Inhibition of vesicular monoamine transporter enhances vulnerability of dopaminergic cells: relevance to Parkinson's disease
Inhibition of vesicular monoamine transporter enhances vulnerability of dopaminergic cells: relevance to Parkinson's disease
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DOI：
10.1016/j.neuint.2004.10.009
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发表时间：
2005-03-01
影响因子：
4.2
通讯作者：
Hwang, OY
中科院分区：
文献类型：
--
作者：
Choi, HJ;Lee, SY;Hwang, OY
帕金森氏病是一种神经退行性疾病，与黑质中多巴胺能细胞的进行性损失相关。氧化应激已被牵连在疾病的发病机制，和多巴胺已被认为是一个促成因素，产生活性氧，由于其不稳定的儿茶酚部分。我们以前已经表明，四氢生物蝶呤（BH 4），多巴胺合成的强制性辅因子，也有助于通过产生氧化应激的多巴胺生产细胞的脆弱性。这项研究表明，细胞质中多巴胺的存在增强了细胞对BH 4的脆弱性。当暴露于酮色林（一种囊泡单胺转运体抑制剂）时，BH 4诱导的多巴胺能细胞死亡加剧，伴随着脂质过氧化和蛋白质结合醌的增加。当酮色林升高DOPAC的细胞内量时，单胺氧化酶抑制剂帕吉林没有显示出显著的保护作用。相反，硫醇试剂N-乙酰半胱氨酸和醌还原酶诱导剂富马酸二甲酯消除了BH 4/酮色林诱导的细胞死亡，这表明醌的产生发挥着重要作用。因此，可以得出结论，多巴胺在胞质溶胶中的存在似乎有助于细胞对BH 4的脆弱性，并且囊泡单胺转运蛋白通过不仅从单胺氧化酶而且从BH 4诱导的氧化应激中螯合多巴胺而在多巴胺能细胞中起保护作用。(C)2004爱思唯尔有限公司保留所有权利。
Parkinson's disease is a neurodegenerative disorder associated with progressive loss of dopaminergic cells in the substantia nigra. Oxidative stress has been implicated in the pathogenesis of the disease, and dopamine has been suggested as a contributing factor that generates reactive oxygen species due to its unstable catechol moiety. We have previously shown that tetrahydrobiopterin (BH4), an obligatory cofactor for dopamine synthesis, also contributes to the vulnerability of dopamine-producing cells by generating oxidative stress. This study shows that the presence of dopamine in the cytosol enhances the cell's vulnerability to BH4. Upon exposure to ketanserin, a vesicular monoamine transporter inhibitor, BH4-induced dopaminergic cell death is exacerbated, accompanied by increased lipid peroxidation and protein bound quinone. While intracellular amount of DOPAC is elevated by ketanserin, the monoamine oxidase inhibitor pargyline showed no significant protection. Instead, the thiol agent N-acetylcysteine and quinone reductase inducer dimethyl fumarate abolish BH4/ketanserin-induced cell death, suggesting that quinone production plays an important role. Therefore, it can be concluded that the presence of dopamine in the cytosol seems to contribute to the cells' vulnerability to BH4 and that vesicular monoamine transporter plays a protective role in dopaminergic cells by sequestering dopamine not only from monoamine oxidase but also from BH4-induced oxidative stress. (C) 2004 Elsevier Ltd. All rights reserved.