Resveratrol Inhibits the Proliferation of Neural Progenitor Cells and Hippocampal Neurogenesis

• Published in: The Journal of biological chemistry 2012-12, Vol.287 (51), p.42588-42600
• Main Authors: Park, Hee Ra, Kong, Kyoung Hye, Yu, Byung Pal, Mattson, Mark P., Lee, Jaewon
• Format: Article
• Language: English
• Subjects: AMP-activated Kinase (AMPK); AMP-Activated Protein Kinases - metabolism; Animals; Brain-derived Neurotrophic Factor (BDNF); Brain-Derived Neurotrophic Factor - metabolism; Cell Death - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; CREB; Cyclic AMP Response Element-Binding Protein - metabolism; Dentate Gyrus - cytology; Embryo, Mammalian - cytology; Embryo, Mammalian - drug effects; Enzyme Activation - drug effects; Hippocampus - cytology; Hippocampus - embryology; Male; Memory - drug effects; Mice; Mice, Inbred C57BL; Neural Stem Cell; Neural Stem Cells - cytology; Neural Stem Cells - drug effects; Neural Stem Cells - enzymology; Neurobiology; Neurogenesis; Neurogenesis - drug effects; Phosphorylation - drug effects; Resveratrol; Stilbenes - administration & dosage; Stilbenes - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.406413

Resveratrol is a phytoalexin and natural phenol that is present at relatively high concentrations in peanuts and red grapes and wine. Based upon studies of yeast and invertebrate models, it has been proposed that ingestion of resveratrol may also have anti-aging actions in mammals including humans. It has been suggested that resveratrol exerts its beneficial effects on health by activating the same cellular signaling pathways that are activated by dietary energy restriction (DR). Some studies have reported therapeutic actions of resveratrol in animal models of metabolic and neurodegenerative disorders. However, the effects of resveratrol on cell, tissue and organ function in healthy subjects are largely unknown. In the present study, we evaluated the potential effects of resveratrol on the proliferation and survival of neural progenitor cells (NPCs) in culture, and in the hippocampus of healthy young adult mice. Resveratrol reduced the proliferation of cultured mouse multi-potent NPCs, and activated AMP-activated protein kinase (AMPK), in a concentration-dependent manner. Administration of resveratrol to mice (1–10 mg/kg) resulted in activation of AMPK, and reduced the proliferation and survival of NPCs in the dentate gyrus of the hippocampus. Resveratrol down-regulated the levels of the phosphorylated form of cyclic AMP response element-binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus. Finally, resveratrol-treated mice exhibited deficits in hippocampus-dependent spatial learning and memory. Our findings suggest that resveratrol, unlike DR, adversely affects hippocampal neurogenesis and cognitive function by a mechanism involving activation of AMPK and suppression of CREB and BDNF signaling. Background: Resveratrol has been suggested to have protective effects against many diseases, but its biological actions on brain in healthy subjects are unclear. Results: Resveratrol impaired hippocampal neurogenesis and memory acquisition by AMPK activation and suppression of pCREB and BDNF. Conclusion: Resveratrol impairs hippocampal neurogenesis and cognitive function. Significance: Unlike DR and exercise, resveratrol can adversely affect neurogenesis and cognition.