p-Quinone mediates 6-hydroxydopamine-induced dopaminergic neuronal death and ferrous iron accelerates the conversion of p-quinone into melanin extracellularly.
Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN). 6-Hydroxydopamine (6-OHDA), a dopaminergic neurotoxin, is detected in human brains and the urine of PD patients. Using SH-SY5Y, a human neuroblastoma cell line, we demonstrated that 6-OHDA toxicity was determined by the amount of p-quinone produced in 6-OHDA auto-oxidation rather than by reactive oxygen species (ROS). Glutathione (GSH), which conjugated with p-quinone, provided significant protection whereas catalase, which detoxified hydrogen peroxide and superoxide anions, failed to block cell death caused by 6-OHDA. Although iron accumulated in the SN of patients with PD can cause dopaminergic neuronal degeneration by enhancing oxidative stress, we found that extracellular ferrous iron promoted the formation of melanin and reduced the amount of p-quinone. The addition of ferrous iron to the culture medium inhibited caspase-3 activation and apoptotic nuclear morphologic changes and blocked 6-OHDA-induced cytotoxicity in SH-SY5Y cells and primary cultured mesencephalic dopaminergic neurons. These data suggested that generation of p-quinone played a pivotal role in 6-OHDA-induced toxicity and extracellular iron in contrast to intracellular iron was protective rather than harmful because it accelerated the conversion of p-quinone into melanin.
Izumi
Yasuhiko
Y
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Sawada
Hideyuki
H
Sakka
Noriko
N
Yamamoto
Noriyuki
N
Kume
Toshiaki
T
Katsuki
Hiroshi
H
Shimohama
Shun
S
Akaike
Akinori
A
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology*; D006690:Bisbenzimidazole; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004563:Electrochemistry / Q000379:methods; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D007501:Iron / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008543:Melanins / Q000378:metabolism*; D008636:Mesencephalon / Q000166:cytology; D008954:Models, Biological; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D016627:Oxidopamine / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000975:Antioxidants; D016227:Benzoquinones; D008543:Melanins; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; C004532:quinone; D016627:Oxidopamine; D006861:Hydrogen Peroxide; D007501:Iron; D007770:L-Lactate Dehydrogenase; D014446:Tyrosine 3-Monooxygenase; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C022616:thiazolyl blue; D006690:Bisbenzimidazole; D004298:Dopamine