Role of cyclooxygenase-2 in tetrahydrobiopterin-induced dopamine oxidation.
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.
Chae
Sung-Wook
SW
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, South Korea.
Bang
Yeo Jin
YJ
Kim
Kyeong-Man
KM
Lee
Kwang Youl
KY
Kang
Bok Yun
BY
Kim
Eun Mee
EM
Inoue
Hiroyasu
H
Hwang
Onyou
O
Choi
Hyun Jin
HJ
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
D018808:Transcription Factor AP-1; D001708:Biopterins; D051546:Cyclooxygenase 2; D048031:JNK Mitogen-Activated Protein Kinases; C003402:sapropterin; D004298:Dopamine