Neuronal Death in Newborn Striatum after Hypoxia-Ischemia Is Necrosis and Evolves with Oxidative Stress

• Main Authors: Lee J. Martin, Ansgar M. Brambrink, Ann C. Price, Adeel Kaiser, Dawn M. Agnew, Rebecca N. Ichord, Richard J. Traystman
• Format: Article
• Language: English
• Published: Elsevier 2000-06-01
• Series: Neurobiology of Disease
• Subjects: apoptosis; cerebral palsy; cytochrome c; DNA damage; mitochondria; RNA oxidation
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996100902821

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 (∼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 ∼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.