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'H MRS. T2 and diffusion weighted imaging (DWI), diffusion tensor imaging (DTI), and 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.
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.
|Waddell, Jaylyn; Hanscom, Marie; Shalon Edwards, N et al. (2016) Sex differences in cell genesis, hippocampal volume and behavioral outcomes in a rat model of neonatal HI. Exp Neurol 275 Pt 2:285-95|
|Demarest, Tyler G; Schuh, Rosemary A; Waddell, Jaylyn et al. (2016) Sex-dependent mitochondrial respiratory impairment and oxidative stress in a rat model of neonatal hypoxic-ischemic encephalopathy. J Neurochem 137:714-29|
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|Kahraman, Sibel; Siegel, Alex; Polster, Brian M et al. (2015) Permeability transition pore-dependent and PARP-mediated depletion of neuronal pyridine nucleotides during anoxia and glucose deprivation. J Bioenerg Biomembr 47:53-61|
|Xu, Su; Waddell, Jaylyn; Zhu, Wenjun et al. (2015) In vivo longitudinal proton magnetic resonance spectroscopy on neonatal hypoxic-ischemic rat brain injury: Neuroprotective effects of acetyl-L-carnitine. Magn Reson Med 74:1530-42|
|Roelofs, Brian A; Ge, Shealinna X; Studlack, Paige E et al. (2015) Low micromolar concentrations of the superoxide probe MitoSOX uncouple neural mitochondria and inhibit complex IV. Free Radic Biol Med 86:250-8|
|McKenna, Mary C; Rae, Caroline D (2015) A new role for Î±-ketoglutarate dehydrogenase complex: regulating metabolism through post-translational modification of other enzymes. J Neurochem 134:3-6|
|McKenna, Mary C; Scafidi, Susanna; Robertson, Courtney L (2015) Metabolic Alterations in Developing Brain After Injury: Knowns and Unknowns. Neurochem Res 40:2527-43|
|Demarest, Tyler G; McCarthy, Margaret M (2015) Sex differences in mitochondrial (dys)function: Implications for neuroprotection. J Bioenerg Biomembr 47:173-88|
|Pershing, Michelle L; Bortz, David M; Pocivavsek, Ana et al. (2015) Elevated levels of kynurenic acid during gestation produce neurochemical, morphological, and cognitive deficits in adulthood: implications for schizophrenia. Neuropharmacology 90:33-41|
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