Congeners of N-alpha-acetyl-L-cysteine, but not aminoguanidine act as neuroprotectants from the lipid peroxidation product 4-hydroxy-2-nonenal

Increased generation of neurotoxic lipid peroxidation products is proposed to contribute to the pathogenesis of Alzheimer's disease (AD). Current anti oxidant therapies are directed at limiting propagation of brain lipid perox idation. Another approach would be to scavenge the reactive aldehyde produc ts of lipid peroxidation. N-alpha-acetyl-L-cysteine (NAC) and aminoguanidin e (AG) react rapidly and irreversibly with 4-hydroxy-2-nonenal (HNE) in vit ro, and both have been proposed as potential scavengers of HNE in biologica l systems. We have compared NAC, AG, and a series of congeners as scavenger s of HNE and as neuroprotectants from HNE. Our results showed that while bo th NAC and AG had comparable chemical reactivity with HNE, only NAC and its congeners were able to block HNE-protein adduct formation in vitro and in neuronal cultures. Moreover, NAC and its congeners, but not AG, effectively protected brain mitochondrial respiration and neuronal microtubule structu re from the toxic effects of HNE. We conclude that NAC and its congeners, b ut not AG, may act as neuroprotectants from HNE. (C) 2000 Elsevier Science Inc.