Chae Sung-Wook, Bang Yeo Jin, Kim Kyeong-Man, Lee Kwang Youl, Kang Bok Yun, Kim Eun Mee, Inoue Hiroyasu, Hwang Onyou, Choi Hyun Jin
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, South Korea.
Biochem Biophys Res Commun. 2007 Aug 3;359(3):735-41. doi: 10.1016/j.bbrc.2007.05.190. Epub 2007 Jun 4.
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.
多巴胺被认为是帕金森病中诱导氧化应激和选择性多巴胺能神经变性的主要因素之一。我们之前报道过，四氢生物蝶呤（BH4）会导致多巴胺氧化，并使产生多巴胺的细胞变得脆弱。在本研究中，我们发现BH4选择性地上调多巴胺能细胞中环氧化酶-2（COX-2）的表达。BH4诱导了COX-2 mRNA的产生，而BH4诱导COX-2转录激活的关键调控基序是CRE/AP-1。COX-2可以氧化多巴胺并引起氧化应激，这一发现证明了BH4诱导的COX-2上调会导致多巴胺-铬形成和蛋白质羰基含量显著增加，而COX-2选择性抑制剂美洛昔康可消除这些增加。COX-2的增加会促进SH-SY5Y细胞和大鼠中脑神经元中的多巴胺能神经变性。这些数据表明，BH4诱导的COX-2表达是多巴胺氧化的原因，导致帕金森病中多巴胺能细胞的优先易损性。
