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L-Lactate protects neurons against excitotoxicity: implication of an ATP-mediated signaling cascade.

Jourdain P, Allaman I, Rothenfusser K, Fiumelli H, Marquet P, Magistretti PJ - Sci Rep (2016)

Bottom Line: In the presence of L-Lactate (or Pyruvate), the percentage of neuronal death decreases to 32%.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.

View Article: PubMed Central - PubMed

Affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.

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.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the mechanisms involved in the neuroprotective effect of L-Lactate against excitotoxicity.Over stimulation of NMDA receptors by glutamate triggers a strong inflow of Ca2+; this overload of Ca2+ leading to excitotoxic cell death processes (1). L-Lactate is transported into the cell (2) and converted to Pyruvate by Lactate Dehydrogenase (LDH) (3). Pyruvate is transported into mitochondria through the Mitochondrial Pyruvate Carrier (MPC) to produce ATP (4). ATP is then released through pannexins and acts on the metabotropic purinergic receptor P2Y, likely P2Y2, in a autocrine/paracine manner (5). Stimulation of purinergic receptors activates the PI3K pathway (6) which, in turn, elicits the opening of KATP channels, hence leading to hyperpolarization of neurons (7), the consequence being a decrease in neuronal excitability leading to neuroprotection.
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f5: Schematic representation of the mechanisms involved in the neuroprotective effect of L-Lactate against excitotoxicity.Over stimulation of NMDA receptors by glutamate triggers a strong inflow of Ca2+; this overload of Ca2+ leading to excitotoxic cell death processes (1). L-Lactate is transported into the cell (2) and converted to Pyruvate by Lactate Dehydrogenase (LDH) (3). Pyruvate is transported into mitochondria through the Mitochondrial Pyruvate Carrier (MPC) to produce ATP (4). ATP is then released through pannexins and acts on the metabotropic purinergic receptor P2Y, likely P2Y2, in a autocrine/paracine manner (5). Stimulation of purinergic receptors activates the PI3K pathway (6) which, in turn, elicits the opening of KATP channels, hence leading to hyperpolarization of neurons (7), the consequence being a decrease in neuronal excitability leading to neuroprotection.

Mentions: Initial phases of cellular death triggered by an excessive glutamate stimulation are characterized by a massive ionic and water inflows56. Taking advantage of the QP-DHM technique to monitor transmembrane water fluxes associated with early stages of neuronal death processes2627, we demonstrate that L-Lactate acts as a signaling molecule conferring neuroprotection against excitotoxic insults through well-coordinated mechanisms based on an increase neuronal energy substrates availability, a release of ATP and an intracellular signaling PI3 kinase pathway triggered by purinergic receptors, likely P2Y2, followed by the activation of the KATP channels as summarized in Fig. 5.


L-Lactate protects neurons against excitotoxicity: implication of an ATP-mediated signaling cascade.

Jourdain P, Allaman I, Rothenfusser K, Fiumelli H, Marquet P, Magistretti PJ - Sci Rep (2016)

Schematic representation of the mechanisms involved in the neuroprotective effect of L-Lactate against excitotoxicity.Over stimulation of NMDA receptors by glutamate triggers a strong inflow of Ca2+; this overload of Ca2+ leading to excitotoxic cell death processes (1). L-Lactate is transported into the cell (2) and converted to Pyruvate by Lactate Dehydrogenase (LDH) (3). Pyruvate is transported into mitochondria through the Mitochondrial Pyruvate Carrier (MPC) to produce ATP (4). ATP is then released through pannexins and acts on the metabotropic purinergic receptor P2Y, likely P2Y2, in a autocrine/paracine manner (5). Stimulation of purinergic receptors activates the PI3K pathway (6) which, in turn, elicits the opening of KATP channels, hence leading to hyperpolarization of neurons (7), the consequence being a decrease in neuronal excitability leading to neuroprotection.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4759786&req=5

f5: Schematic representation of the mechanisms involved in the neuroprotective effect of L-Lactate against excitotoxicity.Over stimulation of NMDA receptors by glutamate triggers a strong inflow of Ca2+; this overload of Ca2+ leading to excitotoxic cell death processes (1). L-Lactate is transported into the cell (2) and converted to Pyruvate by Lactate Dehydrogenase (LDH) (3). Pyruvate is transported into mitochondria through the Mitochondrial Pyruvate Carrier (MPC) to produce ATP (4). ATP is then released through pannexins and acts on the metabotropic purinergic receptor P2Y, likely P2Y2, in a autocrine/paracine manner (5). Stimulation of purinergic receptors activates the PI3K pathway (6) which, in turn, elicits the opening of KATP channels, hence leading to hyperpolarization of neurons (7), the consequence being a decrease in neuronal excitability leading to neuroprotection.
Mentions: Initial phases of cellular death triggered by an excessive glutamate stimulation are characterized by a massive ionic and water inflows56. Taking advantage of the QP-DHM technique to monitor transmembrane water fluxes associated with early stages of neuronal death processes2627, we demonstrate that L-Lactate acts as a signaling molecule conferring neuroprotection against excitotoxic insults through well-coordinated mechanisms based on an increase neuronal energy substrates availability, a release of ATP and an intracellular signaling PI3 kinase pathway triggered by purinergic receptors, likely P2Y2, followed by the activation of the KATP channels as summarized in Fig. 5.

Bottom Line: In the presence of L-Lactate (or Pyruvate), the percentage of neuronal death decreases to 32%.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.

View Article: PubMed Central - PubMed

Affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.

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.

No MeSH data available.


Related in: MedlinePlus