title: Brain redox imaging using blood-brain barrier-permeable nitroxide MRI contrast agent.
abstract: Reactive oxygen species (ROS) and compromised antioxidant defense may contribute to brain disorders such as stroke, amyotrophic lateral sclerosis, etc. Nitroxides are redox-sensitive paramagnetic contrast agents and antioxidants. The ability of a blood-brain barrier (BBB)-permeable nitroxide, methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (MC-P), as a magnetic resonance-imaging (MRI) contrast agent for brain tissue redox imaging was tested. MC-P relaxation in rodent brain was quantified by MRI using a fast Look-Locker T(1)-mapping sequence. In the cerebral cortex and thalamus, the MRI signal intensity increased up to 50% after MC-P injection, but increased only by 2.7% when a BBB-impermeable nitroxide, 3CxP (3-carboxy-2,2,5,5,5-tetramethylpyrrolidine-1-oxyl) was used. The maximum concentrations in the thalamus and cerebral cortex after MC-P injection were calculated to be 1.9+/-0.35 and 3.0+/-0.50 mmol/L, respectively. These values were consistent with the ex vivo data of brain tissue and blood concentration obtained by electron paramagnetic resonance (EPR) spectroscopy. Also, reduction rates of MC-P were significantly decreased after reperfusion following transient MCAO (middle cerebral artery occlusion), a condition associated with changes in redox status resulting from oxidative damage. These results show the use of BBB-permeable nitroxides as MRI contrast agents and antioxidants to evaluate the role of ROS in neurologic diseases.
authors.affiliation: Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1002, USA.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Hyodo
authors.forename: Kai-Hsiang
authors.initials: KH
authors.lastname: Chuang
authors.forename: Artem G
authors.initials: AG
authors.lastname: Goloshevsky
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Sulima
authors.forename: Gary L
authors.initials: GL
authors.lastname: Griffiths
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: Alan P
authors.initials: AP
authors.lastname: Koretsky
authors.forename: Murali C
authors.initials: MC
authors.lastname: Krishna
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D003287:Contrast Media / Q000032:analysis*; D004583:Electrons; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D015394:Molecular Structure; D009589:Nitrogen Oxides / Q000032:analysis*; D010084:Oxidation-Reduction; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003287:Contrast Media; D009589:Nitrogen Oxides; C039900:nitroxyl