Oxidative stress is a widespread phenomenon in the pathology of neurodegenerative diseases such as Alzheimers disease, Parkinsons 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, cellfree brain lipid peroxidation assays, and intracellular peroxide measurements. With halfmaximal effective concentrations of 2075 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 structureactivity relationship model. We conclude that bridged bisarylimines with a single free NHbond, such as iminostilbene, are superior neuroprotective antioxidants, and may be promising lead structures for rational drug development.
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