Abstract
Converging experimental data indicate a neuroprotective action of L-Lactate. Using Digital Holographic Microscopy, we observe that transient application of glutamate (100 μM; 2 min) elicits a NMDA-dependent death in 65% of mouse cortical neurons in culture. In the presence of L-Lactate (or Pyruvate), the percentage of neuronal death decreases to 32%. UK5099, a blocker of the Mitochondrial Pyruvate Carrier, fully prevents L-Lactate-mediated neuroprotection. In addition, L-Lactate-induced neuroprotection is not only inhibited by probenicid and carbenoxolone, two blockers of ATP channel pannexins, but also abolished by apyrase, an enzyme degrading ATP, suggesting that ATP produced by the Lactate/Pyruvate pathway is released to act on purinergic receptors in an autocrine/paracrine manner. Finally, pharmacological approaches support the involvement of the P2Y receptors associated to the PI3-kinase pathway, leading to activation of KATP channels. This set of results indicates that L-Lactate acts as a signalling molecule for neuroprotection against excitotoxicity through coordinated cellular pathways involving ATP production, release and activation of a P2Y/KATP cascade.
Highlights
Excitotoxicity is a pathological process leading to neuronal damage and death triggered by excessive stimulation by glutamate of N-Methyl-D-Aspartate (NMDA) receptors[1]
Results presented here show that L-Lactate acts as a signaling molecule conferring neuroprotection against excitotoxic insults through a set of coordinated mechanisms based on an increase in ATP production and release and the subsequent activation of the P2Y receptors, mainly P2Y2, leading to an intracellular neuroprotective signaling pathway involving PI3 kinase and KATP channels
Early signs of neuronal death elicited by glutamate-induced excitotoxicity can be accurately monitored by analysing quantative phase signals (QPS) using QP-DHM26,27
Summary
Excitotoxicity is a pathological process leading to neuronal damage and death triggered by excessive stimulation by glutamate of N-Methyl-D-Aspartate (NMDA) receptors[1].
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