Dept. of Food & Nutrition, College of Human Ecology, Hanyang University, 133-791 Seoul, South Korea.
Toxicology. 2012 Mar 29;294(1):1-8. doi: 10.1016/j.tox.2012.01.007. Epub 2012 Jan 25.
Ascorbic acid (AA) is a well-known reducing agent; however, under appropriate condition, it can facilitate oxidation. In this study, we investigated the effect of AA on dopamine (DA) and glutathione levels in the nigrostriatal dopaminergic system of male seven-week-old C57BL/6 mice (weight, 23-25 g). Mice were treated with AA (400 mg/kg, i.p.) once per day for four weeks, and changes in tyrosine hydroxylase (TH) immunoreactivity, DA and its metabolites, and glutathione (reduced and oxidized) in the substantia nigra pars compacta (SNpc) and striatum were measured. After repeated AA administration, TH-positive immunoreactivity (TH-IR) decreased compared to the control both in the SNpc and striatum. AA treatment also significantly reduced DA levels, and the reduction of which corresponded to changes in TH expression within the same region. In addition, AA increased DA oxidative metabolism according to increases in the DOPAC/DA ratio both in the SNpc and the striatum, whereas the O-methylation pathway in the striatum remained unchanged. Levels of reduced glutathione (GSH) in both the SNpc and striatum were decreased more in the AA treated group than in the control group. Likewise, levels of total glutathione were also decreased in the corresponding regions. Taken together, our data suggest that repeated AA injection induces dopaminergic neurotoxicity through generation of oxidative stress, and that this toxicity is related to the decline of GSH in both the SNpc and striatum. This neurotoxic mechanism may specifically involve enhancement of the oxidative pathway of DA metabolism through coupling with the antioxidant GSH system of the nigrostriatal dopaminergic system.
抗坏血酸（AA）是一种众所周知的还原剂；然而，在适当的条件下，它可以促进氧化。在这项研究中，我们研究了 AA 对雄性 7 周龄 C57BL/6 小鼠（体重 23-25g）黑质纹状体多巴胺能系统中多巴胺（DA）和谷胱甘肽水平的影响。小鼠每天腹腔注射 AA（400mg/kg）一次，连续四周，测量酪氨酸羟化酶（TH）免疫反应性、DA 及其代谢物以及黑质致密部（SNpc）和纹状体中的谷胱甘肽（还原型和氧化型）的变化。在重复给予 AA 后，与对照组相比，TH 阳性免疫反应性（TH-IR）在 SNpc 和纹状体中均降低。AA 处理还显著降低了 DA 水平，并且这种减少与同一区域内 TH 表达的变化相对应。此外，AA 根据 SNpc 和纹状体中 DOPAC/DA 比值的增加增加了 DA 的氧化代谢，而纹状体中的 O-甲基化途径保持不变。SNpc 和纹状体中的还原型谷胱甘肽（GSH）水平在 AA 处理组中比对照组降低更多。同样，相应区域中的总谷胱甘肽水平也降低。总之，我们的数据表明，重复注射 AA 通过产生氧化应激诱导多巴胺能神经毒性，并且这种毒性与 SNpc 和纹状体中 GSH 的下降有关。这种神经毒性机制可能特别涉及通过与黑质纹状体多巴胺能系统的抗氧化 GSH 系统偶联来增强 DA 代谢的氧化途径。
