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.

Efficient derivation of microglia-like cells from human pluripotent stem cells

“…Glutamate was omitted to avoid the excitotoxicity of this amino-acid in dissociated cultures 47 . We included additional pyruvate 48 , and lactic acid 49 as energy-providing and neuroprotective substrates in addition to the more canonical oxidative substrates (glucose, galactose and glutamine/Glutamax). Biotin and lipid-loaded albumin (Albumax) were added to support de novo synthesis lipid bilayers (e.g.…”

Metabolic Dysfunctions in Amyotrophic Lateral Sclerosis Pathogenesis and Potential Metabolic Treatments

“…Early administration of lactate in rat organotypic hippocampal slices after oxygen-glucose deprivation protected against neuronal death, decreased lesion size and showed better neurologic outcomes in a mouse model of middle cerebral artery occlusion (Berthet et al, 2009, 2012). Lactate has also been shown to provide neuroprotection against glutamate mediated toxicity in rat hippocampal slices (Schurr and Gozal, 2011), in mouse cortical neuron cultures (Jourdain et al, 2016) and in rat cortex in vivo (Ros et al, 2001). In addition, exogenous administration of lactate reduced brain lesion size in a rat controlled cortical impact models of TBI (Alessandri et al, 2012) and in patients with severe TBI (Bouzat et al, 2014).…”

“…The mechanism of lactate was linked to its ability to improve cerebral energy metabolism and preserve ATP levels in injured brain (Holloway et al, 2007; Gallagher et al, 2009; Bouzat et al, 2014; Jourdain et al, 2016). In addition to its effect as an energy fuel, lactate can function as a signaling molecule by activating hydrocarboxylic acid receptor 1 (HCA1) receptors (Castillo et al, 2015).…”

“…In addition to its effect as an energy fuel, lactate can function as a signaling molecule by activating hydrocarboxylic acid receptor 1 (HCA1) receptors (Castillo et al, 2015). ATP produced from lactate was also shown to act on the P2Y receptors (Jourdain et al, 2016). Lactate can be used either directly following its cerebral uptake or indirectly as a gluconeogenic precursor (Glenn et al, 2015a,b).…”

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity

“…Epileptic seizures also induce neuronal death caused by brain ATP decrease (19), and lead to hippocampal-related memory dysfunction (20). Further, lactate plays a neuroprotective role against excitotoxic and ischemic damage through ATP production (21,22). We thus hypothesized that the astrocytic glycogen-derived lactate acts to maintain brain ATP levels during exhaustive exercise, thereby contributing to endurance capacity.…”