Our proposed study will delineate the roles of tissue oxygenation (pO2) and specific free radicals in the pathophysiology of cerebral ischemia and reperfusion. We have developed techniques to measure tissue pO2 and generation of free radicals in vivo, as a function of time in specific focal regions of the brain, using Electron Paramagnetic Resonance (EPR) spectroscopy. Using a middle cerebral artery occlusion (MCAO) model of ischemic stroke in the rat, we have obtained preliminary results showing that decreased pO2 after MCAO leads to a dramatic and unexpected increase in generation of free radicals. Normobaric hyperoxia treatment immediately after an MCAO not only increased tissue pO2, but also decreased free radical generation, contrary to common expectation. Furthermore, hyperoxia treatment during ischemia reduces infarction volume and improves the neurological function of the animal. These results demonstrate that studying the effects of tissue pO2 on free radical generation, and the resulting molecular responses, will be critically important in understanding the molecular events in free radical-induced brain injury, and in developing effective oxygen-based treatment strategies for ischemic stroke. We hypothesize that low levels of localized tissue pO2 during focal cerebral ischemia result in an increased generation of free radicals, which in turn activates deleterious molecular events, including the activation of matrix metalloproteinase (MMP) and the caspase cascade, leading to microvascular damage and cell death. To test this hypothesis, we will: 1) Determine the effect of hyperoxia treatment on tissue pO2 and free radical generation in the ischemic core, penumbra, and control areas in the MCAO model of ischemic stroke in the rat. 2) Determine the effect of hyperoxia treatment on the expression and activation of MMP-2, 3 and 9, and caspase-3, 8, and 9 following cerebral ischemia and reperfusion at the same locations where tissue pO2 and free radical generation are measured. 3) Determine the effects of increasing tissue pO2 with hyperoxia treatment on blood-brain barrier opening, neurological score, infarction volume, and edema. The proposed research will provide new insight into the mechanism of cerebral injury during ischemic stroke, and aid in the design of more effective neuroprotective strategies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Petanceska, Suzana
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University of New Mexico
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Schools of Pharmacy
United States
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Pan, Rong; Liu, Ke Jian (2016) ZNT-1 Expression Reduction Enhances Free Zinc Accumulation in Astrocytes After Ischemic Stroke. Acta Neurochir Suppl 121:257-61
Weaver, John; Liu, Ke Jian (2015) Does normobaric hyperoxia increase oxidative stress in acute ischemic stroke? A critical review of the literature. Med Gas Res 5:11
Pan, Rong; Timmins, Graham S; Liu, Wenlan et al. (2015) Autophagy Mediates Astrocyte Death During Zinc-Potentiated Ischemia--Reperfusion Injury. Biol Trace Elem Res 166:89-95
Zhao, Yongmei; Pan, Rong; Li, Sen et al. (2014) Chelating intracellularly accumulated zinc decreased ischemic brain injury through reducing neuronal apoptotic death. Stroke 45:1139-47
Weaver, John; Yang, Yirong; Purvis, Rebecca et al. (2014) In vivo evidence of methamphetamine induced attenuation of brain tissue oxygenation as measured by EPR oximetry. Toxicol Appl Pharmacol 275:73-8
Li, Ying-Na; Pan, Rong; Qin, Xu-Jun et al. (2014) Ischemic neurons activate astrocytes to disrupt endothelial barrier via increasing VEGF expression. J Neurochem 129:120-9
Pan, Rong; Chen, Chen; Liu, Wen-Lan et al. (2013) Zinc promotes the death of hypoxic astrocytes by upregulating hypoxia-induced hypoxia-inducible factor-1alpha expression via poly(ADP-ribose) polymerase-1. CNS Neurosci Ther 19:511-20
Liu, Jie; Jin, Xinchun; Liu, Ke J et al. (2012) Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood-brain barrier damage in early ischemic stroke stage. J Neurosci 32:3044-57
Jin, Xinchun; Liu, Jie; Yang, Yi et al. (2012) Spatiotemporal evolution of blood brain barrier damage and tissue infarction within the first 3h after ischemia onset. Neurobiol Dis 48:309-16
Liu, Changsuo; Weaver, John; Liu, Ke Jian (2012) Rapid conditioning with oxygen oscillation: neuroprotection by intermittent normobaric hyperoxia after transient focal cerebral ischemia in rats. Stroke 43:220-6

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