Oxidative stress modulates Sir2alpha in rat hippocampus and cerebral cortex.

Silent information regulator 2 (Sir2) helps survival and longevity in lower organisms during challenging situations. We investigated the possibility that Sir2alpha could be involved with brain plasticity under challenging situations. A diet high in saturated fat and sucrose, which has been shown in rodents to reduce synaptic plasticity and cognition, decreased Sir2alpha levels in the hippocampus and cerebral cortex, in proportion to an increase in protein oxidation. Vitamin E supplementation normalized, in the hippocampus and cerebral cortex, Sir2alpha levels that had been reduced by the high-fat diet. Neither the high-fat diet nor vitamin E supplementation affected cerebellar Sir2alpha. Vitamin E reduced, in the hippocampus, the oxidized nucleic acids that were increased by the high-fat diet. Western blot analysis showed higher contents of Sir2alpha in the hippocampus and cerebellum than in the cerebral cortex. Sir2alpha immunostaining was predominantly localized in the mossy fibre system and the dentate gyrus granule layer of the hippocampal formation. The high-fat diet decreased Sir2alpha immunostaining while vitamin E supplementation reversed these effects. Given that oxidative stress is a subproduct of dysfunctional energy homeostasis, we measured AMP-activated protein kinase (AMPK) to have an indication of the energy status of cells. Hippocampal levels of total and phosphorylated AMPK were reduced after high fat consumption and levels were normalized by vitamin E treatment. The present results show that oxidative stress and energy homeostasis associated with the consumption of the high-fat diet are critical for the regulation of Sir2alpha, with important implications for mechanisms of neural repair.