1-methyl-4-phenylpyridinium-induced immortalized rat don alterations of glutathione status in iminemic neurons
1-methyl-4-phenylpyridinium-induced immortalized rat don alterations of glutathione status in iminemic neurons
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DOI：
10.1016/j.taap.2007.02.002
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发表时间：
2007-05-01
影响因子：
3.8
通讯作者：
Patel, Manisha
中科院分区：
文献类型：
--
作者：
Drechsel, Derek A.;Liang, Li-Ping;Patel, Manisha
与氧化应激增加相关的谷胱甘肽水平降低是许多神经退行性疾病的标志，包括帕金森病。 GSH 是一种重要的抗氧化剂分子，也是细胞氧化还原环境的主要决定因素。先前的研究表明，神经毒素会导致还原谷胱甘肽和氧化谷胱甘肽水平发生变化；然而，有关稳态水平的信息仍有待探索。本研究的目的是表征多巴胺能细胞系 (N27) 在用帕金森毒素 1-甲基-4-苯基吡啶鎓 (MPP+) 治疗后细胞 GSH 水平及其调节酶的变化。治疗后 12 小时，细胞 GSH 水平最初显着下降，但随后 24 小时恢复到高于对照组的值。然而，氧化型谷胱甘肽 (GSSG) 水平在处理后 24 小时增加，同时细胞死亡前 GSH/GSSG 比率下降。根据这些变化，ROS 水平也增加，证实了氧化应激的存在。在早期时间点观察到谷胱甘肽还原酶和谷氨酸半胱氨酸连接酶的酶活性降低了 20-25%，这在一定程度上解释了 MPP+ 暴露后 GSH 水平的变化。此外，处理后24小时谷胱甘肽过氧化物酶活性增加。 MPP+处理与培养基中谷胱甘肽流出量的增加无关。这些数据进一步阐明了帕金森毒素 MPP+ 导致 GSH 消耗的机制。 (c) 2007 Elsevier Inc. 保留所有权利。
Decreased glutathione levels associated with increased oxidative stress are a hallmark of numerous neurodegenerative diseases, including Parkinson's disease. GSH is an important molecule that serves as an anti-oxidant and is also a major determinant of cellular redox environment. Previous studies have demonstrated that neurotoxins can cause changes in reduced and oxidized GSH levels; however, information regarding steady state levels remains unexplored. The goal of this study was to characterize changes in cellular GSH levels and its regulatory enzymes in a dopaminergic cell line (N27) following treatment with the Parkinsonian toxin, 1-methyl-4-phenylpyridinium (MPP+). Cellular GSH levels were initially significantly decreased 12 h after treatment, but subsequently recovered to values greater than controls by 24 h. However, oxidized glutathione (GSSG) levels were increased 24 h following treatment, concomitant with a decrease in GSH/GSSG ratio prior to cell death. In accordance with these changes, ROS levels were also increased, confirming the presence of oxidative stress. Decreased enzymatic activities of glutathione reductase and glutamate-cysteine ligase by 20-25% were observed at early time points and partly account for changes in GSH levels after MPP+ exposure. Additionally, glutathione peroxidase activity was increased 24 h following treatment. MPP+ treatment was not associated with increased efflux of glutathione to the medium. These data further elucidate the mechanisms underlying GSH depletion in response to the Parkinsonian toxin, MPP+. (c) 2007 Elsevier Inc. All rights reserved.