CR and Non-Metabolizable Glucose Analogs Stimulate Growth Factor Production in the Brain





Wenzhen Duan, Jaewon Lee, Zhihong Guo, Mark P. Mattson

Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, Baltimore, MD




Dietary restriction (DR, also called calorie restriction CR) increases the survival of laboratory rodents by retarding aging, and delaying the incidence of most age-related diseases. We recently found that DR increased resistance of neurons in several different brain regions to insults relevant to pathogenesis of age-related neurodegenerative disorders in rats and mice (Ann Neurol 45:8-15; J. Neuroscience Res 57:195-206.1999). However, the mechanism is unknown. BDNF is a member of neurotrophin family. Its expression is decreased in selective brain regions in age-related neurodegenerative disorders. Stress induces production of BDNF. We therefore tested the hypothesis that DR is a mild stress that regulated the BDNF levels in the brain. 2-month-old rats or mice were fed either ad libitum (AL) or using a DR regimen (alternative day feeding) for 3 months. NGF, BDNF and GDNF protein levels and mRNA levels were measured. We found that BDNF protein levels increased in several brain regions in DR animals including the hippocampus and cerebral cortex. We employed a BDNF antibody to investigate the possible neuroprotective role of BDNF up-regulation by DR in a kainic acid (KA)-induced seizure model. We found that more neurons survived in CA1, CA3 and hilus of hippocampus following intra-hippocampal injection of KA in mice or rats maintained on the DR regimen than those fed AL. Intraventricular administration of antibodies to BDNF effectively blocked the protective effect of DR. Interestingly, non-metabolizable analogue 2-Deoxy-glucose also has similar effect of DR. The findings suggest a pivotal role for up-regulation of BDNF in the beneficial effects of DR in increasing resistance of neurons to injury.







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