Journal
ACS CHEMICAL NEUROSCIENCE
Volume 4, Issue 11, Pages 1439-1445Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cn400159h
Keywords
Mito-TEMPO; methoxy-TEMPO; TEMPOL; superoxide; nitroxide-enhanced magnetic resonance imaging; Parkinson's disease
Funding
- Ministry of Education, Science and Technology of Japan
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We report a new methodology for direct visualization of superoxide production in the dopaminergic area of the brain in Parkinson's disease, based on the redox cycle of mito-TEMPO, a blood-brain barrier-, cell-, and mitochondria-penetrating nitroxide derivative with superoxide scavenging properties and T-1 magnetic resonance imaging (MRI) contrast. The experiments were conducted on healthy and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. In healthy mice, the nitroxide-enhanced MRI signal was weak and short-lived (half-life similar to 40 s; duration similar to 80 s). The profile of the histograms indicated a high reducing activity of normal brain tissues against mito-TEMPO. In MPTP-treated mice, the nitroxide-enhanced MRI signal was strong and long-lived (half-life > 20 mm; duration > 20 min), especially in the dopaminergic area of the brain. The histograms indicated a high oxidative activity in dopaminergic tissues of MPTP-treated mice. The results show directly, on intact mammals, that superoxide is a major inducer and/or mediator of neurodegenerative damage in Parkinson's disease. The high oxidative status of brain tissue in Parkinson's disease was also confirmed on isolated tissue specimens, using total reducing capacity assay and ROS/RNS assay.
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