title: Neuronal death in newborn striatum after hypoxia-ischemia is necrosis and evolves with oxidative stress.
abstract: The mechanisms for neurodegeneration after hypoxia-ischemia (HI) in newborns are not understood. We tested the hypothesis that striatal neuron death is necrosis and evolves with oxidative stress and selective organelle damage. Piglets ( approximately 1 week old) were used in a model of hypoxia-asphyxia and survived for 3, 6, 12, or 24 h. Neuronal death was progressive over 3-24 h recovery, with approximately 80% of putaminal neurons dead at 24 h. Striatal DNA was digested randomly at 6-12 h. Ultrastructurally, dying neurons were necrotic. Damage to the Golgi apparatus and rough endoplasmic reticulum occurred at 3-12 h, while most mitochondria appeared intact until 12 h. Mitochondria showed early suppression of activity, then a transient burst of activity at 6 h, followed by mitochondrial failure (determined by cytochrome c oxidase assay). Cytochrome c was depleted at 6 h after HI and thereafter. Damage to lysosomes occurred within 3-6 h. By 3 h recovery, glutathione levels were reduced, and peroxynitrite-mediated oxidative damage to membrane proteins, determined by immunoblots for nitrotyrosine, occurred at 3-12 h. The Golgi apparatus and cytoskeleton were early targets for extensive tyrosine nitration. Striatal neurons also sustained hydroxyl radical damage to DNA and RNA within 6 h after HI. We conclude that early glutathione depletion and oxidative stress between 3 and 6 h reperfusion promote damage to membrane and cytoskeletal proteins, DNA and RNA, as well as damage to most organelles, thereby causing neuronal necrosis in the striatum of newborns after HI.
authors.affiliation: Department of Pathology, Division of Neuropathy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. lmartin@welchlink.welch.jhu.edu
authors.forename: L J
authors.initials: LJ
authors.lastname: Martin
authors.forename: A M
authors.initials: AM
authors.lastname: Brambrink
authors.forename: A C
authors.initials: AC
authors.lastname: Price
authors.forename: A
authors.initials: A
authors.lastname: Kaiser
authors.forename: D M
authors.initials: DM
authors.lastname: Agnew
authors.forename: R N
authors.initials: RN
authors.lastname: Ichord
authors.forename: R J
authors.initials: RJ
authors.lastname: Traystman
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D002545:Brain Ischemia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D016923:Cell Death; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology*; D003574:Cytochrome c Group / Q000378:metabolism; D004249:DNA Damage; D004721:Endoplasmic Reticulum / Q000648:ultrastructure; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006056:Golgi Apparatus / Q000648:ultrastructure; D017665:Hydroxyl Radical / Q000494:pharmacology; D000860:Hypoxia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008247:Lysosomes / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000502:physiology; D009336:Necrosis; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D009566:Nitrates / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D013552:Swine
chemical_list: D003574:Cytochrome c Group; D009566:Nitrates; D016877:Oxidants; C039642:peroxynitric acid; D017665:Hydroxyl Radical; D005978:Glutathione