title: Creatine protects against excitoxicity in an in vitro model of neurodegeneration.
abstract: Creatine has been shown to be neuroprotective in aging, neurodegenerative conditions and brain injury. As a common molecular background, oxidative stress and disturbed cellular energy homeostasis are key aspects in these conditions. Moreover, in a recent report we could demonstrate a life-enhancing and health-promoting potential of creatine in rodents, mainly due to its neuroprotective action. In order to investigate the underlying pharmacology mediating these mainly neuroprotective properties of creatine, cultured primary embryonal hippocampal and cortical cells were challenged with glutamate or H(2)O(2). In good agreement with our in vivo data, creatine mediated a direct effect on the bioenergetic balance, leading to an enhanced cellular energy charge, thereby acting as a neuroprotectant. Moreover, creatine effectively antagonized the H(2)O(2)-induced ATP depletion and the excitotoxic response towards glutamate, while not directly acting as an antioxidant. Additionally, creatine mediated a direct inhibitory action on the NMDA receptor-mediated calcium response, which initiates the excitotoxic cascade. Even excessive concentrations of creatine had no neurotoxic effects, so that high-dose creatine supplementation as a health-promoting agent in specific pathological situations or as a primary prophylactic compound in risk populations seems feasible. In conclusion, we were able to demonstrate that the protective potential of creatine was primarily mediated by its impact on cellular energy metabolism and NMDA receptor function, along with reduced glutamate spillover, oxidative stress and subsequent excitotoxicity.
authors.affiliation: Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Just
authors.initials: J
authors.lastname: Genius
authors.forename: Johanna
authors.initials: J
authors.lastname: Geiger
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Möller
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex; D003401:Creatine / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D018698:Glutamic Acid; D006624:Hippocampus / Q000166:cytology; D006861:Hydrogen Peroxide; D051379:Mice; D019636:Neurodegenerative Diseases / Q000517:prevention & control*; D018696:Neuroprotective Agents; D018384:Oxidative Stress; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*
chemical_list: D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D006861:Hydrogen Peroxide; D003401:Creatine