Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilization by brain in vivo
Open accessAbstract
Neuronal cultures in vitro readily oxidized both D-[(14)C]glucose and l-[(14)C]lactate to (14)CO(2), whereas astroglial cultures oxidized both substrates sparingly and metabolized glucose predominantly to lactate and released it into the medium. [(14)C]Glucose oxidation to (14)CO(2) varied inversely with unlabeled lactate concentration in the medium, particularly in neurons, and increased progressively with decreasing lactate concentration. Adding unlabeled glucose to the medium inhibited [(14)C]lactate oxidation to (14)CO(2) only in astroglia but not in neurons, indicating a kinetic preference in neurons for oxidation of extracellular lactate over intracellular pyruvatelactate produced by glycolysis. Protein kinase-catalyzed phosphorylation inactivates pyruvate dehydrogenase (PDH), which regulates pyruvate entry into the tricarboxylic acid cycle. Dichloroacetate inhibits this kinase, thus enhancing PDH activity. In vitro dichloroacetate stimulated glucose and lactate oxidation to CO(2) and reduced lactate release mainly in astroglia, indicating that limitations in glucose and lactate oxidation by astroglia may be due to a greater balance of PDH toward the inactive form. To assess the significance of astroglial export of lactate to neurons in vivo, we attempted to diminish this traffic in rats by administering dichloroacetate (50 mgkg) intravenously to stimulate astroglial lactate oxidation and then examined the effects on baseline and functionally activated local cerebral gl…
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Neurons heavily rely on oxidative metabolism, whereas astrocytes exhibit high glycolytic rates in vivo and in vitro.
“neurons heavily rely on oxidative metabolism, whereas astrocytes exhibit high glycolytic rates in vivo and in vitro (Lebon et al., 2002;Itoh et al., 2003;Bouzier-Sore and Pellerin, 2013).”
From An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014) · cites this paper as Itoh et al., 2003
Phosphorylation-mediated inactivation of Pdh in astrocytes prevents glycolytic pyruvate from entering oxidative phosphorylation.
“Phosphorylation-mediated inactivation of Pdh in astrocytes (Itoh et al., 2003;Halim et al., 2010) prevents glycolytic pyruvate from entering oxidative phosphorylation.”
From An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014) · cites this paper as Itoh et al., 2003
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- Authors
- Itoh, Y., Esaki, T., Shimoji, K., Cook, M., Law, M. J., Kaufman, E., & Sokoloff, L.
- Affiliations
- National Institutes of Health (US)
- ORCID
- Itoh, Yoshiaki
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-03-31
- Volume
- 100
- Issue
- 8
- Pages
- 4879-4884
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC153649
- OpenAlex
- W2123716968
- Cited by
- 297
- References
- 4
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 10 · 2023: 15 · 2022: 15 · 2021: 12 · 2020: 11 · 2019: 19 · 2018: 15 · 2017: 17 · 2016: 13 · 2015: 8 · 2014: 13 · 2013: 15 · 2012: 15
- FWCI
- 6.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- dichloroacetate, glucose oxidation, lactate oxidation, pyruvate dehydrogenase, pyruvate kinase, astroglia, neurons, brain glucose metabolism, lactate shuttle, local cerebral glucose utilization, functional brain activation, pyruvate dehydrogenase kinase
- MeSH terms
- Animals, Astrocytes, Brain, Cells, Cultured, Citric Acid Cycle, Dichloroacetic Acid, Glucose, Kinetics, Male, Neurons, Oxidation-Reduction, Rats, Sprague-Dawley, Lactic Acid, Rats, In Vitro Techniques
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