Oxygen causes cell death in the developing brain.
Substantial neurologic morbidity occurs in survivors of premature birth. Premature infants are exposed to partial oxygen pressures that are fourfold higher compared to intrauterine conditions, even if no supplemental oxygen is administered. Here we report that short exposures to nonphysiologic oxygen levels can trigger apoptotic neurodegeneration in the brains of infant rodents. Vulnerability to oxygen neurotoxicity is confined to the first 2 weeks of life, a period characterized by rapid growth, which in humans expands from the sixth month of pregnancy to the third year of life. Oxygen caused oxidative stress, decreased expression of neurotrophins, and inactivation of survival signaling proteins Ras, extracellular signal-regulated kinase (ERK 1/2), and protein kinase B (Akt). The synRas-transgenic mice overexpressing constitutively activated Ras and phosphorylated kinases ERK1/2 in the brain were protected against oxygen neurotoxicity. Our findings reveal a mechanism that could potentially damage the developing brain of human premature neonates.
Felderhoff-Mueser
Ursula
U
Department of Neonatology, Humboldt University Berlin, Charité, Campus Virchow Klinikum, 13353 Berlin, Germany.
Bittigau
Petra
P
Sifringer
Marco
M
Jarosz
Bozena
B
Korobowicz
Elzbieta
E
Mahler
Lieselotte
L
Piening
Turid
T
Moysich
Axel
A
Grune
Tilman
T
Thor
Friederike
F
Heumann
Rolf
R
Bührer
Christoph
C
Ikonomidou
Chrysanthy
C
D000375:Aging; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn / Q000254:growth & development / Q000378:metabolism; D017209:Apoptosis; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D018496:Hyperoxia / Q000503:physiopathology*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D018631:ras Proteins / Q000378:metabolism
D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins; D010100:Oxygen