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Several studies have indicated that a caloric restriction mimetic or treatment for type 2 diabetes may reverse brain aging. Therefore, we investigated the effect of 1-deoxynojirimycin (DNJ), an alkaloid acting as an inhibitor of α-glucosidase, on age-related behavioral and biochemical changes. SAMP8 mice were randomly assigned to a control group labeled "old" or to the 10- or 20-mg/kg/day DNJ groups. The mice in the DNJ groups were administered DNJ orally from 3 to 9 months of age, and then, a "young" control group was added to analyze the age effect. The old controls exhibited significant declines in sensorimotor ability, open-field anxiety, spatial and nonspatial memory abilities, and age-related biochemical changes, including decreased serum insulin level; increased levels of insulin-like growth factor 1 receptor, presynaptic protein synaptotagmin-1, and astrocyte activation; and decreased levels of insulin receptor, brain-derived neurotrophic factor, presynaptic protein syntaxin-1, and acetylation of histones H4 at lysine 8 in the dorsal hippocampus. Significant correlations exist between the age-related behavioral deficits and the serological and histochemical data. Chronic DNJ treatment alleviated these age-related changes, and the 20-mg/kg/day DNJ group showed more significant improvement. Thus, DNJ may have the potential to maintain successful brain aging.

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