L-Lactate protects neurons against excitotoxicity: implication of an ATP-mediated signaling cascade
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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 K ATP 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/K ATP cascade.
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Additional pyruvate and lactic acid were included as energy-providing and neuroprotective substrates alongside standard oxidative substrates.
“We included additional pyruvate48, and lactic acid 49 as energy-providing and neuroprotective substrates in addition to the more canonical oxidative substrates (glucose, galactose and glutamine/Glutamax).”
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- Authors
- Jourdain, P., Allaman, I., Rothenfusser, K., Fiumelli, H., Marquet, P., & Magistretti, P. J.
- Affiliations
- Centre Hospitalier Universitaire Vaudois (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- King Abdullah University of Science and Technology (SA)
- Corresponding author
- Jourdain, P.
- Magistretti, P. J.
- Venue
- Scientific Reports
- Published
- 2016-02-19
- Volume
- 6
- Issue
- 1
- Pages
- 21250-21250
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4759786
- OpenAlex
- W2281668243
- Cited by
- 116
- References
- 79
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 12 · 2023: 7 · 2022: 11 · 2021: 12 · 2020: 15 · 2019: 13 · 2018: 8 · 2017: 9 · 2016: 3
- FWCI
- 10.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion, other-oa)
- IRIS (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- King Abdullah University of Science and Technology Repository (King Abdullah University of Science and Technology) (submittedVersion, cc-by)
- Funders
- Fonds De La Recherche Scientifique - FNRS
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- L-lactate, neuroprotection, excitotoxicity, glutamate, NMDA receptor, pyruvate, mitochondrial pyruvate carrier, purinergic signaling, P2Y receptors, PI3-kinase, ATP-sensitive potassium channels, cortical neurons, ATP release
- MeSH terms
- Adenosine Triphosphate, Animals, Cells, Cultured, Female, Male, Mitochondria, Models, Biological, Neurons, Oxidation-Reduction, Potassium Channels, Signal Transduction, N-Methylaspartate, Cell Death, Neuroprotective Agents, Glutamic Acid, Lactic Acid, Phosphatidylinositol 3-Kinases, Mice, Receptors, Purinergic P2Y
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