Magnesium induces preconditioning of the neonatal brain via profound mitochondrial protection

Abstract

Magnesium sulphate (MgSO) 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 is not neuroprotective if administered during or after the insult, so we hypothesised that MgSO induces preconditioning in the immature brain. Therefore, we administered MgSO at various time-points before/after unilateral hypoxia-ischemia (HI) in seven-day-old rats. We found that MgSO 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 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. Metabolomic analysis (H-NMR) disclosed that MgSO attenuated HI-induced increases in succinate and prevented depletion of high-energy phosphates. MgSO pretreatment preserved mitochondrial respiration, reducing ROS production and inflammation after HI. Therefore, we propose that MgSO evokes preconditioning via induction of mitochondrial resistance and attenuation of inflammation.

Magnesium sulphate induces preconditioning in preterm rodent models of cerebral hypoxia‐ischemia

“…Additionally, the serum Mg 2+ concentrations measured in both models 3 h post injection were within the therapeutic window (2–4 mmol/L) when MgSO 4 is given antenatally to women for seizure prophylaxis in preeclampsia or for neuroprotection. Taken together with our recently published data (Koning et al, 2017), we have now demonstrated that MgSO 4 provides preconditioning neuroprotection in four brain injury models (HI at PND 4 rat, PND 7 rat and PND 5 mouse as well as mouse PND 5 ibotenate lesion), supporting that this phenomenon is generalizable to some extent irrespective of species, type of insult and developmental age.…”

“…The present results together with our previous report offers some mechanistic insights into how MgSO 4 protects the immature brain, i.e . it has to be given as a pre‐exposure at least ≥12 h prior to the insult (Koning et al, 2017) whereas MgSO 4 is often not effective if given just prior, during or after the insult (de Haan et al, 1997, Galvin and Oorschot 1998, Greenwood et al, 2000; Koning et al, 2017). We believe that MgSO 4 offers preconditioning, i.e.…”

“…Such an interpretation is supported by the fact that the serum magnesium concentrations are normalized (or nearly normalized) at the time of the severe insult and still brain injury is decreased dramatically. MgSO 4 changes the expression of a number of genes which in turn alters the mitochondrial and metabolic state of the immature CNS which renders it more resistant to a subsequent severe insult (Koning et al, 2017). However, this genomic/metabolic transformation into a more resistant state develops over time and is not complete until 12–24 h although it seems to last for over 6 days, at least in the PND 7 rat model.…”

“…Pups of either sex were divided randomly into two groups and injected intraperitoneally ( i.p. ) at PND 3 (rats) or PND 4 (mice) with a single dose of MgSO 4 (Magnesium, Addex; Fresenius Kabi, Halden, Norway) (Koning et al, 2017) or as vehicle an equivalent volume of saline (Saline 9 mg/ml, B Braun Melsungen AG, Melsungen, Germany) 24 h prior to the induction of HI (Table 1). Pups were then returned to their dams.…”

“…Most experimental studies have failed to confirm that MgSO 4 is neuroprotective if given immediately prior to, during or after HI (de Haan et al, 1997; Galvin and Oorschot 1998; Greenwood et al, 2000) but MgSO 4 administered to mothers in preterm labor is actually given hours to days before the presumed most critical period for development of brain injury. In a recent study (Koning et al, 2017), we demonstrated that MgSO 4 induces strong preconditioning when administered as a bolus 6 days to 12 h prior to the induction of HI in the PND 7 rat (which is developmentally similar to that of a human near‐term fetus) (Vannucci and Vannucci 1997). But there is no information whether MgSO 4 also induces preconditioning in the more immature rodent brain better corresponding to extreme prematurity.…”