Creatine mediates neuroprotection towards excitoxicity in an in vitro model of neurodegeneration

In experimental models of neurodegenerative conditions and brain injury, creatine has revealed neuroprotective properties, which may also prove useful in the therapy of neuropsychiatric disease. As a common molecular background oxidative stress and disorders of cellular energy homeostasis seem to be implicated in most of these conditions. Moreover, in a recent report (Bender et al. Neurobiol Aging, 2007), we could demonstrate a significant life-enhancing potential in an in vivo animal model of aging. In order to shed some light on the underlying molecular events mediating the life-enhancing properties of creatine, we established a complementary in vitro model employing primary embryonal hippocampal and cortical cells. In order to emulate aging and neurodegeneration, these cells were challenged with different neurotoxic agents and conditions of enhanced stress, including glutamate challenge, glucose deprivation, exposure to H2O2 and MK-801, a NMDA receptor antagonist, which becomes increasingly popular in schizophrenia models. In good agreement with our in vivo data, creatine mediates a direct effect on the bioenergetic balance, leading to enhanced ATP levels possibly through interference with mitochondrial activity, thus acting as a neuroprotectant, as demonstrated by a set of biochemical markers of cellular integrity. Moreover, creatine could antagonize the H2O2-induced ATP depletion and the excitotoxic response towards glutamate, while not directly acting as an antioxidant. It is important to note that even excessive concentrations of creatine had no neurotoxic potential, so that high-dose creatine supplementation as a health promoting agent in specific pathological situations or as a primary prophylactic agent in risk populations may be useful. In conclusion we were able to demonstrate that the protective potential of creatine was primarily mediated by its impact on cellular energy metabolism, along with reduced glutamate spillover, oxidative stress and subsequent excitotoxicity.