Hyodo Fuminori, Chuang Kai-Hsiang, Goloshevsky Artem G, Sulima Agnieszka, Griffiths Gary L, Mitchell James B, Koretsky Alan P, Krishna Murali C
Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1002, USA.
J Cereb Blood Flow Metab. 2008 Jun;28(6):1165-74. doi: 10.1038/jcbfm.2008.5. Epub 2008 Feb 13.
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.
活性氧（ROS）和抗氧化防御功能受损可能导致中风、肌萎缩侧索硬化症等脑部疾病。氮氧化物是对氧化还原敏感的顺磁性造影剂和抗氧化剂。测试了一种可透过血脑屏障（BBB）的氮氧化物——甲氧基羰基-2,2,5,5-四甲基吡咯烷-1-氧基（MC-P）作为脑组织氧化还原成像的磁共振成像（MRI）造影剂的能力。使用快速Look-Locker T(1)映射序列通过MRI对啮齿动物大脑中的MC-P弛豫进行定量。在大脑皮层和丘脑中，注射MC-P后MRI信号强度增加高达50%，但使用一种不能透过血脑屏障的氮氧化物3CxP（3-羧基-2,2,5,5,5-四甲基吡咯烷-1-氧基）时仅增加2.7%。计算出注射MC-P后丘脑和大脑皮层中的最大浓度分别为1.9±0.35和3.0±0.50 mmol/L。这些值与通过电子顺磁共振（EPR）光谱获得的脑组织和血液浓度的离体数据一致。此外，在短暂性大脑中动脉闭塞（MCAO）后再灌注后，MC-P的还原速率显著降低，MCAO这种情况与氧化损伤导致的氧化还原状态变化有关。这些结果表明，可透过血脑屏障的氮氧化物可作为MRI造影剂和抗氧化剂来评估ROS在神经系统疾病中的作用。
