Hajieva Parvana, Mocko Justyna B, Moosmann Bernd, Behl Christian
Department of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
J Neurochem. 2009 Jul;110(1):118-32. doi: 10.1111/j.1471-4159.2009.06114.x. Epub 2009 May 26.
Strong evidence indicates that oxidative stress may be causally involved in the pathogenesis of Parkinson's disease. We have employed human dopaminergic neuroblastoma cells and rat primary mesencephalic neurons to assess the protective potential of three novel bisarylimine antioxidants on dopaminergic cell death induced by complex I inhibition or glutathione depletion. We have found that exceptionally low concentrations (EC(50) values approximately 20 nM) of these compounds (iminostilbene, phenothiazine, and phenoxazine) exhibited strong protective effects against the toxicities of MPP(+), rotenone, and l-buthionine sulfoximine. Investigating intracellular glutathione levels, it was found that MPP(+), L-buthionine sulfoximine, and rotenone disrupted different aspects of the native glutathione equilibrium, while the aromatic imines did not further influence glutathione levels or redox state on any baseline. However, the imines independently reduced protein oxidation and total oxidant flux, saved the mitochondrial membrane potential, and provided full cytoprotection under conditions of complete glutathione depletion. The unusually potent antioxidant effects of the bisarylimines could be reproduced in isolated mitochondria, which were instantly protected from lipid peroxidation and pathological swelling. Aromatic imines may be interesting lead structures for a potential antioxidant therapy of Parkinson's disease and other disorders accompanied by glutathione dysregulation.
有力证据表明，氧化应激可能在帕金森病的发病机制中具有因果关系。我们使用了人多巴胺能神经母细胞瘤细胞和大鼠原代中脑神经元，以评估三种新型双芳基胺抗氧化剂对由复合体I抑制或谷胱甘肽耗竭诱导的多巴胺能细胞死亡的保护潜力。我们发现，这些化合物（亚氨基茋、吩噻嗪和吩恶嗪）的极低浓度（半数有效浓度值约为20 nM）对MPP⁺、鱼藤酮和L-丁硫氨酸亚砜胺的毒性表现出强大的保护作用。研究细胞内谷胱甘肽水平时发现，MPP⁺、L-丁硫氨酸亚砜胺和鱼藤酮破坏了天然谷胱甘肽平衡的不同方面，而芳香族亚胺在任何基线情况下都不会进一步影响谷胱甘肽水平或氧化还原状态。然而，这些亚胺独立地减少了蛋白质氧化和总氧化剂通量，挽救了线粒体膜电位，并在完全谷胱甘肽耗竭的条件下提供了全面的细胞保护。双芳基胺异常强大的抗氧化作用可以在分离的线粒体中重现，线粒体可立即免受脂质过氧化和病理性肿胀的影响。芳香族亚胺可能是帕金森病和其他伴有谷胱甘肽失调的疾病潜在抗氧化治疗的有趣先导结构。
