Studies in Project 11 address the hypothesis that neural cell death after neonatal hypoxia/ischemia (H/l) arises from both acute impairment in mitochondrial energy metabolism and prolonged metabolic alterations that leave the brain vulnerable to secondary insults including damage from hyperoxic resuscitation. Our studies show that H/l leads to acutely impaired mitochondrial respiration and decreased activity of pyruvate dehydrogenase complex (PDHC) and a-ketoglutarate dehydrogenase (KGDH), loss of aralar1 (the mitochondrial aspartate-glutamate carrier), and long term impairment of metabolism and GABA synthesis in brain. Aralar1, which links the loss of NAD*, energy failure and decreased synthesis of the neuronal integrity marker N-acetylaspartate (NAA), is an important new target for neuroprotection. Our data provide evidence that treatment of pups after H/l injury with acetyl-L-carnitine (ALCAR) protects brain proteins and metabolism. We hypothesize that optimal neuroprotection following H/l injury can be achieved by preserving cerebral energy metabolism, key proteins and GABA synthesis through the post-injury administration of ALCAR. sulforaphane. and/or estradiol;therapeutic agents that protect by different mechanisms. The following Specific Aims will test these hypotheses: 1) Determine if both early and delayed alterations in mitochondrial proteins involved in energy metabolism after H/l are alleviated by normoxic resuscitation and treatment with ALCAR, SFP, estradiol or combined therapy;2) Determine if the early and long-term in vivo brain metabolic and structural changes (detectable by serial spectroscopy and imaging) after H/l are alleviated by ALCAR;3) Determine the long-term effects of H/l on neuronal and glial pathways of metabolism and synthesis of glutamate and GABA by "C-NMR spectroscopy and determine the cell specific efficacy of ALCAR for protecting key pathways of metabolism. A powerful combination of biochemical methods, in vivo 31 P and[1]'H MRS. T2 and diffusion weighted imaging (DWI), diffusion tensor imaging (DTI), and [13]C-NMR, will be used to test these hypotheses. Results are expected to reveal unique insights into the timing, targets and mechanisms of injury in both neuronal and glial metabolic pathways after H/l.

Public Health Relevance

Our studies will determine both acute and long term effects of neonatal hypoxic ischemic injury and normoxic versus hyperoxic recovery on brain metabolism. Our goal is to develop the use of ALCAR and combined treatments of clinically realistic targeted neuroprotecfive interventions to minimize injury to brain based on knowledge of the specific molecular and cellular mechanisms contributing to brain injury.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Pediatrics Subcommittee (CHHD)
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University of Maryland Baltimore
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Jevtovic-Todorovic, V; Absalom, A R; Blomgren, K et al. (2013) Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar. Br J Anaesth 111:143-51
Waddell, Jaylyn; Bowers, J Michael; Edwards, N Shalon et al. (2013) Dysregulation of neonatal hippocampal cell genesis in the androgen insensitive Tfm rat. Horm Behav 64:144-52
Balan, Irina S; Saladino, Andrew J; Aarabi, Bizhan et al. (2013) Cellular alterations in human traumatic brain injury: changes in mitochondrial morphology reflect regional levels of injury severity. J Neurotrauma 30:367-81
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Perez-Pinzon, Miguel A; Stetler, R Anne; Fiskum, Gary (2012) Novel mitochondrial targets for neuroprotection. J Cereb Blood Flow Metab 32:1362-76
Clerc, Pascaline; Polster, Brian M (2012) Investigation of mitochondrial dysfunction by sequential microplate-based respiration measurements from intact and permeabilized neurons. PLoS One 7:e34465
McKenna, Mary C (2011) Glutamate dehydrogenase in brain mitochondria: do lipid modifications and transient metabolon formation influence enzyme activity? Neurochem Int 59:525-33
Kahraman, Sibel; Bambrick, Linda L; Fiskum, Gary (2011) Effects of FK506 and cyclosporin a on calcium ionophore-induced mitochondrial depolarization and cytosolic calcium in astrocytes and neurons. J Neurosci Res 89:1973-8
Scafidi, Susanna; Fiskum, Gary; Lindauer, Steven L et al. (2010) Metabolism of acetyl-L-carnitine for energy and neurotransmitter synthesis in the immature rat brain. J Neurochem 114:820-31
Greco, Tiffany; Fiskum, Gary (2010) Neuroprotection through stimulation of mitochondrial antioxidant protein expression. J Alzheimers Dis 20 Suppl 2:S427-37

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