title: Iron accelerates the conversion of dopamine-oxidized intermediates into melanin and provides protection in SH-SY5Y cells.
abstract: Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN), and it has been suggested that dopamine is one of the main endogenous toxins in the genesis of PD. We demonstrated that thiol antioxidants (the reduced form of glutathione, N-acetyl-L-cysteine, and L-cysteine), which conjugate with one dopamine oxidation intermediate, o-quinone, provided almost complete protection from dopamine-mediated toxicity in SH-SY5Y, a human neuroblastoma cell line. In contrast, catalase partially provided protection against cell death caused by dopamine. These data suggest that the generation of dopamine oxidation intermediates, rather than hydrogen peroxide, plays a pivotal role in dopamine-induced toxicity. Iron accumulated in the SN of patients with PD can cause dopaminergic neuronal degeneration by enhancing oxidative stress. However, we found that iron reduced the total amounts of dopamine oxidation intermediates and enhanced the formation of melanin, a final product of dopamine oxidation. Also, addition of iron inhibited dopamine-induced cytotoxicity. These results suggest that iron can provide protection when it accelerates the conversion of dopamine oxidation intermediates.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences,Kyoto University, Kyoto, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Izumi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sawada
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kume
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katsuki
authors.forename: Shun
authors.initials: S
authors.lastname: Shimohama
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000704:Analysis of Variance; D019540:Area Under Curve; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003553:Cystine / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004563:Electrochemistry / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D045563:Indolequinones / Q000378:metabolism*; D007501:Iron / Q000494:pharmacology*; D008543:Melanins / Q000378:metabolism*; D008954:Models, Biological; D009447:Neuroblastoma; D013482:Superoxide Dismutase / Q000494:pharmacology; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D045563:Indolequinones; D008543:Melanins; D013778:Tetrazolium Salts; D013844:Thiazoles; C091584:aminochrome 1; D003553:Cystine; C104705:dopamine quinone; D019328:Buthionine Sulfoximine; D006861:Hydrogen Peroxide; D007501:Iron; D002374:Catalase; D013482:Superoxide Dismutase; C022616:thiazolyl blue; D004298:Dopamine; D000111:Acetylcysteine