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Molecular Neurobiology

, Volume 54, Issue 2, pp 1046–1077 | Cite as

Glucose Transporters at the Blood-Brain Barrier: Function, Regulation and Gateways for Drug Delivery

  • Simon G. Patching
Article

Abstract

Glucose transporters (GLUTs) at the blood-brain barrier maintain the continuous high glucose and energy demands of the brain. They also act as therapeutic targets and provide routes of entry for drug delivery to the brain and central nervous system for treatment of neurological and neurovascular conditions and brain tumours. This article first describes the distribution, function and regulation of glucose transporters at the blood-brain barrier, the major ones being the sodium-independent facilitative transporters GLUT1 and GLUT3. Other GLUTs and sodium-dependent transporters (SGLTs) have also been identified at lower levels and under various physiological conditions. It then considers the effects on glucose transporter expression and distribution of hypoglycemia and hyperglycemia associated with diabetes and oxygen/glucose deprivation associated with cerebral ischemia. A reduction in glucose transporters at the blood-brain barrier that occurs before the onset of the main pathophysiological changes and symptoms of Alzheimer’s disease is a potential causative effect in the vascular hypothesis of the disease. Mutations in glucose transporters, notably those identified in GLUT1 deficiency syndrome, and some recreational drug compounds also alter the expression and/or activity of glucose transporters at the blood-brain barrier. Approaches for drug delivery across the blood-brain barrier include the pro-drug strategy whereby drug molecules are conjugated to glucose transporter substrates or encapsulated in nano-enabled delivery systems (e.g. liposomes, micelles, nanoparticles) that are functionalised to target glucose transporters. Finally, the continuous development of blood-brain barrier in vitro models is important for studying glucose transporter function, effects of disease conditions and interactions with drugs and xenobiotics.

Keywords

Alzheimer’s disease Blood-brain barrier Diabetes Drug delivery Glucose transporters GLUT1 In vitro models Neurological and neurovascular disorders 

Notes

Compliance with Ethical Standards

Conflict of Interest

The author declares that they have no conflict of interest.

