Fetal Hypoxic Brain Damage, Molecular Mechanism and Prevention by Magnesium Sulfate

Fetal hypoxic brain damage and its prevention by magnesium sulfate – scanning for a molecular mechanism.

Principal Investigators: Dr. Hava M. Golan and Prof. J. Regino Perez-Polo.

Abstract The association between hypoxia and fetal brain damage is well described and has been proven. However, little is known regarding the molecular pathways leading to long-term modification in brain function and subsequent impairments after the insult.

Our goal was to screen for genes whose expression was modified in the embryo brain due to a hypoxic episode and to compare this response to that of embryo brains exposed maternally to MgSO4, commonly used therapeutically in pregnant women. Our specific aims were: A comparative study was performed using Affymetrix DNA MicroArrays. These results were validated by Real-Time PCR, western blot assay analyses, and immunohistochemistry.

Gene-set-enrichment-analysis indicated that maternal hypoxia significant down-regulate cell-cycle gene-set, while pretreatment with MgSO4 induced up-regulation of cell-cycle gene-set, moreover MgSO4 treatment delayed the response of cell cycle genes to hypoxia. Maternal hypoxia induced cell proliferation and altered migration in the cerebellum as validated by analysis of newly born cells (BrdU+). Only partial protection was achieved by MgSO4 treatment in the cerebellum. Finally, different aspects of impairment in the GABA pathway were found in the cerebellum, hippocampus and cerebral cortex suggesting disproportion of excitation- inhibition balance.

Our results suggest that deficient neural migration and GABA pathway may serve the underline mechanism of brain damage following maternal hypoxia. These analyses also support the use of MgSO4 as therapeutic agent but emphasize the need to optimize the drug regimen in order to reduce unwanted effects and increase benefit for patient in its clinical use.