Nitrones as neuroprotectants and antiaging drugs

Specific nitrones have been used for more than 30 years in analytical chemistry and biochemistry to trap and stabilize free radicals for the purpose of their identification and characterization. PBN (alpha-phenyl-tert-butyl nitrone), one of the more widely used nitrones for this purpose, has been shown to have potent pharmacologic activities in models of a number of aging-related diseases, most notably the neurodegenerative diseases of stroke and Alzheimer's disease. Studies in cell and animal models strongly suggest that PBN has potent antiaging activity. A novel nitrone, CPI-1429, has been shown to extend the life span of mice when administration was started in older animals. It has also shown efficacy in the prevention of memory dysfunction associated with normal aging in a mouse model. Mechanistic studies have shown that the neuroprotective activity of nitrones is not due to mass-action free radical-trapping activity, but due to cessation of enhanced signal transduction processes associated with neuroinflammatory processes known to be enhanced in several neurodegenerative conditions. Enhanced neuroinflammatory processes produce higher levels of neurotoxins, which cause death or dysfunction of neurons. Therefore, quelling of these processes is considered to have a beneficial effect allowing proper neuronal functioning. The possible antiaging activity of nitrones may reside in their ability to quell enhanced production of reactive oxygen species associated with age-related conditions. On the basis of novel ideas about the action of secretory products formed by senescent cells on bystander cells, it is postulated that nitrones will mitigate these processes and that this may be the mechanism of their antiaging activity.