Nitrones, their value as therapeutics and probes to understand aging

The nitrone-based free radical traps have significant potential in the treatment of neurodegenerative diseases as well as in the prolongation of life span. The mass action free radical trapping activity of these compounds is the property, which first brought them to the attention of the scientific community. Nevertheless extensive research has demonstrated that these reactions are not responsible for their therapeutic mechanistic basis of activity. Rather the mechanism of action in the case of their neuroprotective activity appears to involve the inhibition of enhanced signal transduction processes that mediate the upregulation of genes, which produce neurotoxic products. The most widely used compound in this series, alpha-phenyl-tert-butyl-nitrone (PBN), has been shown to extend life span in three published studies, i.e. two mouse models and one rat model. Significant prolongation of life span was noted in all three studies. We report the summary of a recent study with a novel nitrone, CPI-1429, which demonstrated the ability to extend life span even though administration of the compound was begun in older animals. Despite these promising studies, much more rigorous research examining the anti-aging activity of the nitrones needs to be conducted. It is not known exactly why the nitrones possess anti-aging activity. They have been shown to quell enhanced signal transduction processes associated with enhanced pro-inflammatory cytokine mediated events. The nitrones interfere in some unknown steps preventing receptor triggered MAP kinase phosphorylation cascades. Stabilization of phosphorylation networks associated with checkpoint proteins could slow cell cycle processes and this could be the basis of the nitrones anti-senescent activity.