The tight relationship between energy production and cerebral blood flow in the nervous system is necessitated by the high metabolic demands of the brain. In fact, it has been estimated that the average adult human brain consumes approximately 4 x 10 21 molecules of ATP per minute, or nearly 20% of all energy produced in the body. Almost all of the energy used to maintain basal cellular functioning is derived from aerobic oxidation of glucose. Since the brain extracts -50% of oxygen and -10% of glucose from the arterial blood. any significant reductions in CBF can have profound consequences in neuronal functioning and survival. It is now well accepted that the acute metabolic response to neural injury is characterized by an immediate increase in glucose metabolism. Paradoxically, this marked increase in glucose metabolism following TBI is accompanied by a persistent decrease in cerebral blood flow (, 1996). In addition, measurements of oxidative capacity after experimental TBI using cytochrome oxidase histochemistry indicates certain limitations in mitochondrial functioning, which may manifest as chronic decreases in oxidative metabolism. The proposed studies reconcile these provocative findings and provide support for the hypothesis that the uncoupling between metabolism and blood flow profoundly affects the long-term viability of injured neurons and determines the eventual outcome after head injury. Thus, we hypothesize that experimental TBI induces a state in which: I) glucose metabolism increases dramatically for the first several hours in an attempt to re-establish neuronal homeostasis, and ii) insufficient amount of energy (ATP) is produced by damaged neurons to meet this increased energy demand due to a compromised cellular metabolic machinery and injury-induced changes to the neurovascular system. To assess this general hypothesis, the specific aims of this project are: 1. To determine what is responsible for this uncoupling. Is it due to unusually high energy demands induced by the injury? Is it due to the loss of vasoreactivity (loss of metabolic autoregulation)? 2. To determine whether TBI-induced uncoupling of glucose metabolism and cerebral blood flow results in delayed cell death. 3. To determine the cellular mechanism by which injured neurons undergo delayed cell death. Is t due to energy failure (depletion of ATP)? Is it is due to apoptosis resulting from a massive Ca sequestration? Is it due to lactic acidosis resulting from high rates of glycolysis?
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