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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.

SUBMITTER: Bergersen LH

PROVIDER: S-EPMC4426752 | biostudies-other | 2015 Feb

REPOSITORIES: biostudies-other

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Project description:Metastatic spine disease is a heterogeneous clinical condition commonly requiring surgical intervention. Despite this heterogeneity, all cases share the common theme of altered tumor metabolism, characterized by aerobic glycolysis and high lactate production. Here we review the existing literature on lactate metabolism as it pertains to tumor progression, metastasis, and the formation of painful bone lesions. We included articles from the English literature addressing the role of lactate metabolism in the following: (I) primary tumor aggressiveness, (II) local tissue invasion, (III) metastasis formation, and (IV) generation of oncologic pain. We also report current investigations into restoring normal lactate metabolism as a means of impeding tumor growth and the formation of bony metastases. Both in vivo and in vitro experiments suggest that high lactate levels may be necessary for tumor cell growth, as small molecules inhibitors of lactate dehydrogenase (LDH5/LDHA) decrease both the rate of tumor growth and formation of metastases. Additionally, in vitro evidence strongly implicates lactate in tumor cell migration by driving the amoeboid movements of these cells. Acidification of the local bony tissue by excess lactate production activates CGRP+ neurons in the bone marrow and periosteum to generate oncologic bone pain. High lactate may also increase expression of acid sensing receptors in these neurons to generate the neuropathic pain seen in some patients with metastatic disease. Lastly, investigation into lactate-directed therapeutics is still early in development. Initial preclinical trials looking at LDH5/LDHA inhibitors as well as inhibitors of lactate transporters (MCT1) have demonstrated promise, but clinical work has been restricted to a single phase I trial. Lactate appears to play a crucial role in the pathogenesis of metastatic spine disease. Efforts are ongoing to identify small molecules inhibitors of targets in the lactogenic pathway capable of preventing the formation of osseous metastatic disease.

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Lactate transport and signaling in the brain: potential therapeutic targets and roles in body-brain interaction.

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