Brain redox imaging using blood-brain barrier-permeable nitroxide MRI contrast agent

Fuminori Hyodo, Kai Hsiang Chuang, Artem G. Goloshevsky, Agnieszka Sulima, Gary L. Griffiths, James B. Mitchell, Alan P. Koretsky, Murali C. Krishna

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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 T1-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.

Original languageEnglish
Pages (from-to)1165-1174
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Volume28
Issue number6
DOIs
Publication statusPublished - Jun 30 2008

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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    Hyodo, F., Chuang, K. H., Goloshevsky, A. G., Sulima, A., Griffiths, G. L., Mitchell, J. B., Koretsky, A. P., & Krishna, M. C. (2008). Brain redox imaging using blood-brain barrier-permeable nitroxide MRI contrast agent. Journal of Cerebral Blood Flow and Metabolism, 28(6), 1165-1174. https://doi.org/10.1038/jcbfm.2008.5