title: One-electron reduction of 6-hydroxydopamine quinone is essential in 6-hydroxydopamine neurotoxicity.
abstract: 6-Hydroxydamine has widely been used as neurotoxin in preclinical studies related on the neurodegenerative process of dopaminergic neurons in Parkinson's disease based on its ability to be neurotoxic as a consequence of free radical formation during its auto-oxidation to topaminequinone. We report that 50-µM 6-hydroxydopamine is not neurotoxic in RCSN-3 cells derived from substantia nigra incubated during 24 h contrasting with a significant sixfold increase in cell death (16 ± 2 %; P < 0.001) was observed in RCSN-3NQ7 cells expressing a siRNA against DT-diaphorase that silence the enzyme expression. To observe a significant cell death in RCSN-3 cells induced by 6-hydroxydopamine (24 ± 1 %; P < 0.01), we have to increase the concentration to 250 μm while a 45 ± 2 % cell death (P < 0.001) was observed at this concentration in RCSN-3NQ7 cells. The cell death induced by 6-hydroxydopamine in RCSN-3NQ7 cells was accompanied with a (i) significant increase in oxygen consumption (P < 0.01), (ii) depletion of reduced glutathione and (iii) a significant decrease in ATP level (P < 0.05) in comparison with RCSN-3 cells. In conclusion, our results suggest that one-electron reduction of 6-hydroxydopamine quinone seems to be the main reaction responsible for 6-hydroxydopamine neurotoxic effects in dopaminergic neurons and DT-diaphorase seems to play an important neuroprotective role by preventing one-electron reduction of topaminequinone.
authors: Program of Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.
authors: Monica
authors: M
authors: Villa
authors: Patricia
authors: P
authors: Muñoz
authors: Ulises
authors: U
authors: Ahumada-Castro
authors: Irmgard
authors: I
authors: Paris
authors: Ana
authors: A
authors: Jiménez
authors: Isabel
authors: I
authors: Martínez
authors: Francisca
authors: F
authors: Sevilla
authors: Juan
authors: J
authors: Segura-Aguilar
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004583:Electrons; D005978:Glutathione / Q000378:metabolism; D006892:Hydroxydopamines / Q000737:chemistry* / Q000633:toxicity*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D016627:Oxidopamine / Q000737:chemistry* / Q000633:toxicity*; D010101:Oxygen Consumption / Q000187:drug effects; D011809:Quinones / Q000737:chemistry* / Q000633:toxicity*; D051381:Rats; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
chemical_list: D006892:Hydroxydopamines; D011809:Quinones; C083552:1,2(4)-topaminequinone; D016627:Oxidopamine; D000255:Adenosine Triphosphate; D016660:NAD(P)H Dehydrogenase (Quinone); D005978:Glutathione
references: Science. 1971 Jun 18;172(3989):1257-8
references: 5576164
references: Science. 1973 Aug 3;181(4098):456-7
references: 4718113
references: Brain Res. 2008 Mar 4;1197:159-69
references: 18234165
references: J Neurochem. 2001 Apr;77(2):519-29
references: 11299314
references: Neurotox Res. 2010 Apr;17(3):299-304
references: 19760476
references: J Biol Chem. 2005 Jun 3;280(22):21212-9
references: 15817478
references: Brain Res Bull. 2010 Apr 5;81(6):543-8
references: 20097273
references: Physiol Plant. 2013 Feb;147(2):194-206
references: 22607494
references: Neuroscience. 2006 Nov 17;143(1):1-6
references: 17027171
references: Neurotox Res. 2008 May-Jun;13(3-4):221-30
references: 18522901
references: Biochim Biophys Acta. 2012 Jul;1822(7):1125-36
references: 22483869
references: Neurotox Res. 2009 Jan;15(1):82-95
references: 19384591
references: Behav Brain Res. 2010 Jun 26;210(1):46-53
references: 20138919
references: Neurotox Res. 2009 May;15(4):359-66
references: 19384569
references: J Biol Chem. 2009 May 15;284(20):13306-13315
references: 19265190
references: J Neurochem. 2005 Mar;92(5):1021-32
references: 15715653
references: Neurotox Res. 2012 Aug;22(2):177-80
references: 22528249
references: Chem Res Toxicol. 2010 Sep 20;23(9):1492-6
references: 20849151
references: Neurotox Res. 2009 Feb;15(2):111-22
references: 19384573
references: Neurobiol Dis. 2006 Nov;24(2):296-307
references: 16978869
references: Brain Res Mol Brain Res. 2003 Nov 26;119(2):125-31
references: 14625079
references: Arch Biochem Biophys. 1984 May 15;231(1):164-8
references: 6426392
references: Neurotox Res. 2010 Jul;18(1):82-92
references: 20087799
references: J Neural Transm Suppl. 1997;50:55-66
references: 9120425
references: Chem Res Toxicol. 2007 May;20(5):776-83
references: 17425337
references: Toxicol Sci. 2011 Jun;121(2):376-88
references: 21427056
references: Biochim Biophys Acta. 1992 Mar 27;1120(1):33-42
references: 1372830
references: Nat Med. 2005 Nov;11(11):1214-21
references: 16227987
references: Parkinsons Dis. 2012;2012:920953
references: 22966478
references: Neurotox Res. 2009 Oct;16(3):271-9
references: 19526278
references: J Med Chem. 1995 Mar 17;38(6):917-22
references: 7699708
references: Neurobiol Dis. 2004 Jul;16(2):468-77
references: 15193303
references: Curr Biol. 2000 Oct 19;10(20):R757-9
references: 11069102
references: Neurobiol Dis. 2009 Jun;34(3):487-500
references: 19332121