Figure 7

Schematic representation of the dual effect of L-Lactate. Extracellular L-Lactate is transported into neurons (1) and is metabolized by Lactate Dehydrogenase (LDH) in presence of NAD⁺ (2) to produce Pyruvate and NADH. Pyruvate and NADH are engaged in two distinct and independent pathways: Potentiation Pathway (or NADH Pathway in red): For a subthreshold concentration of glutamate unable to activate NR2B-containing NMDARs, NADH acts as reducing agent (3) to allow the opening of the NR2B-containing NMDARs’ ion channel resulting in a Ca²⁺ influx (4). Neuroprotective Pathway (or Pyruvate/ATP Pathway in green): When glutamate over-activity triggers a strong inflow of Ca²⁺ through the NR2B-containing NMDARs, Pyruvate is metabolized into the mitochondria to produce ATP then released through pannexins (5) to act on the metabotropic purinergic receptor P2Y2 in an autocrine/paracine manner (6). Stimulation of P2Y2 receptors activates the PI3K pathway (7) which, in turn, elicits the opening of K_ATP channels, hence leading to hyperpolarization of neurons (8), the consequence being a decrease in neuronal excitability leading to neuroprotection (decrease of the Ca²⁺ influx through the closure of NMDARs) (9). Points 6 and 7 have been presented in Jourdain et al.¹⁴.