Abundant clinical data indicate increased morbidity and mortality following trauma to the aging nervous system. Little is currently known about the cellular substrates underlying this amplified adverse response. The proposed studies lead to testing of the hypothesis, that age-related changes associated with traumatic brain injury (TBI) can be negated by enhancing the ability of neurons to produce ATP. This idea is based on the theory that age-related changes in brain mitochondria lead to a disruption of ATP necessary to meet the energy demands of neurons following trauma. Mitochondria are the major source of ATP required for neuronal function. Age-related defects in mitochondrial oxidative phosphorylation result in deceased energy production, impaired cellular calcium buffering, activation of proteases and phospholipases, and the generation of increased free radicals. All of these pathways can lead to enhanced cell death depending on the severity of the insult. Preliminary data from our laboratory demonstrate age-related differences following experimental TBI, supporting its usefulness as an aging animal model. We also present data that a diet supplemented by creatine provides a neuroprotective intervention for TBI. Because of a lack of sufficient information on aged animal models of TBI, this study will first characterize age-related changes.
Specific aim #1 will characterize age-related decline in morphologic and behavioral changes following TBI employing an animal model of controlled cortical contusion.
Specific aim #2 will characterize age-related changes in synaptic and non-synaptic mitochondria following TBI.
Specific aim #3 will explore age-related changes in the generation of lactic acid and free fatty acids, sensitive markers of secondary injury, and changes in isoprostanes and neuroprostanes, markers of lipid peroxidation following TBI.
Specific aim #4 will use a 'creatine-supplemented' dietary intervention that enhances cytosolic phosphocreatine and increases the ability of neurons to produce ATP, an intervention to reverse the age-related response to TBI. ? ?
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