title: Glutathione peroxidase overexpression causes aberrant ERK activation in neonatal mouse cortex after hypoxic preconditioning.
abstract: BACKGROUND
  Preconditioning of neonatal mice with nonlethal hypoxia (HPC) protects the brain from hypoxic-ischemic (HI) injury. Overexpression of human glutathione peroxidase 1 (GPx1), which normally protects the developing murine brain from HI injury, reverses HPC protection, suggesting that a certain threshold of hydrogen peroxide concentration is required for activation of HPC signaling.
  
  
  METHODS
  Activation (phosphorylation) of extracellular-regulated kinase (ERK) 1/2 and Akt, and induction of hypoxia-inducible factor (HIF)-1α were assessed in the cortex, one of the main structures affected by HI and protected by HPC, at different time points after reoxygenation in wild-type (WT) and GPx1-overexpressing animals.
  
  
  RESULTS
  GPx1 overexpression prevented both the global and nuclear increase in activated ERK at 0.5 h after HPC and caused a significant decrease in phospho-ERK (pERK)/ERK levels at 24 h after HPC. In contrast, HIF-1α induction at the end of hypoxia was unaffected by GPx1 overexpression. In the cortex of preconditioned WT animals, enhanced pERK staining was primarily observed in neurons and to a lower extent in astrocytes and endothelial cells, with a nuclear prominence.
  
  
  CONCLUSIONS
  Aberrant activation of ERK probably explains the paradoxical reversal of HPC protection by GPx1 overexpression. The results identify hydrogen peroxide as an important mediator of neuroprotective ERK signaling.
authors.affiliation: Institute of Infectious Diseases, University of Berne, Berne, Switzerland.
authors.forename: Delphine
authors.initials: D
authors.lastname: Autheman
authors.forename: R Ann
authors.initials: RA
authors.lastname: Sheldon
authors.forename: Nondini
authors.initials: N
authors.lastname: Chaudhuri
authors.forename: Sebastian
authors.initials: S
authors.lastname: von Arx
authors.forename: Corinne
authors.initials: C
authors.lastname: Siegenthaler
authors.forename: Donna M
authors.initials: DM
authors.lastname: Ferriero
authors.forename: Stephan
authors.initials: S
authors.lastname: Christen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation
chemical_list: D005979:Glutathione Peroxidase; D048049:Extracellular Signal-Regulated MAP Kinases