The long-term goal of this study is to establish an oxygen therapy for neonatal hypoxia-ischemia and to identify the molecular mechanisms of oxygen treatment in brain protection. The Research Plan is based on our preliminary data that ONE treatment of 100% oxygen at normal baric pressure does in fact offer neuroprotection to the brain by reducing the damage to the ipsilateral hemisphere. These findings have given rise to the overall hypothesis that oxygen therapy will be beneficial to patients that have experienced a hypoxia-ischemia insult. To test this hypothesis, we propose the following four Specific Aims.
The Specific Aim 1 will determine if long term brain protection can be achieved by using a short oxygen exposure (1 hour) at normal baric pressure applied at one hr after hypoxic/ischemic insult. Our specific hypothesis is that oxygen treatment (only one treatment]) will reduce hypoxic-ischemic brain damage in terms of brain weight, morphology (regional differences will be examined and compared between grey and white matters, ischemic core vs. penumbra, and cortex vs. hippocampus) and neurological and behavior functions.
The Specific Aim 2 will examine the possible side effects of oxygen treatment. Our specific hypothesis is that only one oxygen treatment at constant normal baric pressure for short duration (1 hour) will result in no harmful side effects. Lipid peroxidation levels will be examined in the brain and lungs. Inflammatory responses will also be examined in the lungs. The occurrences of retinopathy of prematurity (ROP) will also be examined.
The Specific Aim 3 will study the molecular mechanisms of oxygen-induced brain protection, especially the role of hypoxia-inducible factor-lalpha (HIF-1alpha) and its downstream effectors. Our specific hypothesis is that severe HIF-1alpha up-regulation after neonatal hypoxia leads to the expression of pro-apoptotic genes and cell death. Oxygen treatment will reduce the hypoxic-induced upregulation of HIF-1alpha to a moderate level above normal level and thereby inhibit apoptotic pathways that are associated with HIF-1alpha and promote cell protective mechanisms through VEGF and erythropoietin.
The Specific Aim 4 will continue to study the molecular mechanisms of oxygen-induced brain protection, especially the role of inflammatory cytokines such as interleukin-1beta (IL-1 beta), IL-6, IL-IO, IL-11 and TNFalpha, and the role of inducible nitric oxide synthase (iNOS). Our specific hypothesis is that the level and expression of inflammatory cytokines and iNOS increased in injured brain tissues and lead to cell death.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Brain Disorders and Clinical Neuroscience 5 (BDCN)
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Vitkovic, Ljubisa
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Loma Linda University
Schools of Medicine
Loma Linda
United States
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Lekic, Tim; Klebe, Damon; Poblete, Roy et al. (2015) Neonatal brain hemorrhage (NBH) of prematurity: translational mechanisms of the vascular-neural network. Curr Med Chem 22:1214-38
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