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

Sidhartha Tan, Fen Zhou, Vance G. Nielsen, Ziwei Wang, Candece L. Gladson, Dale A. Parks

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)544-553
Number of pages10
JournalJournal of Neuropathology and Experimental Neurology
Volume57
Issue number6
DOIs
StatePublished - Jun 1998

Keywords

  • Antioxidants
  • Free radicals
  • Hippocampus
  • Nitric oxide
  • Uterus

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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