Moosmann B, Skutella T, Beyer K, Behl C
Max-Planck-Institute of Psychiatry, Munich, Germany.
Biol Chem. 2001 Nov;382(11):1601-12. doi: 10.1515/BC.2001.195.
Oxidative stress is a widespread phenomenon in the pathology of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Neuronal cell death due to oxidative stress may causally contribute to the pathogeneses of these diseases. Therefore, neuroprotective antioxidants are considered to be a promising approach to slow down disease progression. We have investigated different aromatic amine and imine compounds for neuroprotective antioxidant functions in cell culture, and found that these compounds possess excellent cytoprotective potential in diverse paradigms of oxidative neuronal cell death, including clonal cell lines, primary cerebellar neurons, and organotypic hippocampal slice cultures. Aromatic amines and imines are effective against oxidative glutamate toxicity, glutathione depletion, and hydrogen peroxide toxicity. Their mode of action as direct antioxidants was experimentally confirmed by electron spin resonance spectroscopy, cell-free brain lipid peroxidation assays, and intracellular peroxide measurements. With half-maximal effective concentrations of 20-75 nM in different neuroprotection experiments, the aromatic imines phenothiazine, phenoxazine, and iminostilbene proved to be about two orders of magnitude more effective than common phenolic antioxidants. This remarkable efficacy could be directly correlated to calculated properties of the compounds by means of a novel, quantitative structure-activity relationship model. We conclude that bridged bisarylimines with a single free NH-bond, such as iminostilbene, are superior neuroprotective antioxidants, and may be promising lead structures for rational drug development.
氧化应激是阿尔茨海默病、帕金森病和肌萎缩侧索硬化症等神经退行性疾病病理学中的一种普遍现象。氧化应激导致的神经元细胞死亡可能是这些疾病发病机制的原因之一。因此，神经保护性抗氧化剂被认为是减缓疾病进展的一种有前景的方法。我们在细胞培养中研究了不同的芳香胺和亚胺化合物的神经保护性抗氧化功能，发现这些化合物在多种氧化神经元细胞死亡模型中具有出色的细胞保护潜力，包括克隆细胞系、原代小脑神经元和器官型海马切片培养。芳香胺和亚胺对氧化型谷氨酸毒性、谷胱甘肽耗竭和过氧化氢毒性有效。通过电子自旋共振光谱、无细胞脑脂质过氧化测定和细胞内过氧化物测量，实验证实了它们作为直接抗氧化剂的作用模式。在不同的神经保护实验中，芳香亚胺吩噻嗪、吩恶嗪和亚胺芪的半数有效浓度为20 - 75 nM，比常见的酚类抗氧化剂有效约两个数量级。通过一种新颖的定量构效关系模型，这种显著的功效可以直接与化合物的计算性质相关联。我们得出结论，具有单个游离NH键的桥连双芳基亚胺，如亚胺芪，是优异的神经保护性抗氧化剂，可能是合理药物开发的有前景的先导结构。
