Liu Xuebo, Yamada Naruomi, Maruyama Wakako, Osawa Toshihiko
Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Science, Nagoya University, Nagoya 464-8601, Japan.
J Biol Chem. 2008 Dec 12;283(50):34887-95. doi: 10.1074/jbc.M805682200. Epub 2008 Oct 15.
Oxidative stress appears to be directly involved in the pathogenesis of the neurodegeneration of dopaminergic systems in Parkinson disease. In this study, we formed four dopamine modification adducts derived from docosahexaenoic acid (C22:6/omega-3) and arachidonic acid (C18:4/omega-6), which are known as the major polyunsaturated fatty acids in the brain. Upon incubation of dopamine with fatty acid hydroperoxides and an in vivo experiment using rat brain tissue, all four dopamine adducts were detected. Furthermore, hexanoyl dopamine (HED), an arachidonic acid-derived adduct, caused severe cytotoxicity in human dopaminergic neuroblastoma SH-SY5Y cells, whereas the other adducts were only slightly affected. The HED-induced cell death was found to include apoptosis, which also seems to be mediated by reactive oxygen species generation and mitochondrial abnormality. Additionally, the experiments using monoamine transporter inhibitor and mouse embryonic fibroblast NIH-3T3 cells that lack the monoamine transporter indicate that the HED-induced cytotoxicity might specially occur in the neuronal cells. These data suggest that the formation of the docosahexaenoic acid- and arachidonic acid-derived dopamine adducts in vitro and in vivo, and HED, the arachidonic acid-derived dopamine modification adduct, which caused selective cytotoxicity of neuronal cells, may indicate a novel mechanism responsible for the pathogenesis in Parkinson disease.
氧化应激似乎直接参与帕金森病中多巴胺能系统神经退行性变的发病机制。在本研究中，我们合成了四种源自二十二碳六烯酸（C22:6/ω-3）和花生四烯酸（C18:4/ω-6）的多巴胺修饰加合物，这两种酸是大脑中主要的多不饱和脂肪酸。将多巴胺与脂肪酸氢过氧化物一起孵育，并在大鼠脑组织上进行体内实验后，检测到了所有四种多巴胺加合物。此外，花生四烯酸衍生的加合物己酰多巴胺（HED）对人多巴胺能神经母细胞瘤SH-SY5Y细胞具有严重的细胞毒性，而其他加合物的影响较小。发现HED诱导的细胞死亡包括凋亡，这似乎也由活性氧生成和线粒体异常介导。此外，使用单胺转运体抑制剂以及缺乏单胺转运体的小鼠胚胎成纤维细胞NIH-3T3进行的实验表明，HED诱导的细胞毒性可能特别发生在神经元细胞中。这些数据表明，二十二碳六烯酸和花生四烯酸衍生的多巴胺加合物在体外和体内的形成，以及花生四烯酸衍生的多巴胺修饰加合物HED导致神经元细胞的选择性细胞毒性，可能提示了一种帕金森病发病机制的新机制。