References

  1. 1.
    Nicholson C (2001) Diffusion and related transport mechanisms in brain tissue. Rep Prog Phys 64(7):815–884CrossRefGoogle Scholar
  2. 2.
    Avdeef A (2001) Physicochemical profiling (solubility, permeability and charge state). Curr Top Med Chem 1(4):277–351PubMedCrossRefGoogle Scholar
  3. 3.
    Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46(1–3):3–26PubMedCrossRefGoogle Scholar
  4. 4.
    Hawkins RA, O'Kane RL, Simpson IA, Viña JR (2006) Structure of the blood-brain barrier and its role in the transport of amino acids. J Nutr 136(1):218S–226SPubMedGoogle Scholar
  5. 5.
    Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57(2):178–201PubMedCrossRefGoogle Scholar
  6. 6.
    Engelhardt B, Sorokin L (2009) The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol 31(4):497–511PubMedCrossRefGoogle Scholar
  7. 7.
    Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37(1):13–25PubMedCrossRefGoogle Scholar
  8. 8.
    Redzic Z (2011) Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences. Fluids Barriers CNS 8(1):3PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Wong AD, Ye M, Levy AF, Rothstein JD, Bergles DE, Searson PC (2013) The blood-brain barrier: an engineering perspective. Front Neuroeng 6:7PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Sanchez-Covarrubias L, Slosky LM, Thompson BJ, Davis TP, Ronaldson PT (2014) Transporters at CNS barrier sites: obstacles or opportunities for drug delivery? Curr Pharm Des 20(10):1422–1449PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Keaney J, Campbell M (2015) The dynamic blood-brain barrier. FEBS J 282(21):4067–4079PubMedCrossRefGoogle Scholar
  12. 12.
    Enerson BE, Drewes LR (2006) The rat blood-brain barrier transcriptome. J Cereb Blood Flow Metab 26(7):959–973PubMedCrossRefGoogle Scholar
  13. 13.
    Kido Y, Tamai I, Okamoto M, Suzuki F, Tsuji A (2000) Functional clarification of MCT1-mediated transport of monocarboxylic acids at the blood-brain barrier using in vitro cultured cells and in vivo BUI studies. Pharm Res 17(1):55–62PubMedCrossRefGoogle Scholar
  14. 14.
    Deane R, Bell RD, Sagare A, Zlokovic BV (2009) Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer's disease. CNS Neurol Disord Drug Targets 8(1):16–30PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci 12(12):723–738PubMedPubMedCentralGoogle Scholar
  16. 16.
    Pardridge WM (2012) Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab 32(11):1959–1972PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Banks WA, Owen JB, Erickson MA (2012) Insulin in the brain: there and back again. Pharmacol Ther 136(1):82–93PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Bien-Ly N, Yu YJ, Bumbaca D, Elstrott J, Boswell CA, Zhang Y, Luk W, Lu Y et al (2014) Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants. J Exp Med 211(2):233–244PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Strazielle N, Ghersi-Egea JF (2015) Efflux transporters in blood-brain interfaces of the developing brain. Front Neurosci 9:21PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Wittmann G, Szabon J, Mohácsik P, Nouriel SS, Gereben B, Fekete C, Lechan RM (2015) Parallel regulation of thyroid hormone transporters OATP1c1 and MCT8 during and after endotoxemia at the blood-brain barrier of male rodents. Endocrinology 156(4):1552–1564PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Kuzawa CW, Chugani HT, Grossman LI, Lipovich L, Muzik O, Hof PR, Wildman DE, Sherwood CC et al (2014) Metabolic costs and evolutionary implications of human brain development. Proc Natl Acad Sci U S A 111(36):13010–13015PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Benarroch EE (2014) Brain glucose transporters: implications for neurologic disease. Neurology 82(15):1374–1379PubMedCrossRefGoogle Scholar
  23. 23.
    Dick APK, Harik SI, Klip A, Walker DM (1984) Identification and characterization of the glucose transporter of the blood-brain barrier by cytochalasin B binding and immunological reactivity. Proc Natl Acad Sci U S A 81(22):7233–7237PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Joost HG, Thorens B (2001) The extended GLUT-family of sugar/polyol transport facilitators: nomenclature, sequence characteristics, and potential function of its novel members (review). Mol Membr Biol 18(4):247–256PubMedCrossRefGoogle Scholar
  25. 25.
    Uldry M, Thorens B (2004) The SLC2 family of facilitated hexose and polyol transporters. Pflugers Arch 447(5):480–489PubMedCrossRefGoogle Scholar
  26. 26.
    Zhao FQ, Keating AF (2007) Functional properties and genomics of glucose transporters. Curr Genomics 8(2):113–128PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Manolescu AR, Witkowska K, Kinnaird A, Cessford T, Cheeseman C (2007) Facilitated hexose transporters: new perspectives on form and function. Physiology (Bethesda) 22:234–240CrossRefGoogle Scholar
