The Harbor-UCLA Brain Injury Research Center has made fundamental contributions to the understanding of post-traumatic brain injury (TBI) glucose metabolism during the past 3 years of NIH support. We have confirmed our original findings that each and every TBI in animals elicits an immediate increase in glucose uptake (""""""""acute hyperglycolysis"""""""") in order to re-equilibrate ionic and neurochemical imbalances induced by the initial impact, and that this immense energy demand may recur periodically during the first 24 hours with devastating results. We have also shown, using double-label (18F-FDG/14C -glucose) autoradiography, that both the acute and delayed hyperglycolysis occur concomitantly with a 30-40% decrease in oxidative metabolism. We further demonstrated, using in situ ATP measurements, that these altered metabolic states may profoundly influence, or ultimately determine, the injured brain's ability to recover from the initial injury. In the current proposal, we utilize a well-understood model of primary lateral fluid percussion injury followed by secondary inductions of spreading depression using direct K+applications. Using this secondary injury model of K+-induced depolarizations, which induces profound, controlled energy crises within injured tissue, we propose to address, using state-of-the art techniques, 5 fundamental questions regarding energy production and utilization acutely following a TBI. i). Do these secondary depolarizations result in a persistent decrease in energy availability? Does this """"""""energy crisis"""""""" ? precede irreversible degenerative events. ii) Why are injured cells unable to produce sufficient energy following a prolonged secondary insult? Is it a glycolytic or mitochondrial dysfunction? iii) Can we artificially increase energy production during secondary insults by administering downstream or alternative metabolic substrates, e.g., pyruvate, lactate, glutamine, ketone bodies or Krebs cycle intermediates? Does this come at the expense of more free radical production? iv) What is the window of vulnerability to secondary depolarizations, or secondary metabolic challenges, following TBI? Is the time window dependent on the nature and severity of the secondary injury? v) Does increasing energy production during secondary insults increase neuronal survival and improve behavioral outcome? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CDIN (01))
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Hicks, Ramona R
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University of Southern California
Anatomy/Cell Biology
Schools of Medicine
Los Angeles
United States
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Fukushima, Masamichi; Lee, Stefan M; Moro, Nobuhiro et al. (2009) Metabolic and histologic effects of sodium pyruvate treatment in the rat after cortical contusion injury. J Neurotrauma 26:1095-110
Prins, Mayumi L; Hovda, David A (2009) The effects of age and ketogenic diet on local cerebral metabolic rates of glucose after controlled cortical impact injury in rats. J Neurotrauma 26:1083-93
Aoyama, Naoki; Lee, Stefan M; Moro, Nobuhiro et al. (2008) Duration of ATP reduction affects extent of CA1 cell death in rat models of fluid percussion injury combined with secondary ischemia. Brain Res 1230:310-9
Nuwer, Marc R; Hovda, David A; Schrader, Lara M et al. (2005) Routine and quantitative EEG in mild traumatic brain injury. Clin Neurophysiol 116:2001-25