We have found recently that the expression of hypoxia-inducible factor-lalpha (HIF-Ialpha) is enhanced in the ischemic tissues after cerebral ischemia; the time course of HIF-Ialpha expression after ischemia is consistent with the time course of apoptosis; hyper/normal baric oxygen (HBO/NBO) suppresses HIF-lalpha, reduces apoptosis, decreases infarct volume, and improves neurological function. These findings have given rise to an overall hypothesis that HBO/NBO is neuroprotective by inhibition of HIF-la and apoptosis. To test this hypothesis, we propose the following four Specific Aims.
The Specific Aim 1 will study the effect of HBO/NBO on brain protection and HIF-lalpha expression. Our specific hypothesis is that HBO/NBO improves brain morphology and function after cerebral ischemia and decreases HIF-lalpha expression.
The specific Aim 2 will study the mechanism of HBO/NBO on HIF-la degradation. Our specific hypothesis is that HBO/NBO increases tissue oxygen and promotes the degradation of HIF-lalpha, especially the complex of HIF-Ialpha with p53. HBO/NBO modulates other HIF-lalpha regulating factors including proteasomal activity and insulin-like growth factor-l.
The Specific Aim 3 will study the effect of HBO/NBO on HIF-lalpha target genes involved in apoptosis including P53, proapoptotic proteins Nip3, and caspase-9. Our specific hypothesis is that HIF-Ialpha activates apoptotic genes; HBO/NBO reduces HIF-lalpha target apoptotic genes and reduces apoptosis.
The Specific Aim 4 will study the effect of HBO/NBO on HIF-la target genes involved in brain metabolism including glycolytic enzymes, glucose transporters, and inducible nitric oxide synthase (iNOS). Our specific hypothesis is that HBO/NBO reduces glucose, pyruvate, lactate, and nitric oxide (NO) in the ischemic regions by regulating the expression of glycolytic enzymes, glucose transporters and reducing iNOS. We will use a middle cerebral artery occlusion and reperfusion (MCAO/R) rat model in all studies, and we plan to use only one transient (1 hr) HBO/NBO treatment at 3 hrs after reperfusion to avoid the possible harmful effect associated with prolonged HBO/NBO therapy, which might enhance lipid peroxidation. The long-term goal of this study is to establish a role of HBO/NBO as a treatment in acute stroke and to identify the molecular mechanisms of its brain protection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043338-04
Application #
6982795
Study Section
Brain Disorders and Clinical Neuroscience 5 (BDCN)
Program Officer
Golanov, Eugene V
Project Start
2003-12-01
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
4
Fiscal Year
2006
Total Cost
$365,822
Indirect Cost
Name
Loma Linda University
Department
Surgery
Type
Schools of Medicine
DUNS #
009656273
City
Loma Linda
State
CA
Country
United States
Zip Code
92350
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Wang, Yuechun; Sherchan, Prativa; Huang, Lei et al. (2017) Naja sputatrix Venom Preconditioning Attenuates Neuroinflammation in a Rat Model of Surgical Brain Injury via PLA2/5-LOX/LTB4 Cascade Activation. Sci Rep 7:5466
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McBride, Devin W; Legrand, Julia; Krafft, Paul R et al. (2016) Acute Hyperglycemia Is Associated with Immediate Brain Swelling and Hemorrhagic Transformation After Middle Cerebral Artery Occlusion in Rats. Acta Neurochir Suppl 121:237-41
McBride, Devin W; Wang, Yuechun; Sherchan, Prativa et al. (2015) Correlation between subacute sensorimotor deficits and brain water content after surgical brain injury in rats. Behav Brain Res 290:161-71
Wang, Yuechun; Reis, Cesar; Applegate 2nd, Richard et al. (2015) Ischemic conditioning-induced endogenous brain protection: Applications pre-, per- or post-stroke. Exp Neurol 272:26-40
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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