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Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids
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“The abundant expression of MCTs in endothelial cells (75, 92) might facilitate crossing of the BBB by SCFAs since brain uptake of SCFAs has previously been demonstrated in rats following injection of 14C-SCFAs into the carotid artery (93).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [93]
In the citing paper
“A small fraction reaches the systemic circulation and can cross the tightly regulated BBB using their own transporters located on brain vascular epithelial cells (100, 101).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [100]
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Pyruvate and lactate protect striatal neurons against N‐methyl‐ d ‐aspartate‐induced neurotoxicity
Maus, M., Marin, P., Israël, M., Glowinski, J., & Prémont, J. (1999) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.1999.00745.x · Cited by 88
“Pyruvate and lactate can cross the blood±brain barrier (Oldendorf, 1973; Conn et al., 1983).”
BackgroundHaas, E. N. D., & van der Eijk, J. A. J. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.07.007 · Cited by 97
“Thus, the TRP/LNAA ratio reflects TRP availability for transportation across the BBB (Fernstrom and Wurtman, 1972).”
BackgroundInfluentialGut-Brain Axis in the Early Postnatal Years of Life: A Developmental Perspective
Jena, A., Montoya, C. A., Mullaney, J. A., Dilger, R. N., Young, W., McNabb, W. C., & Roy, N. C. (2020) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2020.00044 · Cited by 98
“Brain uptake of SCFA was reported following the injection of a mix of 14C-SCFA into the carotid artery, which suggests that BBB might be permeable to SCFA (Oldendorf, 1973).”
BackgroundCruz, N. F., Lasater, A., Zielke, H. R., & Dienel, G. A. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02935.x · Cited by 88
Patel, A. B., de Graaf, R. A., Rothman, D. L., Behar, K. L., & Mason, G. F. (2010) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2010.2 · Cited by 88
“An Eadie–Hofstee plot of BUI data for acetate reported earlier (Oldendorf, 1973) yields an apparent Kt of 6.7 mmol/L (The KM for acetate transport was estimated from published data (Oldendorf, 1973).”
MethodInfluentialAndersen, J. V., Westi, E. W., Jakobsen, E., Urruticoechea, N., Borges, K., & Aldana, B. I. (2021) · Molecular Brain · doi:10.1186/s13041-021-00842-2 · Cited by 89
Dopamine toxicity in neuroblastoma cells: role of glutathione depletion by l-BSO and apoptosis
Stokes, A. H., Lewis, D. Y., Lash, L. H., Jerome, W. G., Grant, K. W., Aschner, M., & Vrana, K. E. (2000) · Brain Research · doi:10.1016/s0006-8993(99)02329-x · Cited by 85
Soliman, M. L., Combs, C. K., & Rosenberger, T. A. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-012-9426-4 · Cited by 84
“Peripherally-derived acetate crosses the blood brain barrier by simple diffusion, and the rate-limiting step of acetate utilization is its activation by acetyl-CoA synthetase to form acetyl-CoA (Oldendorf 1973; Terasaki 1992).”
Mann, G. E., Zlokovic, B. V., & Yudilevich, D. L. (1985) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(85)90179-8 · Cited by 84
Maiuolo, J., Bulotta, R. M., Ruga, S., Nucera, S., Macrì, R., Scarano, F., Oppedisano, F., Carresi, C., Gliozzi, M., Musolino, V., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25136971 · Cited by 91
“The passage of SCFAs through the BBB was verified through experiments involving radio-labeled SCFAs with 14 C [36,37].”
MethodPyruvate protects against experimental stroke via an anti-inflammatory mechanism
Wang, Q., Hoecke, M. V., Tang, X. N., Lee, H., Zheng, Z., Swanson, R. A., & Yenari, M. A. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.07.018 · Cited by 83
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“Similar to PUFAs, short-chain fatty acids (SCFAs) such as acetate (two carbon atoms), propionate (four carbon atoms) and butyrate (six carbon atoms), which are produced by intestinal bacteria through the fermentation of non-digestible dietary polysaccharides, can cross the BBB 253,254 .”
InfluentialThe blood‐brain barrier: Cellular basis
Janzer, R. C. (1993) · Journal of Inherited Metabolic Disease · doi:10.1007/bf00711897 · Cited by 79
“These markers of the blood-brain barrier phenotype of endothelial cells include alkaline phosphatase (Goldstein and Harris 1981); nucleoside-diphosphatase (Vorbrodt et al 1983); abluminally localized Na ÷ K÷-ATPase (Betz et al 1980); 5'-nucleotidase (Vorbrodt et al 1983); butylcholinesterase (Karcsu and Toth 1982); 7-…”
BackgroundEpigenetic effects of short-chain fatty acids from the large intestine on host cells
Stein, R. A., & Riber, L. (2023) · microLife · doi:10.1093/femsml/uqad032 · Cited by 85
“In 1973, Oldendorf reported that 14 C-SCFAs injected in the arotid artery of rats cross the blood-brain barrier (BBB), and the elativ e order of crossing was butyr ate (highest), pr opionate, and cetate (Oldendorf 1973 ).”
