Institut für Pharmazie/Pharmazeutische Biologie, Freie Universität Berlin, Königin-Luise-Str, 2+4 D-14195 Berlin, Germany.
Neurotoxicology. 2012 Jun;33(3):424-8. doi: 10.1016/j.neuro.2012.04.007. Epub 2012 Apr 13.
There is increasing evidence that endogenously produced toxins may be involved in the development of a number of neurodegenerative diseases such as Alzheimer's, Parkinson's or Huntington's disease and that the mechanisms leading to cell loss are a combination of oxidative stress, mitochondrial dysfunction and a decrease in antioxidant defenses. The purpose of this study was to investigate the effects of glutathione on 3-hydroxykynurenine, 6-hydroxydopamine and salsolinol mediated neurotoxicity in the human neuroblastoma SH-SY5Y cell line in order to find a possible therapeutic application of this compound to neurodegenerative disorders. In this study, we tested the protective effect of glutathione on SH-SY5Y cells against 3-hydroxykynurenine, 6-hydroxydopamine and salsolinol induced cytotoxicity and demonstrated that glutathione inhibits cell death and adenosine-5'triphosphate depletion caused by 3-hydroxykynurenine and 6-hydroxydopamine. However, unexpectedly salsolinol neurotoxicity toward SH-SY5Y cells was potentiated during treatment with concentrations of glutathione below 250 μM, whereas glutathione concentrations above 250 μM resulted in protection against salsolinol induced neuronal cell death. We also report that the incubation of salsolinol and low concentrations of glutathione led to increased apoptosis. Hence, salsolinol in the presence of low glutathione concentration may be involved in neurodegeneration. These data may provide new promising insights into the pathophysiology of neudegenerative disorders such as Parkinson's disease.
越来越多的证据表明，内源性产生的毒素可能参与了许多神经退行性疾病的发展，如阿尔茨海默病、帕金森病或亨廷顿病，导致细胞死亡的机制是氧化应激、线粒体功能障碍和抗氧化防御减少的结合。本研究旨在研究谷胱甘肽对 3-羟基犬尿氨酸、6-羟多巴胺和索丝菌素介导的人神经母细胞瘤 SH-SY5Y 细胞系神经毒性的影响，以寻找该化合物对神经退行性疾病的可能治疗应用。在这项研究中，我们测试了谷胱甘肽对 SH-SY5Y 细胞对 3-羟基犬尿氨酸、6-羟多巴胺和索丝菌素诱导的细胞毒性的保护作用，结果表明谷胱甘肽抑制了 3-羟基犬尿氨酸和 6-羟多巴胺引起的细胞死亡和三磷酸腺苷耗竭。然而，出人意料的是，在低于 250 μM 的谷胱甘肽浓度下，索丝菌素对 SH-SY5Y 细胞的神经毒性增强，而高于 250 μM 的谷胱甘肽浓度则对索丝菌素诱导的神经元细胞死亡起到保护作用。我们还报告说，索丝菌素和低浓度谷胱甘肽孵育导致细胞凋亡增加。因此，在低谷胱甘肽浓度存在下的索丝菌素可能参与神经退行性变。这些数据可能为帕金森病等神经退行性疾病的病理生理学提供新的有希望的见解。
