Protective effect of the energy precursor creatine against toxicity of glutamate and beta-amyloid in rat hippocampal neurons.
The loss of ATP, which is needed for ionic homeostasis, is an early event in the neurotoxicity of glutamate and beta-amyloid (A(beta)). We hypothesize that cells supplemented with the precursor creatine make more phosphocreatine (PCr) and create larger energy reserves with consequent neuroprotection against stressors. In serum-free cultures, glutamate at 0.5-1 mM was toxic to embryonic hippocampal neurons. Creatine at >0.1 mM greatly reduced glutamate toxicity. Creatine (1 mM) could be added as late as 2 h after glutamate to achieve protection at 24 h. In association with neurotoxic protection by creatine during the first 4 h, PCr levels remained constant, and PCr/ATP ratios increased. Morphologically, creatine protected against glutamate-induced dendritic pruning. Toxicity in embryonic neurons exposed to A(beta) (25-35) for 48 h was partially prevented by creatine as well. During the first 6 h of treatment with A(beta) plus creatine, the molar ratio of PCr/ATP in neurons increased from 15 to 60. Neurons from adult rats were also partially protected from a 24-h exposure to A(beta) (25-35) by creatine, but protection was reduced in neurons from old animals. These results suggest that fortified energy reserves are able to protect neurons against important cytotoxic agents. The oral availability of creatine may benefit patients with neurodegenerative diseases.
Brewer
G J
GJ
Department of Medical Microbiology/Immunology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9626, USA. gbrewer@siumed.edu
Wallimann
T W
TW
D000375:Aging / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000506:poisoning*; D000818:Animals; D002478:Cells, Cultured; D003401:Creatine / Q000494:pharmacology*; D003712:Dendrites / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D018698:Glutamic Acid / Q000506:poisoning*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010725:Phosphocreatine; D018698:Glutamic Acid; D003401:Creatine