Cyclooxygenase-2 is involved in oxidative damage and alpha-synuclein accumulation in dopaminergic cells.
Cyclooxygenase (COX) is the rate-limiting enzyme that catalyzes the formation of prostaglandins from arachidonic acid. The inducible isoform COX-2 is upregulated in the dopaminergic neurons of the substantia nigra of postmortem Parkinson's disease (PD) patients and in neurotoxin-induced Parkinsonism models. COX-2 has attracted significant attention as an important source of oxidative stress in dopaminergic neurons due to its potential to oxidize catechols including dopamine. However, the role of COX-2 in the pathogenesis of PD has not been fully evaluated. Here, we show that COX-2 induces dopamine oxidation, as evidenced by the findings that COX-2 can facilitate dopamine oxidation in a cell-free system and in COX-2-overexpressing SH-SY5Y cells, and that this can be completely abolished by the selective COX-2 inhibitor meloxicam. Increased COX-2 expression causes oxidative protein modification and alpha-synuclein accumulation in dopaminergic cells. These data suggest that an abnormal increase in COX-2 expression causes dopamine oxidation and contributes to the preferential vulnerability of dopaminergic cells as in PD.
Chae
Sung-Wook
SW
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, 300 Yongbong-dong, Buk-gu, Gwangju 500-757, South Korea.
Kang
Bok Yun
BY
Hwang
Onyou
O
Choi
Hyun Jin
HJ
D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D000077239:Meloxicam; D009447:Neuroblastoma; D018384:Oxidative Stress / Q000187:drug effects*; D013050:Spectrometry, Fluorescence; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D051844:alpha-Synuclein / Q000378:metabolism*
D016861:Cyclooxygenase Inhibitors; D013843:Thiazines; D013844:Thiazoles; D051844:alpha-Synuclein; D006427:Hemin; D051546:Cyclooxygenase 2; D000077239:Meloxicam; D004298:Dopamine