Department of Brain Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
Neurochem Res. 2012 Sep;37(9):1944-51. doi: 10.1007/s11064-012-0813-2. Epub 2012 Jun 7.
Prostaglandin H synthase exerts not only cyclooxygenase activity but also peroxidase activity. The latter activity of the enzyme is thought to couple with oxidation of dopamine to dopamine quinone. Therefore, it has been proposed that cyclooxygenase inhibitors could suppress dopamine quinone formation. In the present study, we examined effects of various cyclooxygenase inhibitors against excess methyl L-3,4-dihydroxyphenylalanine (L-DOPA)-induced quinoprotein (protein-bound quinone) formation and neurotoxicity using dopaminergic CATH.a cells. The treatment with aspirin inhibited excess methyl L-DOPA-induced quinoprotein formation and cell death. However, acetaminophen did not show protective effects, and indomethacin and meloxicam rather aggravated these methyl L-DOPA-induced changes. Aspirin and indomethacin did not affect the level of glutathione that exerts quenching dopamine quinone in dopaminergic cells. In contrast with inhibiting effects of higher dose in the previous reports, relatively lower dose of aspirin that affected methyl L-DOPA-induced quinoprotein formation and cell death failed to prevent cyclooxygenase-induced dopamine chrome generation in cell-free system. Furthermore, aspirin but not acetaminophen or meloxicam showed direct dopamine quinone-scavenging effects in dopamine-semiquinone generating systems. The present results suggest that cyclooxygenase shows little contribution to dopamine oxidation in dopaminergic cells and that protective effects of aspirin against methyl L-DOPA-induced dopamine quinone neurotoxicity are based on its cyclooxygenase-independent property.
前列腺素 H 合酶不仅具有环氧化酶活性，还具有过氧化物酶活性。该酶的后一种活性被认为与多巴胺的氧化偶联，形成多巴胺醌。因此，有人提出环氧化酶抑制剂可以抑制多巴胺醌的形成。在本研究中，我们使用多巴胺能 CATH.a 细胞，研究了各种环氧化酶抑制剂对过量的甲基 L-3,4-二羟基苯丙氨酸（L-DOPA）诱导的醌蛋白（蛋白结合醌）形成和神经毒性的作用。阿司匹林的处理抑制了过量的甲基 L-DOPA 诱导的醌蛋白形成和细胞死亡。然而，对乙酰氨基酚没有表现出保护作用，而吲哚美辛和美洛昔康反而加重了这些甲基 L-DOPA 诱导的变化。阿司匹林和吲哚美辛不影响谷胱甘肽的水平，谷胱甘肽在多巴胺能细胞中具有淬灭多巴胺醌的作用。与之前报道的较高剂量的抑制作用相反，在细胞外系统中，阿司匹林对环氧化酶诱导的多巴胺铬生成的抑制作用低于其影响甲基 L-DOPA 诱导的醌蛋白形成和细胞死亡的作用剂量。此外，阿司匹林而不是对乙酰氨基酚或美洛昔康在多巴胺半醌生成系统中显示出直接的多巴胺醌清除作用。本研究结果表明，环氧化酶在多巴胺能细胞中对多巴胺的氧化作用贡献较小，而阿司匹林对甲基 L-DOPA 诱导的多巴胺醌神经毒性的保护作用基于其环氧化酶非依赖性。
