This renewal proposal is designed to investigate the mechanisms of hyperbaric oxygen induced preconditioning (HBO-PC) in a focal cerebral ischemic model produced by Middle Cerebral Artery Occlusion (MCAO). For broadening of clinical applicability, it was also designed to evaluate efficacy of HBO-PC against other brain injuries by using a global cerebral ischemia model produced by Four Vessel Occlusion (4VO);and a Surgical Brain Injury (SBI) model which represents brain injury caused by neurosurgical procedures. Based on these preliminary results demonstrating HIF-1 specifically responds to HBO, publications by us and others, and the fact that HIF-1 is the main oxygen sensing protein, our Central Hypothesis is that HBO produces preconditioning by transiently inducing HIF-1 and its downstream target genes responsible for cell death and blood-brain barrier (BBB) disruption and thereby leads to ischemic tolerance to subsequent major brain insult. The following specific aims are proposed to address our hypothesis.
Aim 1 : To determine the mechanism of HIF-1 induction by HBO-PC in brain tissue and broad efficacy of HBO-PC. Our specific hypothesis is that HBO-PC produces moderate levels of reactive oxygen species (ROS) which, by destabilization of prolyl hydroxylase 2 (PHD2), induces HIF-1 accumulation in brain tissue. Interventions such as quenching ROS or enhancing PHD2 will abolish induction of HIF-1 by HBO-PC and thereby abolish preconditioning effects. It is expected that HBO-PC is a broadly effective modality that reduces brain injuries as a consequence of MCAO, SBI, and 4VO models.
Aim 2 : To determine the mechanism by which HIF-1 induction leads to tolerance against apoptotic cell death after cerebral ischemia. Our specific hypothesis is that HIF-1, induced by HBO-PC, binds to and stabilizes p53. This p53 accumulation and activation of its downstream proteins: Bax and caspase-3 result in tolerance against subsequent cerebral ischemia-induced cell death. Interventions such as pharmacological inhibition of p53 and caspase-3 are expected to abolish HBO-PC-induced cell protection.
Aim 3 : To determine the mechanism by which HIF-1 induction leads to tolerance against BBB disruption after cerebral ischemia. Our specific hypothesis is that HIF-1, induced by HBO-PC, activates VEGF and its down streams through three possible pathways which will provide tolerance against subsequent cerebral ischemia-induced BBB disruption and brain edema. The long term goal of this proposal is to establish HBO-PC as a clinically means to prevent or reduce brain injuries that can either complicate major cardiac or liver surgeries (4VO model) or that are a result of neurosurgical procedures (MCAO, SBI models). To pursue this goal we will establish the mechanistic basis for HBO-PC at a molecular level. We will also determine the long term beneficial effect of HBO-PC as measured by neurological and neurobehavioral outcomes. The clinical implication of HBO-PC, as an effective, easy to use, and safe modality, could be expanded to multiple brain injuries complicating major surgical procedures.

Public Health Relevance

This project intends to establish mechanisms of brain protection induced by oxygen at elevated pressures for patients with elective surgeries including neurosurgery, cardiac thoracic surgery and liver transplant.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043338-08
Application #
8254477
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2002-04-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$318,347
Indirect Cost
$103,972
Name
Loma Linda University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
009656273
City
Loma Linda
State
CA
Country
United States
Zip Code
92350
Hu, Qin; Liang, Xiping; Chen, Di et al. (2014) Delayed hyperbaric oxygen therapy promotes neurogenesis through reactive oxygen species/hypoxia-inducible factor-1?/?-catenin pathway in middle cerebral artery occlusion rats. Stroke 45:1807-14
Liang, Xiping; Hu, Qin; Li, Bo et al. (2014) Follistatin-like 1 attenuates apoptosis via disco-interacting protein 2 homolog A/Akt pathway after middle cerebral artery occlusion in rats. Stroke 45:3048-54
Fathali, Nancy; Ostrowski, Robert P; Hasegawa, Yu et al. (2013) Splenic immune cells in experimental neonatal hypoxia-ischemia. Transl Stroke Res 4:208-19
Manaenko, Anatol; Lekic, Tim; Ma, Qingyi et al. (2013) Hydrogen inhalation ameliorated mast cell-mediated brain injury after intracerebral hemorrhage in mice. Crit Care Med 41:1266-75
Lekic, Tim; Rolland, William; Manaenko, Anatol et al. (2013) Evaluation of the hematoma consequences, neurobehavioral profiles, and histopathology in a rat model of pontine hemorrhage. J Neurosurg 118:465-77
Mu, Jun; Ostrowski, Robert P; Soejima, Yoshiteru et al. (2013) Delayed hyperbaric oxygen therapy induces cell proliferation through stabilization of cAMP responsive element binding protein in the rat model of MCAo-induced ischemic brain injury. Neurobiol Dis 51:133-43
Hasegawa, Yu; Suzuki, Hidenori; Altay, Orhan et al. (2013) Role of the sphingosine metabolism pathway on neurons against experimental cerebral ischemia in rats. Transl Stroke Res 4:524-32
Soejima, Yoshiteru; Hu, Qin; Krafft, Paul R et al. (2013) Hyperbaric oxygen preconditioning attenuates hyperglycemia-enhanced hemorrhagic transformation by inhibiting matrix metalloproteinases in focal cerebral ischemia in rats. Exp Neurol 247:737-43
Lekic, Tim; Manaenko, Anatol; Rolland, William et al. (2012) Rodent neonatal germinal matrix hemorrhage mimics the human brain injury, neurological consequences, and post-hemorrhagic hydrocephalus. Exp Neurol 236:69-78
Hu, Qin; Ma, Qingyi; Zhan, Yan et al. (2011) Isoflurane enhanced hemorrhagic transformation by impairing antioxidant enzymes in hyperglycemic rats with middle cerebral artery occlusion. Stroke 42:1750-6

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