Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Apr;17(4):788-790.
doi: 10.4103/1673-5374.322459.

Potential use of lactate for the treatment of neonatal hypoxic-ischemic encephalopathy

Isadora D'Ávila Tassinari  1 , Luciano Stürmer de Fraga  1
Affiliations

Potential use of lactate for the treatment of neonatal hypoxic-ischemic encephalopathy

Isadora D'Ávila Tassinari et al. Neural Regen Res. 2022 Apr.
No abstract available

PubMed Disclaimer

Conflict of interest statement

None

Figures

Figure 1
Figure 1
Hypoxic-ischemic encephalopathy is one of the main causes of mortality and disabilities in newborns, and therapeutic hypothermia (TH) is the only standard clinical treatment used to date. As TH presents some limitations, it furnishes space for complementary therapies, such as lactate, which is now recognized as a potential energy substrate to the brain, as well as an anti-inflammatory signaling molecule. (A) In the brain, there is a lactate transport system known as the astrocyte-neuron lactate shuttle (ANLS) (Pellerin and Magistretti, 1994), in which lactate is continuously produced in astrocytes to be transferred and used by neurons to sustain energy requirements. Blood glucose is taken up by astrocytes through GLUT1. In astrocytes, lactate is produced in a reaction mediated by LDH5 and exported through MCT4 to neurons, where it is taken up by MCT2 and oxidized into pyruvate through LDH1 (to simplify the ANLS scheme, the astrocyte soma and end-feet were not represented). (B) In addition to astrocytes, lactate may be produced by oligodendrocytes, and the existence of a putative lactate transfer system from oligodendrocytes to axons has been proposed (Magistretti and Allaman, 2018). (C) Regarding peripheral organs, it is possible that the activation of lactate receptor GPR81 may lead to a reduction in the immune response. (D) Activation of the lactate receptor GPR81 activates the intracellular adaptor protein, ARRB2 which, in turn, inhibits the activation of the NLRP3 inflammasome, reducing NF-κB activity and pro-inflammatory cytokines production (Hu, 2020). (E) It is also possible that lactate plays a role in microglia cells, preventing classical polarization, known as the M1 pro-inflammatory phenotype (Kong, 2019). These postulated mechanisms of action deserve further experimental analysis since they could provide evidence for the potential use of lactate as a clinical therapy for the treatment of HIE (see the main text for more details and references). ARRB2: Arrestin beta 2; EAAT: excitatory amino acid transporter; Glu: glutamate; GluR: glutamate receptor; GLUT1: glucose transporter 1; GPR81: G protein-coupled receptor 81; LDH1: lactate dehydrogenase 1; LDH5: lactate dehydrogenase 5; M1: microglia classical polarization phenotype; MCT1: monocarboxylate transporter 1; MCT2: monocarboxylate transporter 2; MCT4: monocarboxylate transporter 4; NAD+: nicotinamide adenine dinucleotide oxidized; NADH: nicotinamide adenine dinucleotide reduced; NF-κB: nuclear factor kappa B; NLRP3: nod-like receptor protein 3. The figure is schematic, and the mechanisms are represented in a simplified way. Cells and structures are not represented to scale. Figure created by the authors with the assistance from Mind the Graph® and Biorender®.
See this image and copyright information in PMC

References

    1. Brooks GA. Lactate: Glycolytic End Product and Oxidative Substrate During Sustained Exercise in Mammals — The “Lactate Shuttle”. In: Gilles R, editor. Circulation, Respiration, and Metabolism: Current Comparative Approaches. Berlin, Heidelberg: Springer Berlin Heidelberg; 1985. pp. 208–218.
    1. Gunn AJ, Thoresen M. Neonatal encephalopathy and hypoxic-ischemic encephalopathy. Handb Clin Neurol. 2019;162:217–237. - PubMed
    1. Hu J, Cai M, Liu Y, Liu B, Xue X, Ji R, Bian X, Lou S. The roles of GRP81 as a metabolic sensor and inflammatory mediator. J Cell Physiol. 2020;235:8938–8950. - PubMed
    1. Kong L, Wang Z, Liang X, Wang Y, Gao L, Ma C. Monocarboxylate transporter 1 promotes classical microglial activation and pro-inflammatory effect via 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3. J Neuroinflammation. 2019;16:240. - PMC - PubMed
    1. Lee WLA, Michael-Titus AT, Shah DK. Hypoxic-ischaemic encephalopathy and the blood-brain barrier in neonates. Dev Neurosci. 2017;39:49–58. - PubMed