Pyruvate and lactate protect striatal neurons against N‐methyl‐d‐aspartate‐induced neurotoxicity

Abstract

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.

Pyruvate protects mitochondria from oxidative stress in human neuroblastoma SK-N-SH cells

“…Indeed, a recently study also suggested that cytoprotection could be afforded even when pyruvate was provided 1-3 hr after H 2 O 2 insult in primary cortical neurons [38]. Moreover, pyruvate protection is not limited to H 2 O 2 -induced cytotoxicity, and has been demonstrated in response to various cytochemical insults, including zinc [27], menadion [13], NMDA [32], glutamate [42], β-amyloid [1], and 1-methy-4-phenylpyridinium ion (MPP+) [33].…”

Blockade of quinolinic acid-induced neurotoxicity by pyruvate is associated with inhibition of glial activation in a model of Huntington's disease

“…In vitro, pyruvate protects against NMDA or zinc-mediated cell death by enhancing energy metabolism (Maus et al, 1999;Sheline et al, 2000). In addition, pyruvate increases neuronal survival against hydrogen peroxide (Desagher et al, 1997) and cysteine-mediated oxidative stress (Wang and Cynader, 2001).…”

Short-Term Feeding of Fish Oil Down-Regulates the Expression of Pyruvate Dehydrogenase E1 Alpha Subunit mRNA in Mouse Brain

“…23) In fact, recent studies have indicated that caloric restriction and intermittent fasting suppress cumulative oxidative stress and induce neurotrophic factor. [24][25][26] Additionally, the down-regulation of PDHE1 mRNA expression might increase a pyruvate that protects neurons against hydrogen peroxide, 27) NMDA, 28) or quinolinic-induced toxicity. 29) Further investigation will be needed to examine these possibilities for the protective roles via PDHE1.…”