title: In vivo imaging of brain ischemia using an oxygen-dependent degradative fusion protein probe.
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.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Youshi
authors.initials: Y
authors.lastname: Fujita
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kuchimaru
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kadonosono
authors.forename: Shotaro
authors.initials: S
authors.lastname: Tanaka
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hase
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tomimoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiraoka
authors.forename: Shinae
authors.initials: S
authors.lastname: Kizaka-Kondoh
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery; D007275:Injections, Intravenous; D002546:Ischemic Attack, Transient / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057054:Molecular Imaging / Q000379:methods*; D015335:Molecular Probes / Q000008:administration & dosage / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015335:Molecular Probes; D011993:Recombinant Fusion Proteins; D010100:Oxygen