Mitochondrial dysfunction plays a critical role in etiology of neural cell death associated with ischemia, hypoxia and traumatic brain injury (TBI). Despite the large number of neonates who suffer permanent neurologic impairment due to hypoxia, and the high incidence of childhood traumatic brain injury, no information about the effects of stress on the activities of mitochondria from the brains of immature animals is available. We have recently discovered that compared to brain mitochondria from adult rats, mitochondria from immature rats exhibit resistance to bioenergetic failure caused by exposure to high levels of Ca 2+, and exhibit greatly enhanced sensitivity to release of pro-apoptotic cytochrome c by a peptide containing the BH3 """"""""cell death"""""""" domain. We hypothesize that the molecular and physiological characteristics of immature brain mitochondria are important determinants in the sensitivity of the immature brain to cell death caused by metabolic and pro-apoptotic insults. We further hypothesize that acetyI-L-carnitine, an agent that we have shown to be neuroprotective in adult ischemic brain injury, will protect the immature brain from acute neurodegeneration due to its beneficial effects on neuronal and astrocyte mitochondria and on neuronal/astrocyte metabolic interactions. The following specific aims will test these hypotheses and provide novel information important in designing strategies for treating infants and children at risk for mental retardation. 1. Establish relationships between developmental changes in mitochondrial metabolic and apoptotic protein levels and activities and sensitivity of brain mltochondria to metabolic stress, oxidative stress, Ca2+induced dysfunction, and pro-apoptotic molecular signals. 2. Determine the pattern of molecular, metabolic, and apoptotic alterations to brain mitochondria caused by acute brain injury caused by neonatal hypoxia/ischemia. 3. Test the ability of acetyI-L-carnitine to ameliorate the mitochondrial alterations, metabolic derangements, and cell death in an animal model of neonatal hypoxia/ischemia and cell models of metabolic stress. This project will lay the foundation for the molecular etiology of neural cell death in immature animals following acute ischemic, hypoxic, and traumatic brain injury. These and future studies will aid in the development of targeted neuroprotective interventions that will minimize the neurologic impairment caused by acute brain injury in neonates and children.
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