Magnesium induces preconditioning of the neonatal brain via profound mitochondrial protection

Koring, G; Leverin, A L; Nair, S; Schwendimann, L; Ek, J; Carlsson, Y; Gressens, P; Thornton, C; Wang, X; Mallard, C; Hagberg, H

doi:10.1177/0271678X17746132

Magnesium induces preconditioning of the neonatal brain via profound mitochondrial protection

Koring, G; Leverin, A L; Nair, S; Schwendimann, L; Ek, J; Carlsson, Y; Gressens, P; Thornton, C; Wang, X; Mallard, C; Hagberg, H

Authors

G Koring

A L Leverin

S Nair

L Schwendimann

J Ek

Y Carlsson

P Gressens

C Thornton

X Wang

C Mallard

H Hagberg

Abstract

Magnesium sulphate (MgSO4) 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 MgSO4 is not neuroprotective if administered during or after the insult, so we hypothesised that MgSO4 induces preconditioning in the immature brain. Therefore, we administered MgSO4 at various time-points before/after unilateral hypoxia-ischemia (HI) in seven-day-old rats. We found that MgSO4 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 MgSO4 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 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, reducing ROS production and inflammation after HI. Therefore, we propose that MgSO4 evokes preconditioning via induction of mitochondrial resistance and attenuation of inflammation.

Citation

Koring, G., Leverin, A. L., Nair, S., Schwendimann, L., Ek, J., Carlsson, Y., Gressens, P., Thornton, C., Wang, X., Mallard, C., & Hagberg, H. (2019). Magnesium induces preconditioning of the neonatal brain via profound mitochondrial protection. https://doi.org/10.1177/0271678X17746132

Journal Article Type	Article
Acceptance Date	Nov 6, 2017
Publication Date	Jan 1, 2019
Deposit Date	Aug 8, 2019
Journal	Journal of Cerebral Blood Flow & Metabolism
Peer Reviewed	Peer Reviewed
Volume	39
Issue	6
Pages	1038-1055
DOI	https://doi.org/10.1177/0271678X17746132
Public URL	https://rvc-repository.worktribe.com/output/1384347