title: Imaging of superoxide generation in the dopaminergic area of the brain in Parkinson's disease, using mito-TEMPO.
abstract: 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 T1 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 ∼ 40 s; duration ∼ 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 min; 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.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Zhivko
authors.initials: Z
authors.lastname: Zhelev
authors.forename: Rumiana
authors.initials: R
authors.lastname: Bakalova
authors.forename: Ichio
authors.initials: I
authors.lastname: Aoki
authors.forename: Dessislava
authors.initials: D
authors.lastname: Lazarova
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000633:toxicity; D003497:Cyclic N-Oxides / Q000633:toxicity*; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000378:metabolism / Q000633:toxicity*; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D016166:Free Radical Scavengers / Q000378:metabolism / Q000633:toxicity; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000633:toxicity; D007274:Injections, Intraperitoneal; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D009498:Neurotoxins / Q000008:administration & dosage / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000633:toxicity; D013113:Spin Labels; D013378:Substantia Nigra / Q000187:drug effects* / Q000502:physiology; D013481:Superoxides / Q000378:metabolism* / Q000633:toxicity
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D015259:Dopamine Agents; D016166:Free Radical Scavengers; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D013113:Spin Labels; D013481:Superoxides; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D006861:Hydrogen Peroxide; C003959:TEMPO
references.citation: Mol Pharm. 2009 Mar-Apr;6(2):504-12
references.pmid: 19718801
references.citation: Mol Biosyst. 2012 Oct;8(10):2733-40
references.pmid: 22832934
references.citation: J Biol Chem. 1991 Feb 15;266(5):2724-31
references.pmid: 1993652
references.citation: J Am Chem Soc. 2003 Jan 22;125(3):789-95
references.pmid: 12526680
references.citation: Free Radic Res. 2011 Apr;45(4):417-30
references.pmid: 21128732
references.citation: Free Radic Biol Med. 2011 Feb 1;50(3):459-68
references.pmid: 21130158
references.citation: Chem Commun (Camb). 2009 Jan 7;(1):53-5
references.pmid: 19081996
references.citation: Nat Protoc. 2007;2(1):141-51
references.pmid: 17401348
references.citation: Cancer Res. 2006 Oct 15;66(20):9921-8
references.pmid: 17047054
references.citation: Antioxid Redox Signal. 2013 Aug 1;19(4):344-9
references.pmid: 23373855
references.citation: Free Radic Biol Med. 1997;22(6):967-76
references.pmid: 9034235
references.citation: Biochim Biophys Acta. 2008 Nov;1780(11):1362-7
references.pmid: 18358848
references.citation: Nat Rev Neurosci. 2006 Mar;7(3):207-19
references.pmid: 16495942
references.citation: Methods Mol Biol. 2011;711:397-419
references.pmid: 21279614
references.citation: Free Radic Biol Med. 2007 Feb 1;42(3):404-12
references.pmid: 17210453
references.citation: J Cereb Blood Flow Metab. 2008 Jun;28(6):1165-74
references.pmid: 18270519
references.citation: Biol Pharm Bull. 2011;34(1):142-5
references.pmid: 21212532
references.citation: Free Radic Biol Med. 2013 Sep;62:90-101
references.pmid: 23200807
references.citation: Circ Res. 2010 Jul 9;107(1):106-16
references.pmid: 20448215
references.citation: Eur J Cancer. 2013 Apr;49(6):1467-78
references.pmid: 23265713
references.citation: Clin Cancer Res. 2006 Apr 15;12(8):2455-62
references.pmid: 16638852
references.citation: Clin Cancer Res. 2013 May 1;19(9):2503-17
references.pmid: 23532887
references.citation: Science. 1983 Feb 25;219(4587):979-80
references.pmid: 6823561
references.citation: Neurodegeneration. 1995 Sep;4(3):257-69
references.pmid: 8581558
references.citation: Neuron. 2003 Sep 11;39(6):889-909
references.pmid: 12971891
references.citation: Nat Rev Neurosci. 2003 May;4(5):365-75
references.pmid: 12728264
references.citation: Antioxid Redox Signal. 2010 Sep 15;13(6):877-918
references.pmid: 20095865
references.citation: Brain Res. 1997 Aug 15;765(2):183-8
references.pmid: 9313890