation and many NAD-dehydrogenases. It also likely reduced protein translation by the repression of many ribosomal proteins, essentially located in synapses. All these effects appeared under the putative regulatory MgSO4 induction of the mTORC2 Rictor coding gene. Lasting effects through Sirt1 and Frm1 could account for this epigenetic footprint.
Highlights
Magnesium appears to be a potent tool for the prevention of cerebral palsy and resulting disabilities when administered as MgSO4 to women in danger of preterm delivery before 33 completed weeks of gestation (GWs) [1,2,3,4]
Its putative effects resulting in fetal neuroprotection are very numerous, and its actual modes of action remain elusive
Transcriptome were performed performedon onthe the basis of three independent experiExperiment compared the effects of single injection to phosphate buffered saline ments
Summary
Magnesium appears to be a potent tool for the prevention of cerebral palsy and resulting disabilities when administered as MgSO4 to women in danger of preterm delivery before 33 completed weeks of gestation (GWs) [1,2,3,4]. MgSO4 used as a tocolytic did not prove to have efficiency in retarding delivery, but retrospectively it has shown neuroprotection effects at low doses [5,6]. The Mg2+ ion has innumerable biological targets e.g., as co-factor in nucleic acid biology, protein synthesis, enzymatic systems, or protein–. Its putative effects resulting in fetal neuroprotection are very numerous, and its actual modes of action remain elusive. Given at neuroprotective (low) doses, MgSO4 has no deleterious side effects, which is a requirement for prophylactic treatment. Owing to its large spectrum of putative effects, it appears necessary to strengthen the evidences of its harmlessness at neuroprotection doses, since high doses of
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