Creatine enhances survival of glutamate-treated neuronal/glial cells, modulates Ras/NF-kappaB signaling, and increases the generation of reactive oxygen species.
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.
Juravleva
Elena
E
Institute of Physiology, Georgian Academy of Sciences, Tbilisi, Georgia.
Barbakadze
Tamar
T
Mikeladze
David
D
Kekelidze
Téa
T
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
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