Elevated lactate suppresses neuronal firing in vivo and inhibits glucose metabolism in hippocampal slice cultures

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

“…This may explain the limited success of strategies designed to promote ATP synthesis via provision of TCA precursors or intermediates such as lactate or pyruvate [93], or ketones [94] in the context of acute brain injury. These substances do not generally elevate brain slice ATP levels, [95][96][97], and nor indeed does creatine [98], likely because the adenine nucleotide backbone is not available.…”

The metabolic trinity, glucose–glycogen–lactate, links astrocytes and neurons in brain energetics, signaling, memory, and gene expression

“…Using a different calculation, if the microdialysis transfer efficiency were ∼7.5% [9], the peak concentration in the histogram in Fig. 1C of [24] would be 18.8 mmol/L (250 × 0.075), and calculated lactate levels at ∼0.54 and 0.9 mm are 4.5 and 1.1 mmol/L, respectively. Thus, the estimated lactate concentration range of ∼4-13 mmol/L markedly suppresses neuronal firing, which others have also observed (cited in [24]).…”

“…Lactate diffuses ∼1.1-1.5 mm within 10-20 min after injection into brain [8] or perfusion of hippocampus by microdialysis [24], and nearphysiological levels of lactate would be expected only at the margins of the lactate-flooded tissue volume. l-Lactate estimated to be 12.5 mmol/L at the recording electrode (i.e., anticipated 20-fold dilution of 250 mmol/L in perfusate delivered by microdialysis) reversibly suppressed firing of hippocampal pyramidal neurons in awake rats in vivo, whereas perfusate delivering an estimated 5 mmol/L had no effect and 25 mmol/L caused irreversible firing inhibition [24]. Using a different calculation, if the microdialysis transfer efficiency were ∼7.5% [9], the peak concentration in the histogram in Fig.…”

“…1C of [24] would be 18.8 mmol/L (250 × 0.075), and calculated lactate levels at ∼0.54 and 0.9 mm are 4.5 and 1.1 mmol/L, respectively. Thus, the estimated lactate concentration range of ∼4-13 mmol/L markedly suppresses neuronal firing, which others have also observed (cited in [24]). Using the same histogram and assigning injected 100 mmol/L as the peak, the lactate concentration would be ∼24 and 5.9 mmol/L at 0.54 and 0.9 mm from the source, suggesting that neuronal firing suppression should occur within a large fraction of the tissue volume and in the culture medium flooded by high-doses of lactate.…”

Microdialysate concentration changes do not provide sufficient information to evaluate metabolic effects of lactate supplementation in brain-injured patients

“…103 This level of lactate is approximated or exceeded in the TBI studies (Table 2) and during spreading depression and seizures in rat brain (Table 3). In addition, 12.5 mmol/L lactate attenuates hippocampal pyramidal cell firing in vivo by 85%, 104 and 10 mmol/L lactate suppresses field potentials, population spikes, and population excitatory postsynaptic potentials in hippocampal slices. 55 Thus, lactate supplementation should enhance neuronal shutdown, thereby reducing neuronal energy demand and contributing to glucose sparing independent of any lactate metabolism.…”