Interferon-gamma is Up-regulated in the Hippocampus in Response to Intermittent Fasting and Protects Hippocampal Neurons Against Excitotoxicity

Dietary restriction (DR) increases the life span of many different organisms, and recent findings have demonstrated neuroprotective effects of DR in rodent and nonhuman primate models of neurodegenerative disorders. The neuroprotective mechanism of action of DR is unknown, but it may result from a mild cellular stress response involving increased production of neurotrophic factors. Because several different cytokines are known to be up-regulated in brain cells in response to stress, we determined whether DR affected cytokine expression in the rat brain. Levels of expression of interferon-gamma (IFN-gamma) and its receptor were significantly increased in the hippocampus of rats that had been maintained on an intermittent fasting DR regimen compared with rats on the ad libitum control diet. Pretreatment of embryonic rat hippocampal cell cultures with IFN-gamma protected neurons against glutamate-induced death. IFN-gamma-mediated neuroprotection was associated with an enhanced recovery of intracellular Ca(2+) concentrations following exposure to glutamate. Our data show that intermittent fasting DR stimulates IFN-gamma-mediated neuroprotective signaling in the hippocampus, suggesting a role for this cytokine in the previously reported ability of DR to protect neurons in animal models of severe epileptic seizures, stroke, and neurodegenerative disorders.