BackgroundpH dependence of blood-brain barrier permeability to lactate and nicotine.
Oldendorf, W. H., Braun, L. D., & Cornford, E. M. (1979) · Stroke · doi:10.1161/01.str.10.5.577 · Cited by 78
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“This was evidenced by that 14 C-labeled butyrate was detected in the brain 15 s after injection from the carotid artery (Oldendorf 1973), indicating that SCFAs might cross the BBB easily.”
Acetate‐Mediated Effects of Ethanol
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“For the first time, 14 C-SCFA uptake in the brain was discovered after injection into the carotid artery of rats [10, 11].”
BackgroundRegional metabolism of experimental brain tumors
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“fusion [43, 44] and thus, an increase in Pyr plasma concentration following IV administration should substantially increase the Pyr transport into brain along with an increase of its blood Glu scavenging activity.”
BackgroundKuijer, E. J., & Steenbergen, L. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105296 · Cited by 76
“…PYY, GLP-1, and ghrelin of which the vagal-dependent satiety inducing and putative mnemonic effects have previously been described, and secondly, by directly affecting the CNS after crossing the BBB via endothelial monocarboxylate transporters (Oldendorf, 1973; see for review Silva et al., 2020).”
Measurement of β‐hydroxybutyrate in acute hyperketonemia in human brain
Pan, J. W., Telang, F., Lee, J. H., et al. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00575.x · Cited by 69
Diet-induced ketosis increases capillary density without altered blood flow in rat brain
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“Using the then-novel brain uptake index method, Oldendorf (27) was the first to describe the carrier-mediated BBB transport of short-chain monocarboxylate anions.”
MethodBerntman, L., Dahlgren, N., & Siesjö, B. K. (1978) · Acta Physiologica Scandinavica · doi:10.1111/j.1748-1716.1978.tb06255.x · Cited by 69
Tridecanoin is anticonvulsant, antioxidant, and improves mitochondrial function
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“Bolus injection of (14)C-octanoate and decanoate lead to brain uptake of 94% and 88%, respectively.(33) In addition, infusion of (13)C-octanoate shows that octanoate readily crossed the blood brain barrier and when given in high amounts can contribute approximately 20% to total brain oxidative energy production.”
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“There may be differences in the capacity of each isomer of lactic acid to initiate anxiety as Dlactic acid appears to be absorbed across the blood brain barrier by passive diffusion, in contrast to L-lactic acid, which has a higher affinity to the monocarboxylic acid carrier-mediated transport system [60,61].”
Characterization of alpha-keto acid transport across blood-brain barrier in rats
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“In humans, the intestinal microbiota profile associated with the Medi diet consists of a high abundance of SCFA-producing bacteria [Firmicutes such as Roseburia, Lactobacillus, and Bifidobacterium (Actinobacteria)], and low abundance of pro-inflammatory bacteria [Prevotella (Bacteroidetes), Clostridium (Firmicutes)] (…”
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Starvation‐induced changes in transport of ketone bodies across the blood‐brain barrier
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Exploring the microbiota-gut-brain axis: impact on brain structure and function
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“…the high levels of monocarboxylate transporters in endothelial cells facilitate the crossing of SCFAs across the BBB, as evidenced by previous studies in which rats absorbed 14C-SCFAs injected into the carotid artery (Oldendorf, 1973; Kekuda et al., 2013; Liu et al., 2015; Sun et al., 2016).”
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Reabsorption of monocarboxylic acids in the proximal tubule of the rat kidney
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“To the extent that MCT transporter kinetics, simple diffusion, and the ANLS can support glial-derived lactate use in neurons (Oldendorf, 1973; Dienel and Cruz, 2004; Simpson et al., 2007), there is ample support for the cerebral uptake and use of lactate to support neuronal energy production and…”
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“Such observations were also made historically in an experiment with carbon-14 labelled SCFAs injected into the carotid artery to be uptaken by the brain [118]; however, small amounts were injected according to each human body [119].”
BackgroundOxidation of ethanol in the rat brain and effects associated with chronic ethanol exposure
Wang, J., Du, H., Jiang, L., Ma, X., de Graaf, R. A., Behar, K. L., & Mason, G. F. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1306011110 · Cited by 48
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“Notably, SCFAs have the capacity to traverse the BBB and enhance its integrity, playing a pivotal role in brain homeostasis [215, 216] and might potentially contribute to the limitation of ABI-associated inflammatory injury of peripheral organs, including the gut and the lung.”
