Protective activity of aromatic amines and imines against oxidative nerve cell death

Oxidative stress is a widespread phenomenon in the pathology of neurodegene rative diseases such as Alzheimer's disease, Parkinson's disease, and amyot rophic lateral sclerosis. Neuronal cell death due to oxidative stress may c ausally contribute to the pathogeneses of these diseases. Therefore, neurop rotective antioxidants are considered to be a promising approach to slow do wn disease progression. We have investigated different aromatic amine and i mine compounds for neuroprotective antioxidant functions in cell culture, a nd 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 cultur es. Aromatic amines and imines are effective against oxidative glutamate to xicity, glutathione depletion, and hydrogen peroxide toxicity. Their mode o f action as direct antioxidants; was experimentally confirmed by electron s pin resonance spectroscopy, cell-free brain lipid peroxidation assays, and intracellular peroxide measurements. With half-maximal effective concentrat ions of 20-75 nm in different neuroprotection experiments, the aromatic imi nes phenothiazine, phenoxazine, and iminostilbene proved to be about two or ders of magnitude more effective than common phenolic antioxidants. This re markable efficacy could be directly correlated to calculated properties of the compounds by means of a novel, quantitative structure-activity relation ship model. We conclude that bridged bisarylimines with a single free NH-bo nd, such as iminostilbene, are superior neuroprotective antioxidants, and m ay be promising lead structures for rational drug development.