Lactate and related monocarboxylic acids are important substrates and metabolic products of brain metabolism. Under conditions such as starvation, high fat consumption, and early development (newborn or suckling neonates), monocarboxylates such as lactate, pyruvate and ketone bodies may be extracted from the blood and used by the brain as fuels. Recent evidence suggests metabolic coupling occurs between astrocytes and neurons whereby lactate produced by astrocytes is utilized by neurons during neural activation. The overall objective of this proposal is to characterize the monocarboxylic acid transporters in brain and their role in blood-brain transport and cerebral metabolism. This includes molecular identification of the membrane proteins responsible for transporting monocarboxylic acids (lactic, pyruvic, acetoacetic and ^D- hydroxybutyric acids) across the plasma membranes of endothelial cells, astrocytes, and neurons; characterization of their cellular location, expression, regulation, and role in cerebral metabolism. The principal hypotheses to be tested are that: 1) the requisite monocarboxylate transporters (MCTs) for metabolic coupling between astrocytes and neurons are present in rat brain cortex, hippocampus and cerebellum; 2) upregulation of at least two separate MCT genes (MCT1 and MCT2) occurs independently (spatially and temporally) during postnatal development; 3) animals with elevated expression of brain MCTs from dietary manipulations are more resistant to hypoxic/ischemic cell damage than control animals; and 4) brain lactic acidosis associated with hypoxia/ischemia induces increased expression of MCTs. Specific antibodies and oligonucleotide probes for MCT1 and MCT2 will be used to analyze and quantify transporter proteins and mRNA. mRNA will be determined by ribonuclease protection assays and by in situ hybridization. MCT proteins will be determined by immunoblot detection and light and electron immunocytochemistry. The expression of MCTs in response to dietary alterations and global forebrain ischemia will be examined. Animals with experimentally increased levels of MCTs will be assessed for their ability to resist neurological damage following global forebrain ischemia. The genomic sequence of MCT1 and MCT2 will be closed and characterized and other brain MCTs will be identified. These proposed studies will contribute to a better understanding of the metabolic interrelationships among cells of the brain and therefore may lead to improved therapies, or preventive measures for patients with stroke or neurodegenerative disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-NLS-3 (01))
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Jacobs, Tom P
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University of Minnesota Duluth
Schools of Medicine
United States
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Westholm, Daniel E; Stenehjem, David D; Rumbley, Jon N et al. (2009) Competitive inhibition of organic anion transporting polypeptide 1c1-mediated thyroxine transport by the fenamate class of nonsteroidal antiinflammatory drugs. Endocrinology 150:1025-32
Henry, Pierre-Gilles; Russeth, Kevin P; Tkac, Ivan et al. (2007) Brain energy metabolism and neurotransmission at near-freezing temperatures: in vivo (1)H MRS study of a hibernating mammal. J Neurochem 101:1505-15
Smith, Jeffrey P; Drewes, Lester R (2006) Modulation of monocarboxylic acid transporter-1 kinetic function by the cAMP signaling pathway in rat brain endothelial cells. J Biol Chem 281:2053-60
Enerson, Bradley E; Drewes, Lester R (2006) The rat blood-brain barrier transcriptome. J Cereb Blood Flow Metab 26:959-73
Drewes, L R (2001) Molecular architecture of the brain microvasculature: perspective on blood-brain transport. J Mol Neurosci 16:93-8; discussion 151-7
Duelli, R; Enerson, B E; Gerhart, D Z et al. (2000) Expression of large amino acid transporter LAT1 in rat brain endothelium. J Cereb Blood Flow Metab 20:1557-62
Gerhart, D Z; Leino, R L; Drewes, L R (1999) Distribution of monocarboxylate transporters MCT1 and MCT2 in rat retina. Neuroscience 92:367-75
Ishihara, H; Wang, H; Drewes, L R et al. (1999) Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in beta cells. J Clin Invest 104:1621-9
Drewes, L R (1999) What is the blood-brain barrier? A molecular perspective. Cerebral vascular biology. Adv Exp Med Biol 474:111-22