A rapid decline in the cerebral blood flow leads to regions with very low levels of oxygen, which is a major cause of tissue damage in ischemic stroke. Several strategies have been developed to rescue ischemic tissue using animal models, especially rodents, but they failed in the clinical trials. In order to rationally develop effectiv therapies, it is crucial to understand the effect of ischemic stroke on cerebral tissue oxygen (pO2, partial pressure of oxygen) in the ischemic as well as contralateral regions of a clinically pertinent model of stroke. However, there are no suitable techniques for repeated measurement of cerebral pO2 and this has severely limited the understanding and development of effective therapies to improve the outcome of ischemic stroke. Our goal is to develop in vivo Electron Paramagnetic Resonance (EPR) oximetry with a novel class of implantable resonators for real-time monitoring of cerebral pO2 during ischemic stroke induced by embolic clot in rabbits. The rabbit embolic clot model has shown promising translational potential with the development of plasminogen activator for thrombolysis during ischemic stroke in humans. We hypothesize that the changes in cerebral pO2 during ischemic stroke can be used as a marker to predict outcome, testing the validity of the method by correlating with outcome when blood flow is restored by recombinant tissue plasminogen activator (rtPA). We will test the hypothesis by using the proposed implantable resonator-based EPR oximetry. We will first establish the implantable resonator technology for pO2 measurement in the ischemic and contralateral regions of the rabbit brain by EPR oximetry. Ischemic stroke will be induced by embolic clot for 3 hour and 6 hour, followed by treatment with rtPA to investigate the temporal changes in cerebral pO2. The position of the implantable resonator in the cerebral subcortex, perfusion, apparent diffusion coefficient of water (ADC) and infarct volume will be assessed non-invasively by MRI. The extent of decrease in cerebral pO2 during ischemia and re-oxygenation after rtPA treatment and its effect on the infarct volume will be determined to test the hypothesis. Additionally, we will study the effect of changes in the blood flow on cerebral pO2 and ADC in stroke. The data from these studies will facilitate the potential translation of the approaches developed in rabbit embolic clot model to treat patient's using MRI to guide the treatment. The research team, Drs. Khan and Hou (in vivo EPR oximetry and stroke), and Dr. Gimi (MRI) along with the consultants Drs. Swartz and Kuppusamy (pioneers of EPR technique), Dr. Gui (biostatistician) and Dr. Culp (stroke research) have the expertise and resources necessary to carry out the study. If successful, this project will establish the validity of using in vivo EPR oximetry to assess the dynamics of cerebral pO2 in a clinically relevant model of ischemic stroke, a unique capability not available at present.

Public Health Relevance

The development of therapies to counteract low levels of oxygen that leads to tissue damage in ischemic stroke has been restricted by the lack of a reliable method that can provide repeated assessment of cerebral oxygen (pO2, partial pressure of oxygen). We will develop a new method to repeatedly measure temporal changes in cerebral pO2 during stroke. The studies will be performed using a rabbit model of ischemic stroke induced by embolic clot, a model successfully used to predict the efficacy of tissue plasminogen activator in patients. The results will provide new insights on the effect of ischemia on cerebral pO2 and thus facilitate the development of therapies to prevent tissue damage in stroke.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Biomedical Imaging Technology Study Section (BMIT)
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Koenig, James I
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Dartmouth College
Schools of Medicine
United States
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Khan, Nadeem; Hou, Huagang; Eskey, Clifford J et al. (2015) Deep-tissue oxygen monitoring in the brain of rabbits for stroke research. Stroke 46:e62-6
Khan, Nadeem; Hou, Huagang; Swartz, Harold M et al. (2015) Direct and Repeated Measurement of Heart and Brain Oxygenation Using In Vivo EPR Oximetry. Methods Enzymol 564:529-52
Hou, Huagang; Li, Hongbin; Dong, Ruhong et al. (2014) Real-time monitoring of ischemic and contralateral brain pO2 during stroke by variable length multisite resonators. Magn Reson Imaging 32:563-9