Magnesium Preconditioning of the Neonatal Brain

Perinatal brain injury in both term and preterm infants is a paramount clinical problem associated with development of motor impairment, cognitive deficits and neuropsychiatric conditions. Magnesium sulphate (MgSO4) given to women in preterm labor reduces the risk of cerebral palsy in their offspring but the mechanisms behind these neuroprotective effects remain unclear, limiting its effective and safe clinical implementation. Experimentally, MgSO4 is not neuroprotective if administered during or after the insult but we hypothesized that it induces preconditioning in the immature brain. The aims of this thesis were to explore whether MgSO4 induces tolerance (preconditioning) in the immature brain and the underlying molecular mechanisms. Furthermore, the objectives were to establish rat preterm models of hypoxia-ischemia (HI) and germinal matrix hemorrhage (GMH) and evaluate the effect of MgSO4 in these models. We found that MgSO4 treatment administered as a bolus between 6 days-12 h prior to HI in the postnatal day (PND) 7 rat markedly reduced brain injury; with maximal protection achieved by 1.1 mg/g MgSO4 administered 24 h before HI. In all animal models tested (HI PND 4 & 7 rat; PND 5 mouse; GMH PND 5 rat; ibotenate PND 5 mouse) we found a significant reduction of brain injury in both grey and white matter in the MgSO4 preconditioned animals. The serum magnesium levels were studied in all three HI models and we detected that the serum magnesium levels returned to baseline before the induction of HI and therefore ascribed this reduction in brain injury to preconditioning. Further evaluation of the mechanisms behind this neuroprotective effect revealed that mRNAs/miRNAs involved in mitochondrial function and metabolism were modulated by MgSO4. Metabolomic analysis (H+-NMR) disclosed that MgSO4 attenuated HI-induced increases in succinate and prevented depletion of high energy phosphates. MgSO4 pretreatment preserved mitochondrial respiration, reduced ROS production and inflammation after HI. Therefore we propose that MgSO4 evokes preconditioning via induction of mitochondrial resistance and attenuation of inflammation. We have now demonstrated that MgSO4 provides preconditioning neuroprotection in five brain injury models supporting that this phenomenon is generalizable to some extent irrespective of species, type of insult and developmental age