The brain is particularly vulnerable to ischaemia; however, neurons can become tolerant to ischaemic insult. This tolerance has been shown to involve activation of NMDA receptors, but its mechanisms have not yet been fully elucidated. Using a preconditioning protocol, we show that neurons surviving to a transient NMDA exposure become resistant to the glutamatergic agonist. Using a proteomic approach, we found that alterations of the protein pattern of NMDA-resistant neurons are restricted mainly to the five collapsin response mediator proteins (CRMPs). A sustained increase in calpain activity following NMDA treatment is responsible for the production of cleaved CRMPs. Finally, we provide evidence for the involvement of the cleaved form of WT-CRMP2 in the down-regulation of NR2B. Our data suggests that, beside their role in neuronal morphogenesis, CRMPs may contribute to neuronal plasticity.

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.

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