Brain redox imaging using blood-brain barrier-permeable nitroxide MRI contrast agent.
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.
Hyodo
Fuminori
F
Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1002, USA.
Chuang
Kai-Hsiang
KH
Goloshevsky
Artem G
AG
Sulima
Agnieszka
A
Griffiths
Gary L
GL
Mitchell
James B
JB
Koretsky
Alan P
AP
Krishna
Murali C
MC
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
D003287:Contrast Media; D009589:Nitrogen Oxides; C039900:nitroxyl