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The Journal of Neuroscience, March 15, 2001, 21(6):1931-1938
Delayed Neurodegeneration in Neonatal Rat Thalamus after Hypoxia-Ischemia Is Apoptosis
Frances J. Northington1, Donna M. Ferriero3, Debra L. Flock1, and Lee J. Martin2 Eudowood Neonatal Pulmonary Division, Departments of 1 Pediatrics and 2 Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, and 3 Departments of Neurology and Pediatrics, University of California-San Francisco, San Francisco, California 94143
Brain injury in newborns can cause deficits in motor and sensory function. In most models of neonatal brain injury, thalamic damage often occurs. Using the Rice-Vannucci model of neonatal hypoxic-ischemic brain injury, we have shown that neuronal degeneration in somatosensory thalamus is delayed in onset (~24 hr) compared with cortical and striatal injury and exhibits prominent structural features of apoptosis. In the present study, we examined whether cell death in the thalamus has molecular features of apoptosis. Fas death receptor protein expression increased rapidly after neonatal hypoxia-ischemia, in concert with cleavage of procaspase 8 to its active form. Concurrently, the levels of Bax in mitochondrial-enriched cell fractions increase, and cytochrome c accumulates in the soluble fraction. Mitochondria accumulate in a perinuclear distribution by 6 hr after hypoxia-ischemia. Cytochrome oxidase subunit 1 protein levels also increase at 6 hr after hypoxia-ischemia. Increased levels of Fas death receptor, Bax, and cytochrome c, activation of caspase 8, and abnormalities in mitochondria in the thalamus significantly precede the activation of caspase 3 and the appearance of neuronal apoptosis at 24 hr. We conclude that the delayed neurodegeneration in neonatal rat ventral basal thalamus after hypoxic-ischemic injury is apoptosis mediated by death receptor activation.
Key words: mitochondria; neonatal brain injury; Bax; Fas death receptor; caspase; cytochrome oxidase
Copyright © 2001 Society for Neuroscience 0270-6474/01/2161931-08$05.00/0
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