Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes

Stephen A. Back, Ning Ling Luo, Rebecca A. Mallinson, Jean P. O'Malley, Linda D. Wallen, Balz Frei, Jason D. Morrow, Carol K. Petito, Charles T. Roberts, Geoffrey H. Murdoch, Thomas J. Montine

Research output: Contribution to journalArticle

179 Scopus citations

Abstract

Periventricular white matter injury (PWMI) is the leading cause of cerebral palsy and chronic neurological disability in survivors of prematurity. Despite the large number of affected children, the pathogenetic mechanisms related to PWMI remain controversial. Through studies of 33 human autopsy brains, we determined that early PWMI was related to oxidative damage that particularly targeted the oligodendrocyte lineage, whereas other neuronal and glial cell types were markedly more resistant. F2-isoprostanes, an arachidinate metabolite/lipid peroxidation marker of oxidative damage, were significantly increased in early PWMI lesions but not in cerebral cortex. That deleterious lipid peroxidation accompanied early PWMI was supported by similar increases in F2-isoprostanes levels in the cerebral cortex from term infants with hypoxic-ischemic cortical injury. Detection of F4-neuroprostanes, a neuronal-specific oxidative damage marker, confirmed that neuroaxonal elements were resistant to injury in cerebral cortex and white matter. Significant protein nitration was not detected in PWMI lesions by 3-nitrotyrosine staining. Significant cellular degeneration was confirmed in early PWMI lesions by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and a marked depletion of oligodendrocyte progenitors of 71 ± 8%. Hence, the predilection of preterm infants for PWMI is related to selective lipid peroxidation-mediated injury of cerebral white matter and targeted death of oligodendrocyte progenitors.

Original languageEnglish (US)
Pages (from-to)108-120
Number of pages13
JournalAnnals of Neurology
Volume58
Issue number1
DOIs
StatePublished - Jul 1 2005

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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    Back, S. A., Luo, N. L., Mallinson, R. A., O'Malley, J. P., Wallen, L. D., Frei, B., Morrow, J. D., Petito, C. K., Roberts, C. T., Murdoch, G. H., & Montine, T. J. (2005). Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes. Annals of Neurology, 58(1), 108-120. https://doi.org/10.1002/ana.20530