The pathophysiology of hypoxia-induced injury to the immature brain is not well understood but is linked to a vicious cycle between oxidative stress and mitochondrial dysfunction. In an effort to promote aerobic energy metabolism, neonates often receive hyperoxic ventilation following global cerebral hypoxia or ischemia. We have found that hyperoxic reoxygenation promotes oxidative stress, damages metabolic enzymes, and worsens energy metabolism and neurologic outcome. These studies have uncovered mechanisms of metabolic failure, including impaired pyruvate dehydrogenase complex (PDHC) activity and loss of mitochondrial NAD(H). Preliminary evidence also indicates that combination therapeutic approaches are available that both ameliorate the metabolic abnormalities and improve outcome. These approaches include genomic post-conditioning by administration of agents, e.g., sulforaphane (SFP), which stimulate the Nr^ mediated transcriptional activation of Phase 2 response, antioxidant and anti-inflammatory genes. We therefore hypothesize that optimal neuroprotection following neonatal cerebral hypoxic ischemia (HII) can be achieved by eariy minimization of oxidative stress and optimization of mitochondrial energy metabolism through the combined interventions of avoiding unnecessary hyperoxia and post-administration of SFP. There are two main aims for this grant period: 1. Determine If both early and delayed oxidative stress, neuronal death, and neurologic Impairment after HII are alleviated by the individual and combined approaches of normoxic re-oxygenatlon and sulforaphane administration. 2. Identify the mechanisms by which mitochondrial metabolic dysfunction contributes to neurodegeneration after neonatal HII, and determine how they are Influenced by gender, levels of ambient [Ozj and activation of the Nrt2-regulated pathway of gene expression. Methods of approach to these aims include the use of male and female rats and Nrf2 +/+ and -/- mice, behavioral outcomes, stereologic histopathology, immunohistochemistry, measurements of mitochondrial proteins and bioenergetic activities, and exposure of cultured Nrf2 +/+ and - /-neurons to transient O2 and glucose deprivation (OGD), and unique quantitative measures of neuronal respiration and glycolysis. The use of both animal and cellular models of H/l in collaboration with Projects 2 and 3 will allow us to elucidate mitochondrial mechanisms of ischemic neuronal dysfunction and death and the molecular pathways through which normoxic re-oxygenation and genomic post-conditioning by SFP reduce neurodegeneration in the immature brain.

Public Health Relevance

The translational significance of these studies is that they could identify one or more combinations of neuroprotective interventions that could be safely tested in clinical trials with neonates that experience asphyxial hypoxia. The mechanistic significance of our work is that it will provide a much needed identification ofthe factors that limit brain energy metabolism at different periods after HI and how different levels of oxidative stress modulate these factors.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD016596-27
Application #
8438435
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
27
Fiscal Year
2013
Total Cost
$185,207
Indirect Cost
$61,740
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Ferreira, Gustavo C; McKenna, Mary C (2017) L-Carnitine and Acetyl-L-carnitine Roles and Neuroprotection in Developing Brain. Neurochem Res 42:1661-1675
Tang, Shiyu; Xu, Su; Lu, Xin et al. (2016) Neuroprotective Effects of Acetyl-L-Carnitine on Neonatal Hypoxia Ischemia-Induced Brain Injury in Rats. Dev Neurosci 38:384-396
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
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; McCarthy, Margaret M (2015) Sex differences in mitochondrial (dys)function: Implications for neuroprotection. J Bioenerg Biomembr 47:173-88
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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
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
McKenna, Mary C; Scafidi, Susanna; Robertson, Courtney L (2015) Metabolic Alterations in Developing Brain After Injury: Knowns and Unknowns. Neurochem Res 40:2527-43

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