Involvement of brain lactate in neuronal metabolism

Abstract

The involvement of brain lactate in neuronal metabolism was analyzed by ex vivo NMR spectroscopy with rats under the effects of pentobarbital, chloralose or morphine, which were infused with a solution of either [1-13 C]glucose þ lactate or glucose þ [3-13 C]lactate for 20 min. Electroencephalogram recordings indicated different brain electrical activity levels under the three drugs with a clear distinction between pentobarbital, on the one hand, and chloralose and morphine on the other. Labeling of metabolites in brain perchloric acid extracts and of blood glucose and lactate was determined by 13 C-and/or 1 H-observed/ 13 C-edited-NMR spectroscopy. The following were found: (i) the ratio between glutamate C3 and C4 13 C-enrichments increased from pentobarbital to chloralose and morphine whatever the labeled precursor, indicating a link between metabolic and electrical activity; (ii) under glucose þ [3-13 C]lactate infusion, alanine C3 and acetyl-CoA C2 enrichments were higher than that of lactate C3, revealing the occurrence of an isotopic dilution of the brain exogenous lactate (arising from blood) by lactate from brain (endogenous lactate); the latter was synthesized from glycolysis in a compartment other than the neurons; (iii) the contributions of labeled glucose and lactate to acetyl-CoA C2 enrichment indicated that the involvement of blood glucose relative to that of blood lactate to brain metabolism was correlated with brain activity. It can therefore be concluded that the brain electrical activity-dependent increase in the contribution of blood glucose relative to that of blood lactate to brain metabolism occurred partly via the increase in the metabolism of lactate generated from astrocytic glycolysis. This conclusion supports the hypothesis of an astrocyte-neuron lactate shuttle component in the coupling mechanism between cerebral activity and energy metabolism.

Ex Vivo Analysis of Lactate and Glucose Metabolism in the Rat Brain under Different States of Depressed Activity

“…The sole potential pyruvate source was the lactate endogenous to brain, providing that the latter was synthesized in a compartment other than the neurons. As evidenced previously from acetylCoA enrichment analysis (17), the astrocytes were mainly responsible for the brain lactate production, a finding in agreement with the much more efficient lactate production by astrocytes than by neurons (15). Therefore, the amino acid labeling patterns could be due to a progressively more pronounced involvement of astrocytic glycolytic lactate than of blood lactate in the move from pentobarbital to morphine.…”

“…Physiological Status of the Infused Rats-As reported previously, an electroencephalogram recording indicated that the rat cerebral activity was strongly depressed under pentobarbital anesthesia, whereas a slight increase in spectral power in the 1-20 Hz frequency band was noted under both ␣-chloralose and morphine as a consequence of a large power increase in the ␦ band, whereas ␣-chloralose induced a slight power decrease in the band (17). At the end of infusion, PaO 2 was 74 Ϯ 5, 84 Ϯ 1, or 82 Ϯ 2 and PaCO 2 was 53 Ϯ 2, 51 Ϯ 1, or 40 Ϯ 1 under pentobarbital, ␣-chloralose, or morphine anesthesia, respectively.…”

“…Thus, assuming that blood lactate entry into brain would have been similar under the three drugs, the contribution of glycolytic lactate to the lactate pool would have been ϳ85% under morphine. These results emphasize therefore that the increase in brain lactate production and the increase in cerebral activity from pentobarbital to morphine (17,22) were linked. The increased brain lactate concentration from pentobarbital to morphine was hence more likely due to this increase in lactate production than to changes in blood lactate influx.…”

“…To investigate in vivo the relevance of the ANLS hypothesis, we therefore used an alternative approach in which brain lactate metabolism was investigated by analyzing the competition between the lactate endogenous to brain and the exogenous lactate intravenously administrated to the animals through the infusion of a solution of either [1-13 C]glucose plus lactate or glucose with [3-13 C]lactate. Thus, using rats treated with various drugs leading to different levels of cerebral activity, we recently demonstrated from the analysis of alanine, lactate, and acetyl-CoA labeling that astrocytic glycolysis was the main source of the endogenous brain lactate and that the contribution of blood glucose relative to the contribution of blood lactate to the neuronal metabolism was linked to brain activity (17). Using the same experimental approach, in the present study we analyzed the amino acid enrichments reached under the different conditions.…”

Role and Function of Dehydrogenases in CNS and Blood-Brain Barrier Pathophysiology

“…Although this concept of lactate shuttle was proposed long ago, it received lot of resistance from the scientific community especially from those who believed that glucose is the sole substrate in the brain (30;31). However now, it is getting accepted that lactose is also used as a main substrate for energy production under normal conditions (32)(33)(34). The direction of lactate flow between various cell types in the brain as well as its relative contribution with respect to glucose to the overall energy production is still debatable and not yet fully understood.…”