title: Role of cyclooxygenase-2 in tetrahydrobiopterin-induced dopamine oxidation.
abstract: Dopamine is considered one of the main contributing factors in the induction of oxidative stress and selective dopaminergic neurodegeneration in Parkinson's disease. We have previously reported that tetrahydrobiopterin (BH4) leads to dopamine oxidation and renders dopamine-producing cells vulnerable. In the present study, we found that BH4 selectively upregulates cyclooxygenase-2 (COX-2) expression in dopaminergic cells. BH4 caused an induction of COX-2 mRNA, and a critical regulatory motif for BH4-induced transcriptional activation of COX-2 is CRE/AP-1. COX-2 can oxidize dopamine and cause oxidative stress, which is evidenced by the findings that significant increase in dopamine-chrome formation and protein carbonyl contents by BH4-induced COX-2 up-regulation, and the increases are abolished by COX-2 selective inhibitor meloxicam. Increased COX-2 promotes dopaminergic neurodegeneration in both SH-SY5Y cells and rat mesencephalic neurons. These data suggest that BH4-induced COX-2 expression is responsible for dopamine oxidation, leading to the preferential vulnerability of dopaminergic cells in Parkinson's disease.
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, South Korea.
authors.forename: Sung-Wook
authors.initials: SW
authors.lastname: Chae
authors.forename: Yeo Jin
authors.initials: YJ
authors.lastname: Bang
authors.forename: Kyeong-Man
authors.initials: KM
authors.lastname: Kim
authors.forename: Kwang Youl
authors.initials: KY
authors.lastname: Lee
authors.forename: Bok Yun
authors.initials: BY
authors.lastname: Kang
authors.forename: Eun Mee
authors.initials: EM
authors.lastname: Kim
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Inoue
authors.forename: Onyou
authors.initials: O
authors.lastname: Hwang
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Choi
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008636:Mesencephalon / Q000187:drug effects / Q000201:enzymology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D015854:Up-Regulation
chemical_list: D018808:Transcription Factor AP-1; D001708:Biopterins; D051546:Cyclooxygenase 2; D048031:JNK Mitogen-Activated Protein Kinases; C003402:sapropterin; D004298:Dopamine