Lipid peroxidation, caspase-3 immunoreactivity, and pyknosis in late-gestation fetal sheep brain after umbilical cord occlusion

Pediatr Res. 2004 May;55(5):864-71. doi: 10.1203/01.PDR.0000115679.86566.C4. Epub 2004 Feb 5.


Umbilical cord occlusion (UCO), a known risk factor for perinatal brain damage, causes severe fetal asphyxia leading to oxidative stress, lipid peroxidation, and cell death. We have determined the effects of two 10-min UCO on the distribution of the lipid peroxidation marker 4-hydroxynonenal (4-HNE) and the activated form of the apoptosis marker caspase-3 in the brains of late-gestation fetal sheep. UCO caused asphyxia, hypertension, and bradycardia, but these parameters normalized 2 h after the occlusion. At postmortem, 48 h after the second UCO there were significantly higher numbers of 4-HNE-positive cells in all layers of the hippocampus and cerebellum, the parietal cortex, substantia nigra, caudate nucleus, putamen, and thalamus compared with control brains. 4-HNE immunoreactivity was also found in white matter tracts of the subcallosal bundle, external medullary lamina, reticular thalamic nucleus, and cerebellar fiber tracts only in UCO brains. Double-labeling identified these cells as predominantly neurons and astrocytes, with oligodendrocytes showing lower levels of 4-HNE immunoreactivity. After UCO, the number of caspase-3-immunopositive cells was increased significantly in the hippocampal CA1, molecular layer and dentate gyrus, ventrolateral thalamic nucleus, substantia nigra, putamen, and cerebellar granular and molecular layers compared with controls. Double-labeling revealed caspase-3 immunoreactivity was mainly in neurons, and to lesser extent in astrocytes and oligodendrocytes. Pyknotic cell numbers were significantly increased in hippocampal CA1 and CA3, parietal cortex, caudate nucleus, putamen, and cerebellar Purkinje cells after UCO. These data indicate that brief asphyxia induces widespread lipid peroxidation involving all cell types of the fetal brain and apoptosis in both neurons and glia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / pharmacology
  • Animals
  • Apoptosis
  • Arteries / pathology
  • Blood Pressure
  • Brain / embryology*
  • Caspase 3
  • Caspases / metabolism*
  • Constriction
  • Enzyme Activation
  • Fetal Hypoxia / metabolism*
  • Gestational Age
  • Hydrogen-Ion Concentration
  • Immunohistochemistry
  • Lipid Peroxidation*
  • Male
  • Neurons / metabolism
  • Oligodendroglia / metabolism
  • Oxidative Stress*
  • Oxygen / metabolism
  • Sheep
  • Time Factors
  • Umbilical Cord / pathology*


  • Aldehydes
  • Caspase 3
  • Caspases
  • 4-hydroxy-2-nonenal
  • Oxygen