Nitrone spin-traps release nitric oxide reaction with reactive oxygen species: Possible mechanism of biological activity

Abstract

The nitrone spin trap, N-tert-butyl-α-phenylnitrone (PBN) has a number of unexpected pharmacological effects when administrated to rodent species including reversal of the age-dependent decline of spatial memory and dopamine release response. We have proposed that the anti-aging mechanism of action of PBN includes not only its antioxidant properties but also its capacity to release nitric oxide to the degree and extent it reacts with a free radical. That is, nitric oxide is delivered only to a region of oxidative stress and to the extent that this stress exists. This hypothesis suggests that a nitric oxide deficiency occurs in tissues of older animals-particularly in specific region of the brain that is associated with an oxidative stress. We report here experiments testing the part of the hypothesis predicting that nitrone spin traps do release nitric oxide after reaction with free radicals. Two other spin traps were tested in addition to PBN. These were α-(pyridyl-1-oxide)-N-tert-butyl-nitrone (POBN) and 5,5-dimethyl-1-pyrrolyne-N-oxide (DMPO). Hydroxyl and superoxide radical generation systems were used to interact with the nitrone spin traps in a physiological solution and nitric oxide production was measured by activation of guanylate cyclase and direct physical/chemical techniques. Results indicate that PBN, POBN and DMPO do release nitric oxide but only after interaction with the hydroxyl radical. These data support the “nitric oxide deficiency hypothesis of aging” and suggest that a new class of pharmacological drugs based on these novel nitric oxide releasing properties may prove a possibility in the treatment of age-related disease as well as other pathologies associated with an oxidative-based injury.