Reversal of age-related learning deficits and brain oxidative stress in mice with superoxide dismutase/catalase mimetics

Abstract

Oxidative stress has been implicated in cognitive impairment in both old experimental animals and aged humans. This implication has led to the notion that antioxidant defense mechanisms in the brain are not sufficient to prevent age-related increase in oxidative damage and that dietary intake of a variety of antioxidants might be beneficial for preserving brain function. Here we report a dramatic loss of learning and memory function from 8 to 11 months of age in mice, associated with marked increases in several markers of brain oxidative stress. Chronic systemic administration of two synthetic catalytic scavengers of reactive oxygen species, Eukarion experimental compounds EUK-189 and EUK-207, from 8 to 11 months almost completely reversed cognitive deficits and increase in oxidative stress taking place during this time period in brain. In particular, increase in protein oxidation was completely prevented, whereas increase in lipid peroxidation was decreased by Ϸ50%. In addition, we observed a significant negative correlation between contextual fear learning and levels of protein oxidation in brain. These results further support the role of reactive oxygen species in age-related learning impairment and suggest potential clinical applications for synthetic catalytic scavengers of reactive oxygen species.A ging in humans, as well as in experimental animals, is associated with a slow deterioration of cognitive performance and, in particular, of learning and memory (1-5). In humans, recent studies (6) have indicated the importance of impaired learning and memory processes, because 12% of humans with mild cognitive impairment will develop Alzheimer's disease as opposed to 2% of the general population. Oxidative damage has long been proposed to be critically involved in several pathological manifestations of aging (7,8). Numerous studies (9 -12) have indeed reported increases in protein oxidation and lipid peroxidation in various regions of aged mammalian brains. These findings have led to the notion that antioxidant defense mechanisms in the brain are not sufficient to prevent age-related increase in oxidative damage and that dietary intake of a variety of antioxidants might be beneficial for preserving brain function. In agreement with this idea, synthetic catalytic molecules that exhibit both superoxide dismutase (SOD) and catalase activity significantly increase the mean and maximum lifespan in Caenorhabditis elegans (13) and alleviate lethal oxidative pathologies in mice with genetically deleted . The present studies tested, in wild-type mice, the effects of such molecules on age-related learning and memory impairment, and on markers of oxidative damage in the brain. We found that C57BL͞6N Sim mice exhibit a dramatic decrease in learning and memory function between 8 and 11 months of age, accompanied by a marked increase in brain oxidative damage. Chronic treatment of mice with two recently developed SOD͞catalase mimetics over a 3-month period almost completely reversed the age-related decline in cognitive functi...

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