  28. 28.
    Carruthers A, DeZutter J, Ganguly A, Devaskar SU (2009) Will the original glucose transporter isoform please stand up! Am J Physiol Endocrinol Metab 297(4):E836–E848PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Augustin R (2010) The protein family of glucose transport facilitators: it's not only about glucose after all. IUBMB Life 62(5):315–333PubMedGoogle Scholar
  30. 30.
    Thorens B, Mueckler M (2010) Glucose transporters in the 21st century. Am J Physiol Endocrinol Metab 298(2):E141–E145PubMedCrossRefGoogle Scholar
  31. 31.
    Cura AJ, Carruthers A (2012) Role of monosaccharide transport proteins in carbohydrate assimilation, distribution, metabolism, and homeostasis. Compr Physiol 2(2):863–914PubMedPubMedCentralGoogle Scholar
  32. 32.
    Mueckler M, Thorens B (2013) The SLC2 (GLUT) family of membrane transporters. Mol Asp Med 34(2–3):121–138CrossRefGoogle Scholar
  33. 33.
    Madej MG, Sun L, Yan N, Kaback HR (2014) Functional architecture of MFS D-glucose transporters. Proc Natl Acad Sci U S A 111(7):E719–E727PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Pao SS, Paulsen IT, Saier MH Jr (1998) Major facilitator superfamily. Microbiol Mol Biol Rev 62(1):1–34PubMedPubMedCentralGoogle Scholar
  35. 35.
    Saier MH Jr, Beatty JT, Goffeau A, Harley KT, Heijne WH, Huang SC, Jack DL, Jähn PS et al (1999) The major facilitator superfamily. J Mol Microbiol Biotechnol 1(2):257–279PubMedGoogle Scholar
  36. 36.
    Reddy VS, Shlykov MA, Castillo R, Sun EI, Saier MH Jr (2012) The major facilitator superfamily (MFS) revisited. FEBS J 279(111):2022–2035PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Iancu CV, Zamoon J, Woo SB, Aleshin A, Choe JY (2013) Crystal structure of a glucose/H+ symporter and its mechanism of action. Proc Natl Acad Sci U S A 110(44):17862–17867PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Wright EM, Loo DD, Hirayama BA (2011) Biology of human sodium glucose transporters. Physiol Rev 91(2):733–794PubMedCrossRefGoogle Scholar
  39. 39.
    Wright EM (2013) Glucose transport families SLC5 and SLC50. Mol Asp Med 34(2–3):183–196CrossRefGoogle Scholar
  40. 40.
    Kasahara M, Hinkle PC (1997) Reconstitution and purification of the D-glucose transporter from human erythrocytes. J Biol Chem 252(20):7384–7390Google Scholar
  41. 41.
    Zoccoli MA, Baldwin SA, Lienhard GE (1978) The monosaccharide transport system of the human erythrocyte. Solubilization and characterization on the basis of cytochalasin B binding. J Biol Chem 253(19):6923–6930PubMedGoogle Scholar
  42. 42.
    Mueckler M, Caruso C, Baldwin SA, Panico M, Blench I, Morris HR, Allard WJ, Lienhard GE et al (1985) Sequence and structure of a human glucose transporter. Science 229(4717):941–945PubMedCrossRefGoogle Scholar
  43. 43.
    Baldwin SA, Lienhard GE (1989) Purification and reconstitution of glucose transporter from human erythrocytes. Methods Enzymol 174:39–50PubMedCrossRefGoogle Scholar
  44. 44.
    Deng D, Xu C, Sun P, Wu J, Yan C, Hu M, Yan N (2014) Crystal structure of the human glucose transporter GLUT1. Nature 510(7503):121–125PubMedCrossRefGoogle Scholar
  45. 45.
    Sun L, Zeng X, Yan C, Sun X, Gong X, Rao Y, Yan N (2012) Crystal structure of a bacterial homologue of glucose transporters GLUT1-4. Nature 490(7420):361–366PubMedCrossRefGoogle Scholar
  46. 46.
    Barnett JE, Holman GD, Munday KA (1973) Structural requirements for binding to the sugar transport system of the human erythrocyte. Biochem J 131(2):211–221PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Leitch JM, Carruthers A (2009) Alpha- and beta-monosaccharide transport in human erythrocytes. Am J Physiol Cell Physiol 296(1):C151–C161PubMedCrossRefGoogle Scholar
  48. 48.
    Lowe AG, Walmsley AR (1986) The kinetics of glucose transport in human red blood cells. Biochim Biophys Acta 857(2):146–154PubMedCrossRefGoogle Scholar
  49. 49.
    Wheeler TJ, Hinkle PC (1981) Kinetic properties of the reconstituted glucose transporter from human erythrocytes. J Biol Chem 256(17):8907–8914PubMedGoogle Scholar
  50. 50.
    Wheeler TJ, Cole D, Hauck MA (1998) Characterization of glucose transport activity reconstituted from heart and other tissues. Biochim Biophys Acta 1414(1–2):217–230PubMedCrossRefGoogle Scholar
  51. 51.
    Keller K, Strube M, Mueckler M (1989) Functional expression of the human HepG2 and rat adipocyte glucose transporters in Xenopus oocytes. Comparison of kinetic parameters. J Biol Chem 264(32):18884–18889PubMedGoogle Scholar
  52. 52.
    Gould GW, Lienhard GE (1989) Expression of a functional glucose transporter in Xenopus oocytes. Biochemistry 28(24):9447–9452PubMedCrossRefGoogle Scholar
