title: L-Lactate protects neurons against excitotoxicity: implication of an ATP-mediated signaling cascade.
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.
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.|Centre de Neurosciences Psychiatriques, CHUV, Département de Psychiatrie, Site de Cery, CH-1008 Prilly/Lausanne, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Jourdain
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Allaman
authors.affiliation: Centre de Neurosciences Psychiatriques, CHUV, Département de Psychiatrie, Site de Cery, CH-1008 Prilly/Lausanne, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Rothenfusser
authors.affiliation: King Abdullah University of Science and Technology (KAUST), Thuwal, Kingdom of Saudi Arabia.
authors.forename: H
authors.initials: H
authors.lastname: Fiumelli
authors.affiliation: Centre de Neurosciences Psychiatriques, CHUV, Département de Psychiatrie, Site de Cery, CH-1008 Prilly/Lausanne, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Marquet
authors.affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.|King Abdullah University of Science and Technology (KAUST), Thuwal, Kingdom of Saudi Arabia.|Centre de Neurosciences Psychiatriques, CHUV, Département de Psychiatrie, Site de Cery, CH-1008 Prilly/Lausanne, Switzerland.
authors.forename: P J
authors.initials: PJ
authors.lastname: Magistretti
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity; D019344:Lactic Acid / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D058470:Receptors, Purinergic P2Y / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018696:Neuroprotective Agents; D015221:Potassium Channels; D058470:Receptors, Purinergic P2Y; C117780:mitochondrial K(ATP) channel; D019344:Lactic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases