title: Creatine enhances survival of glutamate-treated neuronal/glial cells, modulates Ras/NF-kappaB signaling, and increases the generation of reactive oxygen species.
abstract: The protective effects of creatine against glutamate cytotoxicity have been demonstrated in neuronal cells and animal models of neurodegenerative diseases. The mechanisms underlying creatine neuroprotection against glutamate-induced cell death are understood poorly. For the first time, we demonstrate a correlation between the protective effect of creatine and the modulation of Ras-mediated redox-dependent signaling pathways, which involve nuclear factor kappaB (NF-kappaB) and reactive oxygen species (ROS). In primary cerebrocortical cultures of mixed neurons and glia, creatine significantly reduced glutamate-induced cell death. The increase in cell survival was accompanied by increased generation of oxygen radicals and decreased levels of farnesylated Ras and IkappaB, an inhibitor of NF-kappaB. Non-farnesylated Ras and ROS-dependent activation of NF-kappaB have been shown to promote neuronal survival. Our data suggest that creatine may enhance survival signaling via activation of the Ras/NF-kappaB system. Possible mechanisms underlying the protective effect of creatine are discussed, including normalization of cellular GTP levels.
authors.affiliation: Institute of Physiology, Georgian Academy of Sciences, Tbilisi, Georgia.
authors.forename: Elena
authors.initials: E
authors.lastname: Juravleva
authors.forename: Tamar
authors.initials: T
authors.lastname: Barbakadze
authors.forename: David
authors.initials: D
authors.lastname: Mikeladze
authors.forename: Téa
authors.initials: T
authors.lastname: Kekelidze
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects*; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D003401:Creatine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D018698:Glutamic Acid / Q000633:toxicity; D006165:Guanylyl Imidodiphosphate / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D015151:Immunoblotting / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D019097:Spin Trapping / Q000379:methods; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; D006165:Guanylyl Imidodiphosphate; D018698:Glutamic Acid; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue; D003401:Creatine