In vivo imaging of brain ischemia using an oxygen-dependent degradative fusion protein probe

• Published in: PloS one 2012-10, Vol.7 (10), p.e48051-e48051
• Main Authors: Fujita, Youshi, Kuchimaru, Takahiro, Kadonosono, Tetsuya, Tanaka, Shotaro, Hase, Yoshiki, Tomimoto, Hidekazu, Hiraoka, Masahiro, Kizaka-Kondoh, Shinae, Ihara, Masafumi, Takahashi, Ryosuke
• Format: Article
• Language: English
• Subjects: Animals; Biotechnology; Blood flow; Brain; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain injury; Brain research; Cancer; Carotid arteries; Cerebral blood flow; Cerebral ischemia; Diagnosis; Diagnostic imaging; Drug delivery; Drug delivery systems; Fusion protein; Gene expression; Head injuries; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Hypoxia-Ischemia, Brain - diagnosis; Hypoxia-Ischemia, Brain - metabolism; Hypoxia-Ischemia, Brain - pathology; I.R. radiation; Imaging; In vivo methods and tests; Infarction, Middle Cerebral Artery; Injections, Intravenous; Ischemia; Ischemic Attack, Transient - diagnosis; Ischemic Attack, Transient - metabolism; Ischemic Attack, Transient - pathology; Male; Medical research; Medicine; Mice; Mice, Inbred C57BL; Molecular Imaging - methods; Molecular Probes - administration & dosage; Molecular Probes - metabolism; Neuroimaging; Neurology; Occlusion; Oxygen; Oxygen - metabolism; Patient outcomes; Perfusion; pOH; Proteins; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - metabolism; Stroke; Traumatic brain injury; Veins & arteries
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0048051

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.