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The Journal of Neuroscience, November 1, 2000, 20(21):7994-8004
Apoptosis Has a Prolonged Role in the Neurodegeneration after Hypoxic Ischemia in the Newborn Rat
Wako Nakajima1, 2, Akira Ishida1, 2, Mary S. Lange1, Kathleen L. Gabrielson6, Mary Ann Wilson1, 2, Lee J. Martin4, 5, Mary E. Blue1, 2, and Michael V. Johnston1, 2, 3 1 Kennedy Krieger Research Institute and Departments of 2 Neurology, 3 Pediatrics, 4 Pathology, Division of Neuropathology, and 5 Neuroscience, Johns Hopkins University School of Medicine, and 6 Department of Toxicological Sciences, the Johns Hopkins University School of Public Health, Baltimore, Maryland 21205
Birth asphyxia can cause moderate to severe brain injury. It is unclear to what degree apoptotic or necrotic mechanisms of cell death account for damage after neonatal hypoxia-ischemia (HI). In a 7-d-old rat HI model, we determined the contributions of apoptosis and necrosis to neuronal injury in adjacent Nissl-stained, hematoxylin and eosin-stained, and terminal deoxynucleotidyl transferase-mediated UTP nick end-labeled sections. We found an apoptotic-necrotic continuum in the morphology of injured neurons in all regions examined. Eosinophilic necrotic neurons, typical in adult models, were rarely observed in neonatal HI. Electron microscopic analysis showed "classic" apoptotic and necrotic neurons and "hybrid" cells with intermediate characteristics. The time course of apoptotic injury varied regionally. In CA3, dentate gyrus, medial habenula, and laterodorsal thalamus, the density of apoptotic cells was highest at 24-72 hr after HI and then declined. In contrast, densities remained elevated from 12 hr to 7 d after HI in most cortical areas and in the basal ganglia. Temporal and regional patterns of neuronal death were compared with expression of caspase-3, a cysteine protease involved in the execution phase of apoptosis. Immunocytochemical and Western blot analyses showed increased caspase-3 expression in damaged hemispheres 24 hr to 7 d after HI. A p17 peptide fragment, which results from the proteolytic activation of the caspase-3 precursor, was detected in hippocampus, thalamus, and striatum but not in cerebral cortex. The continued expression of activated caspase-3 and the persistence of cells with an apoptotic morphology for days after HI suggests a prolonged role for apoptosis in neonatal hypoxic ischemic brain injury.
Key words: apoptosis; necrosis; hypoxia-ischemia; cysteine proteases; caspase-3 cleavage; cell death continuum; cerebral palsy; newborn brain injury; developmental brain
Copyright © 2000 Society for Neuroscience 0270-6474/00/20217994-11$05.00/0
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