Sustained hypoxia-ischemia results in reactive nitrogen and oxygen species production and injury in the premature fetal rabbit brain

J Neuropathol Exp Neurol. 1998 Jun;57(6):544-53. doi: 10.1097/00005072-199806000-00002.


Free radical-mediated injury is implicated in hypoxic-ischemic encephalopathy observed in neonates. We investigated in utero free radical production and injury following hypoxia-ischemia to premature fetal brain utilizing a rabbit model of acute placental insufficiency. Pregnant rabbits at 29 days gestation were randomized to uterine ischemia for 50 minutes (min) (hypoxia) or nonischemic controls. Fetal brains were obtained immediately after ischemia for oxidative and acute-injury markers or 24 hours (h) post-ischemia for histopathology. Nitrotyrosine formation, a marker of NO-derived species such as peroxynitrite, was observed only in hypoxic brains. Hypoxia resulted in a significant increase in nitrogen oxides, lipid peroxidation, and protein oxidation, with a concomitant decrease in total antioxidant capacity, compared with controls. Peroxynitrite addition to brain homogenate increased nitrogen oxides linearly (1:1), although protein carbonyls were unchanged. Concomitantly, in vitro cortical and hippocampal cell viability and ATP levels decreased, with an increase in brain edema in hypoxic brains. Fetuses delivered 24 h post-ischemia had increased hippocampal nuclear karyorrhexis on histology compared with controls. Antioxidant administration (ascorbic acid and Trolox) intraperitoneally ameliorated changes in cellular viability and brain edema. Acute fetal hypoxia-ischemia without reoxygenation results in increased nitrogen and oxygen free radical production that may cause brain injury. The merits of the described model are discussed.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Ascorbic Acid / pharmacology
  • Brain / cytology
  • Brain / embryology
  • Brain / metabolism*
  • Brain Ischemia / metabolism*
  • Cell Death / drug effects
  • Cell Survival / drug effects
  • Chromans / pharmacology
  • Female
  • Free Radicals / metabolism
  • Hypoxia, Brain / metabolism*
  • Nitrogen / metabolism*
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Pregnancy
  • Rabbits
  • Reactive Oxygen Species / metabolism*
  • Uterus / blood supply


  • Antioxidants
  • Chromans
  • Free Radicals
  • Reactive Oxygen Species
  • Nitrogen
  • Ascorbic Acid
  • 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid