Journal
JOURNAL OF NEUROCHEMISTRY
Volume 74, Issue 5, Pages 1968-1978Publisher
WILEY
DOI: 10.1046/j.1471-4159.2000.0741968.x
Keywords
creatine; phosphocreatine; ATP; energy; glutamate toxicity; beta-amyloid
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Funding
- NIA NIH HHS [R01 AG13435] Funding Source: Medline
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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 vats 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.
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