Cyclooxygenase-2 is involved in oxidative damage and alpha-synuclein accumulation in dopaminergic cells
Cyclooxygenase-2 is involved in oxidative damage and alpha-synuclein accumulation in dopaminergic cells
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DOI：
10.1016/j.neulet.2008.03.031
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发表时间：
2008-05-09
影响因子：
2.5
通讯作者：
Choi, Hyun Jin
中科院分区：
文献类型：
--
作者：
Chae, Sung-Wook;Kang, Bok Yun;Choi, Hyun Jin
环氧合酶（考克斯）是催化花生四烯酸生成异黄酮的限速酶。诱导型异构体考克斯-2上调，在黑质多巴胺能神经元的帕金森病（PD）患者死后和神经毒素诱导的帕金森病模型。考克斯-2由于其氧化包括多巴胺在内的儿茶酚的潜力，作为多巴胺能神经元中氧化应激的重要来源而引起了显著的关注。然而，考克斯-2在PD发病机制中的作用尚未得到充分评价。在这里，我们表明，考克斯-2诱导多巴胺氧化，作为证据的发现，考克斯-2可以促进多巴胺的氧化在无细胞系统和考克斯-2过表达的SH-SY 5 Y细胞，这可以完全取消的选择性考克斯-2抑制剂美洛昔康。增加的考克斯-2表达导致多巴胺能细胞中的氧化蛋白修饰和α-突触核蛋白积累。这些数据表明，考克斯-2表达的异常增加导致多巴胺氧化，并有助于优先的多巴胺能细胞的脆弱性，如在PD。(c)2008爱思唯尔爱尔兰有限公司保留所有权利。
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. (c) 2008 Elsevier Ireland Ltd. All rights reserved.