Magnesium induces preconditioning of the neonatal brain via profound mitochondrial protection

Magnesium sulphate (MgSO 4 ) given to women in preterm labor reduces cerebral palsy in their offspring but the mechanism behind this protection is unclear, limiting its effective, safe clinical implementation. Previous studies suggest that MgSO 4 is not neuroprotective if administered during or after the insult, so we hypothesised that MgSO 4 induces preconditioning in the immature brain. Therefore, we administered MgSO 4 at various time-points before/after unilateral hypoxia-ischemia (HI) in seven-day-old rats. We found that MgSO 4 treatment administered as a bolus between 6 days and 12 h prior to HI markedly reduced the brain injury, with maximal protection achieved by 1.1 mg/g MgSO 4 administered 24 h before HI. As serum magnesium levels returned to baseline before the induction of HI, we ascribed this reduction in brain injury to preconditioning. Cerebral blood flow was unaffected, but mRNAs/miRNAs involved in mitochondrial function and metabolism were modulated by MgSO 4 . Metabolomic analysis (H + -NMR) disclosed that MgSO 4 attenuated HI-induced increases in succinate and prevented depletion of high-energy phosphates. MgSO 4 pretreatment preserved mitochondrial respiration, reducing ROS production and inflammation after HI. Therefore, we propose that MgSO 4 evokes preconditioning via induction of mitochondrial resistance and attenuation of inflammation.