Lactate Transport and Signaling in the Brain: Potential Therapeutic Targets and Roles in Body—Brain Interaction

Abstract

Lactate acts as a 'buffer' between glycolysis and oxidative metabolism. In addition to being exchanged as a fuel by the monocarboxylate transporters (MCTs) between cells and tissues with different glycolytic and oxidative rates, lactate may be a 'volume transmitter' of brain signals. According to some, lactate is a preferred fuel for brain metabolism. Immediately after brain activation, the rate of glycolysis exceeds oxidation, leading to net production of lactate. At physical rest, there is a net efflux of lactate from the brain into the blood stream. But when blood lactate levels rise, such as in physical exercise, there is net influx of lactate from blood to brain, where the lactate is used for energy production and myelin formation. Lactate binds to the lactate receptor GPR81 aka hydroxycarboxylic acid receptor (HCAR1) on brain cells and cerebral blood vessels, and regulates the levels of cAMP. The localization and function of HCAR1 and the three MCTs (MCT1, MCT2, and MCT4) expressed in brain constitute the focus of this review. They are possible targets for new therapeutic drugs and interventions. The author proposes that lactate actions in the brain through MCTs and the lactate receptor underlie part of the favorable effects on the brain resulting from physical exercise.

A Probable Dual Mode of Action for Both L- and D-Lactate Neuroprotection in Cerebral Ischemia

“…24 Lactate is produced under physiologic conditions, 25,26 and it is suggested to have an important role in the metabolic support of long axons 6,27 as well as in longterm memory formation. 28 Lack of adequate lactate supply has also been implicated in some neurodegenerative diseases such as amyotrophic lateral sclerosis.…”

Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters

“…However, transport also depends on the concentration gradients of monocarboxylate and H + [62, 64]. Thus, MCT1 and MCT4 could both serve to import as well as export pyruvate into and out of the cell, albeit with differing affinities.…”

Oligodendroglia: metabolic supporters of neurons

“…The cellular source of the lactate that provides long-term memory benefits was originally suggested to be astrocytes; however, the subsequent identification of MCT1 expression in oligodendrocytes suggests that oligodendroglia also may mediate these effects (43). Lactate has been shown to have neuroprotective effects in brain injury models, either as a neuronal metabolite or as a signaling molecule that binds the neuronal lactate receptor HCA1 (GPR81) (60)(61)(62)(63)(64). This finding underscores the potential role of lactate in models of neurodegeneration wherein neurons are metabolically stressed.…”