Lactate Is Answerable for Brain Function and Treating Brain Diseases: Energy Substrates and Signal Molecule

Abstract

Research to date has provided novel insights into lactate's positive role in multiple brain functions and several brain diseases. Although notable controversies and discrepancies remain, the neurobiological role and the metabolic mechanisms of brain lactate have now been described. A theoretical framework on the relevance between lactate and brain function and brain diseases is presented. This review begins with the source and route of lactate formation in the brain and food; goes on to uncover the regulatory effect of lactate on brain function; and progresses to gathering the application and concentration variation of lactate in several brain diseases (diabetic encephalopathy, Alzheimer's disease, stroke, traumatic brain injury, and epilepsy) treatment. Finally, the dual role of lactate in the brain is discussed. This review highlights the biological effect of lactate, especially L-lactate, in brain function and disease studies and amplifies our understanding of past research.

Keywords: brain diseases; brain function; energy substrates; lactate; signal molecule.

Figure 1

The formation and metabolism of lactate in the brain. The action of the glutamate-glutamine cycle switches on the glycolysis in the astrocytes, a process of glutamate released by neuronal terminals and then is taken up by astrocytes via the EAATs to convert into glutamine or GSH. Pfkfb3 (a key positive modulator of glycolysis) is a high expression in astrocytes and low in neurons, while the activity of PDH is low in astrocytes and low in neurons. These characteristics determine that astrocytes have strong glycolysis ability and neurons have strong aerobic oxidation ability. Astrocytic glycogen first decomposes into glucose-6P catalyzed by GP and finally into pyruvate through a series of catalytic reactions. During this process, a tiny amount of MG generates and then converts into endogenic D-lactate or GSH. The newly formed pyruvate can be either converted to acetyl-CoA for the astrocytic TCA cycle or transformed into L-lactate by LDH5. The L-lactate in the astrocytes and in the brain blood vessel is transported into the neurons through MCTs (MCT1, MCT2, and MCT4) and then oxidized at the Krebs cycle. EAATs, excitatory amino acid transporters; GSH, glutathione; Pfkfb3, phosphofructokinase-2/fructose-2,6-bisphosphatase 3; PDH, pyruvate dehydrogenase; Glucose-6P, glucose-6-Phosphate; GP, glycogen phosphorylase; MG, methylglyoxal; acetyl-CoA, acetyl coenzyme A; lactate dehydrogenase 5, LDH5; Monocarboxylic acid transporters, MCTs.

Figure 2

The effect of L-lactate and its possible mechanism on the brain. L-lactate is capable of regulating brain function in the terms of learning and memory, cerebral blood flow, neurogenesis and cerebral microangiogenesis, energy metabolism, neuronal activity, and neuroprotection via different pathways.

Figure 3

Graphical summary of the neurobiological role of L-lactate in the brain. On the one hand, L-lactate serves as an energy pool for neurons to facilitate mitochondrial energy production through converting into pyruvate. On the other hand, L-lactate may act as the role like the hormone, defined as lactormone. It triggers multiple downstream signaling cascades via influencing the intracellular NADH/NAD⁺ ratio, mediating the ROS generation, and activating the receptor GPR81. NADH, nicotinamide adenine dinucleotide; ROS, reactive oxygen species; GPR81, G_i-protein-coupled receptor 81.