Pyruvate and lactate protect striatal neurons against N-methyl-D-aspartate-induced neurotoxicity.
A sustained release of glutamate contributes to neuronal loss during cerebral ischaemia. Using cultured mouse striatal neurons, we observed that glucose deprivation, which occurs in this pathological process, enhanced the N-Methyl-D-aspartate (NMDA)- or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-induced neurotoxicity. The end products of glycolysis, lactate and pyruvate, strongly protected neurons from these neurotoxic effects. The neuroprotective effect of pyruvate (which is more prominent in the absence of glucose) was not related to its ability to react with H2O2 by a decarboxylation process. Pyruvate and L-lactate strongly counteracted the deep decrease in the neuronal ATP content induced by NMDA, indicating that they might protect striatal neurons by rescuing cellular energy charge. Addition of MK-801 after the NMDA withdrawal completely protected neurons, suggesting that NMDA neurotoxicity resulted from a delayed NMDA receptor activation probably linked to a delayed release of an endogenous agonist in the extracellular medium. The strong accumulation of extracellular glutamate which was found in both sham and NMDA-treated cultures was markedly decreased by pyruvate. Thus, pyruvate might also exert its protecting activity by decreasing the delayed accumulation of glutamate which seemed to be neurotoxic only after a preexposure of neurons to NMDA.
Maus
M
M
INSERM U114, Collége de France, Paris.
Marin
P
P
Israël
M
M
Glowinski
J
J
Prémont
J
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005947:Glucose / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D007700:Kinetics; D019344:Lactic Acid / Q000627:therapeutic use*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016202:N-Methylaspartate / Q000633:toxicity*; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D020258:Neurotoxicity Syndromes / Q000473:pathology / Q000517:prevention & control*; D010101:Oxygen Consumption / Q000187:drug effects; D019289:Pyruvic Acid / Q000627:therapeutic use*
D018690:Excitatory Amino Acid Agonists; D016166:Free Radical Scavengers; D019344:Lactic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D005947:Glucose; D002118:Calcium