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Erythropoietin protects the developing brain from hyperoxia‐induced cell death and proteome changes
Author(s) -
Kaindl Angela M.,
Sifringer Marco,
Koppelstaetter Andrea,
Genz Kerstin,
Loeber Rebecca,
Boerner Constanze,
Stuwe Janine,
Klose Joachim,
FelderhoffMueser Ursula
Publication year - 2008
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21471
Subject(s) - hyperoxia , oxygen toxicity , erythropoietin , apoptosis , proteome , brain damage , oxidative stress , medicine , toxicity , western blot , andrology , programmed cell death , endocrinology , biology , bioinformatics , biochemistry , lung , gene
Objective Oxygen toxicity has been identified as a risk factor for adverse neurological outcome in survivors of preterm birth. In infant rodent brains, hyperoxia induces disseminated apoptotic neurodegeneration. Because a tissue‐protective effect has been observed for recombinant erythropoietin (rEpo), widely used in neonatal medicine for its hematopoietic effect, we examined the effect of rEpo on hyperoxia‐induced brain damage. Methods Six‐day‐old C57Bl/6 mice or Wistar rats were exposed to hyperoxia (80% O 2 ) or normoxia for 24 hours and received rEpo or normal saline injections intraperitoneally. The amount of degenerating cells in their brains was determined by DeOlmos cupric silver staining. Changes of their brain proteome were determined through two‐dimensional electrophoresis and mass spectrometry. Western blot, enzyme activity assays and real‐time polymerase chain reaction were performed for further analysis of candidate proteins. Results Systemic treatment with 20,000 IE/kg rEpo significantly reduced hyperoxia‐induced apoptosis and caspase‐2, ‐3, and ‐8 activity in the brains of infant rodents. In parallel, rEpo inhibited most brain proteome changes observed in infant mice when hyperoxia was applied exclusively. Furthermore, brain proteome changes after a single systemic rEpo treatment point toward a number of mechanisms through which rEpo may generate its protective effect against oxygen toxicity. These include reduction of oxidative stress and restoration of hyperoxia‐induced increased levels of proapoptotic factors, as well as decreased levels of neurotrophins. Interpretation These findings are highly relevant from a clinical perspective because oxygen administration to neonates is often inevitable, and rEpo may serve as an adjunctive neuroprotective therapy. Ann Neurol 2008;64:523–534