Abstract
Within the ischemic penumbra, blood flow is sufficiently reduced that it results in hypoxia severe enough to arrest physiological function. Nevertheless, it has been shown that cells present within this region can be rescued and resuscitated by restoring perfusion and through other protective therapies. Thus, the early detection of the ischemic penumbra can be exploited to improve outcomes after focal ischemia. Hypoxia-inducible factor (HIF)-1 is a transcription factor induced by a reduction in molecular oxygen levels. Although the role of HIF-1 in the ischemic penumbra remains unknown, there is a strong correlation between areas with HIF-1 activity and the ischemic penumbra. We recently developed a near-infrared fluorescently labeled-fusion protein, POH-N, with an oxygen-dependent degradation property identical to the alpha subunit of HIF-1. Here, we conduct in vivo imaging of HIF-active regions using POH-N in ischemic brains after transient focal cerebral ischemia induced using the intraluminal middle cerebral artery occlusion technique in mice. The results demonstrate that POH-N enables the in vivo monitoring and ex vivo detection of HIF-1-active regions after ischemic brain injury and suggest its potential in imaging and drug delivery to HIF-1-active areas in ischemic brains.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / drug effects
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Brain / metabolism*
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Brain / pathology
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Hypoxia-Ischemia, Brain / diagnosis*
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Hypoxia-Ischemia, Brain / metabolism
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Hypoxia-Ischemia, Brain / pathology
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Infarction, Middle Cerebral Artery
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Injections, Intravenous
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Ischemic Attack, Transient / diagnosis*
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Ischemic Attack, Transient / metabolism
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Ischemic Attack, Transient / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Molecular Imaging / methods*
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Molecular Probes / administration & dosage
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Molecular Probes / metabolism*
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Oxygen / metabolism*
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / metabolism*
Substances
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Molecular Probes
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Recombinant Fusion Proteins
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Oxygen
Grants and funding
This work was supported by Grants-in-Aid for Young Scientists (B) (to YF) and for Scientific Research (B) (to MI) from the Japanese Ministry of Education, Science, and Culture and by the Global COE Program “Center for Frontier Medicine” funded by the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan. This study is part of a joint research program focusing on the development of technology to establish a Center of Excellence for nanomedicine and carried out by the Kyoto City Collaboration of Regional Entities for Advancing Technology Excellence assigned by the Japan Science and Technology Agency. The funders had no role in study design, data collection and analysis, the decision to publish, or manuscript preparation.