BackgroundPellizoni, F. P., Leite, A. Z., Rodrigues, N. D. C., Ubaiz, M. J., Gonzaga, M. I., Takaoka, N. N. C., Mariano, V. S., Omori, W. P., Pinheiro, D. G., Matheucci, E., et al. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18094621 · Cited by 50
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BackgroundInfluence of the Microbiota-Gut-Brain Axis on Cognition in Alzheimer’s Disease
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Entry and Deposit of Aluminum in the Brain
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Animal models for studying transport across the blood-brain barrier
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“Lactic acid is readily transported into the brain by either diffusion [55] or via a carrier mediated monocarboxylic acid transport system [56] and whole brain lactic acid increases following intravenous infusion in both rats [57] and humans [58].”
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Blood-Brain Barrier Transport of Glucose, Free Fatty Acids, and Ketone Bodies
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Octanoic acid in alcohol-responsive essential tremor
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“Animal studies showed a high permeability of OA across the blood-brain barrier.(16) Therefore, a rapid resorption and transport across the blood-brain barrier with prolonged effect in the CNS serves as a possible explanation.”
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Characterization of β-hydroxybutyrate transport in rat erythrocytes and thymocytes
Andersen, B. L., Tarpley, H. L., & Regen, D. M. (1978) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(78)90097-4 · Cited by 39
Recent progress in blood-brain barrier transportation research
Li, G., Shao, K., & Umeshappa, C. S. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-814001-7.00003-2 · Cited by 44
Leipnitz, G., Schuck, P. F., Ribeiro, C. A. J., Dalcin, K. B., de Assis, D. R., Barschak, A. G., Pulrolnik, V., Wannmacher, C. M. D., Wyse, Â. T. D. S., & Wajner, M. (2003) · Neurochemical Research · doi:10.1023/a:1022874103630 · Cited by 37
“Furthermore, it is expected that butyryl-CoA and its derivative EMA produced in high amounts in the liver of these patients can penetrate into brain because short chain fatty acids easily cross the blood-brain barrier (46).”
BackgroundHertz, M. M., & Paulson, O. B. (1982) · Microvascular Research · doi:10.1016/0026-2862(82)90023-1 · Cited by 38
Acid‐Base Balance in Cerebral Fluids
Fencl, V. (1986) · Comprehensive physiology · doi:10.1002/cphy.cp030204 · Cited by 39
Dalile, B., Fuchs, A., Torre, D. L., Vervliet, B., Oudenhove, L. V., & Verbeke, K. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2024.110939 · Cited by 37
Pardridge, W. M. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114234 · Cited by 40
Transport of prostaglandin E1 across the blood-brain barrier in rats
Taogoshi, T., Nomura, A., Murakami, T., et al. (2004) · Journal of Pharmacy and Pharmacology · doi:10.1211/0022357055173 · Cited by 36
“Monocarboxylic acids such as acetic acid and lactic acid are well known to be transported via a carriermediated system at the BBB (Oldendorf 1973; Terasaki et al 1991; Kido et al 2000).”
Background2‐Oxoacids Regulate Kynurenic Acid Production in the Rat Brain
Hodgkins, P., Wu, H., Zielke, R. H., & Schwarcz, R. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0720643.x · Cited by 36
Escrig, M. A., Pardo, M., Aragón, C. M. G., & Correa, M. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.10.002 · Cited by 35
“Acetate is then redistributed throughout the body, and is rapidly taken up into the brain by a carrier-mediated process (Oldendorf, 1973).”
Metadata
- Authors
- Oldendorf, W.
- Corresponding author
- Oldendorf, WH
- Venue
- American Journal of Physiology-Legacy Content
- Publisher
- American Physiological Society
- Published
- 1973-06-01
- Volume
- 224
- Issue
- 6
- Pages
- 1450-1453
- ISSN
- 0002-9513 (ISSN-L)
- OpenAlex
- W2294335852
- Cited by
- 463
- References
- 0
- Citations by year
- 2026: 16 · 2025: 17 · 2024: 21 · 2023: 20 · 2022: 32 · 2021: 13 · 2020: 7 · 2019: 5 · 2018: 9 · 2017: 2 · 2016: 9 · 2015: 4 · 2014: 4 · 2013: 9 · 2012: 6
- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Legacy Content (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- blood-brain barrier, carrier-mediated transport, organic acids, brain uptake, monocarboxylate transporters
- MeSH terms
- Acetates, Amino Acids, Animals, Biological Transport, Blood-Brain Barrier, Brain, Butyrates, Carbon Isotopes, Carboxylic Acids, Dicarboxylic Acids, Female, Glucose, Lactates, Male, Propionates, Pyruvates, Tricarboxylic Acids, Tritium, Rats
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