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1.
Sci Rep ; 8(1): 13472, 2018 09 07.
Article in English | MEDLINE | ID: mdl-30194439

ABSTRACT

L-Lactate is a positive modulator of NMDAR-mediated signaling resulting in plasticity gene induction and memory consolidation. However, L-Lactate is also able to protect neurons against excito-toxic NMDAR activity, an indication of a mitigating action of L-Lactate on NMDA signaling. In this study, we provide experimental evidence that resolves this apparent paradox. Transient co-application of glutamate/glycine (1 µM/100 µM; 2 min) in primary cultures of mouse cortical neurons triggers a NMDA-dependent Ca2+ signal positively modulated by L-Lactate (10 mM) or DTT (1 mM) but decreased by Pyruvate (10 mM). This L-Lactate and DTT-induced potentiation is blocked by Ifenprodil (2 µM), a specific blocker of NMDARs containing NR2B sub-units. In contrast, co-application of glutamate/glycine (1 mM/100 µM; 2 min) elicits a NMDAR-dependent excitotoxic death in 49% of neurons. L-Lactate and Pyruvate significantly reduce this rate of cell death processes (respectively to 23% and 9%) while DTT has no effect (54% of neuronal death). This L-Lactate-induced neuroprotection is blocked by carbenoxolone and glibenclamide, respectively blockers of pannexins and KATP. In conclusion, our results show that L-Lactate is involved in two distinct and independent pathways defined as NMDAR-mediated potentiation pathway (or NADH pathway) and a neuroprotective pathway (or Pyruvate/ATP pathway), the prevalence of each one depending on the strength of the glutamatergic stimulus.


Subject(s)
Lactic Acid/pharmacology , Membrane Potentials , Neurons/drug effects , Neuroprotective Agents/pharmacology , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Calcium/metabolism , Cell Death , Cells, Cultured , Cerebral Cortex/cytology , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Glutamic Acid/pharmacology , Glycine/pharmacology , Mice , Neurons/metabolism , Neurons/physiology , Piperidines/pharmacology , Pyruvic Acid/pharmacology , Receptors, N-Methyl-D-Aspartate/agonists , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors
2.
Sci Rep ; 6: 21250, 2016 Feb 19.
Article in English | MEDLINE | ID: mdl-26893204

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.


Subject(s)
Lactic Acid/metabolism , Neurons/metabolism , Adenosine Triphosphate/metabolism , Animals , Cell Death/drug effects , Cells, Cultured , Female , Glutamic Acid/metabolism , Glutamic Acid/toxicity , Lactic Acid/pharmacology , Male , Mice , Mitochondria/drug effects , Mitochondria/metabolism , Models, Biological , N-Methylaspartate/toxicity , Neurons/drug effects , Neuroprotective Agents/pharmacology , Oxidation-Reduction/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Potassium Channels/metabolism , Receptors, Purinergic P2Y/metabolism , Signal Transduction/drug effects
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