Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes.
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. F(2)-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 F(2)-isoprostanes levels in the cerebral cortex from term infants with hypoxic-ischemic cortical injury. Detection of F(4)-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.
Department of Pediatrics, Oregon Health and Science University, Portland OR 97239-3098, USA. backs@ohsu.edu
Stephen A
SA
Back
Ning Ling
NL
Luo
Rebecca A
RA
Mallinson
Jean P
JP
O'Malley
Linda D
LD
Wallen
Balz
B
Frei
Jason D
JD
Morrow
Carol K
CK
Petito
Charles T
CT
Roberts
Geoffrey H
GH
Murdoch
Thomas J
TJ
Montine
D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D019070:Cell Lineage / Q000502:physiology; D028441:F2-Isoprostanes / Q000032:analysis*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007231:Infant, Newborn; D007969:Leukomalacia, Periventricular / Q000503:physiopathology*; D008297:Male; D009457:Neuroglia / Q000166:cytology / Q000473:pathology; D009474:Neurons / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D011247:Pregnancy; D047928:Premature Birth; D013234:Stem Cells / Q000502:physiology
D028441:F2-Isoprostanes; D005904:Glial Fibrillary Acidic Protein