  53. 53.
    Vera JC, Rosen OM (1989) Functional expression of mammalian glucose transporters in Xenopus laevis oocytes: evidence for cell-dependent insulin sensitivity. Mol Cell Biol 9(10):4187–4195PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Nishimura H, Pallardo FV, Seidner GA, Vannucci S, Simpson IA, Birnbaum MJ (1993) Kinetics of GLUT1 and GLUT4 glucose transporters expressed in Xenopus oocytes. J Biol Chem 268(12):8514–8520PubMedGoogle Scholar
  55. 55.
    Vera JC, Rivas CI, Fischbarg J, Golde DW (1993) Mammalian facilitative hexose transporters mediate the transport of dehydroascorbic acid. Nature 364(32):79–82PubMedCrossRefGoogle Scholar
  56. 56.
    Sage JM, Carruthers A (2014) Human erythrocytes transport dehydroascorbic acid and sugars using the same transporter complex. Am J Physiol Cell Physiol 306(10):C910–C917PubMedCentralCrossRefPubMedGoogle Scholar
  57. 57.
    KC S, Cárcamo JM, Golde DW (2005) Vitamin C enters mitochondria via facilitative glucose transporter 1 (Glut1) and confers mitochondrial protection against oxidative injury. FASEB J 19(12):1657–1667PubMedCrossRefGoogle Scholar
  58. 58.
    Jiang X, McDermott JR, Ajees AA, Rosen BP, Liu Z (2010) Trivalent arsenicals and glucose use different translocation pathways in mammalian GLUT1. Metallomics 2(3):211–219PubMedCrossRefGoogle Scholar
  59. 59.
    Patching SG (2015) Roles of facilitative glucose transporter GLUT1 in [18F]FDG positron emission tomography (PET) imaging of human diseases. J Diagn Imaging Ther 2(1):30–102CrossRefGoogle Scholar
  60. 60.
    Bloch R (1973) Inhibition of glucose transport in the human erythrocyte by cytochalasin B. Biochemistry 12(23):4799–4801PubMedCrossRefGoogle Scholar
  61. 61.
    Basketter DA, Widdas WF (1978) Asymmetry of the hexose transfer system in human erythrocytes. Comparison of the effects of cytochalasin B, phloretin and maltose as competitive inhibitors. J Physiol 278:389–401PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Sergeant S, Kim HD (1985) Inhibition of 3-O-methylglucose transport in human erythrocytes by forskolin. J Biol Chem 260(27):14677–14682PubMedGoogle Scholar
  63. 63.
    Martin HJ, Kornmann F, Fuhrmann GF (2003) The inhibitory effects of flavonoids and antiestrogens on the Glut1 glucose transporter in human erythrocytes. Chem Biol Interact 146(3):225–235PubMedCrossRefGoogle Scholar
  64. 64.
    Robichaud T, Appleyard AN, Herbert RB, Henderson PJ, Carruthers A (2011) Determinants of ligand binding affinity and cooperativity at the GLUT1 endofacial site. Biochemistry 50(15):3137–3148PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Farrell CL, Pardridge WM (1991) Blood-brain barrier glucose transporter is asymmetrically distributed on brain capillary endothelial lumenal and ablumenal membranes: an electron microscopic immunogold study. Proc Natl Acad Sci U S A 88(13):5779–5783PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Hawkins RA, Peterson DR, Viña JR (2002) The complementary membranes forming the blood-brain barrier. IUBMB Life 54(3):101–107PubMedCrossRefGoogle Scholar
  67. 67.
    Gerhart DZ, LeVasseur RJ, Broderius MA, Drewes LR (1989) Glucose transporter localization in brain using light and electron immunocytochemistry. J Neurosci Res 22(4):464–472PubMedCrossRefGoogle Scholar
  68. 68.
    Cornford EM, Hyman S, Swartz BE (1994) The human brain glut1 glucose transporter: ultrastructural localization to the blood-brain barrier endothelia. J Cereb Blood Flow Metab 14(1):106–112CrossRefPubMedGoogle Scholar
  69. 69.
    Duelli R, Maurer MH, Staudt R, Heiland S, Duembgen L, Kuschinsky W (2000) Increased cerebral glucose utilization and decreased glucose transporter Glut1 during chronic hyperglycemia in rat brain. Brain Res 858(2):338–347PubMedCrossRefGoogle Scholar
  70. 70.
    Duelli R, Kuschinsky W (2001) Brain glucose transporters: relationship to local energy demand. News Physiol Sci 16:71–76PubMedGoogle Scholar
  71. 71.
    McAllister MS, Krizanac-Bengez L, Macchia F, Naftalin RJ, Pedley KC, Mayberg MR, Marroni M, Leaman S et al (2001) Mechanisms of glucose transport at the blood-brain barrier: an in vitro study. Brain Res 904(1):20–30PubMedCrossRefGoogle Scholar
  72. 72.
    Simpson IA, Vannucci SJ, DeJoseph MR, Hawkins RA (2001) Glucose transporter asymmetries in the bovine blood-brain barrier. J Biol Chem 276(16):12725–12729PubMedCrossRefGoogle Scholar
  73. 73.
    Cornford EM, Hyman S (2005) Localization of brain endothelial luminal and abluminal transporters with immunogold electron microscopy. NeuroRx 2(1):27–43PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Kubo Y, Ohtsuki S, Uchida Y, Terasaki T (2015) Quantitative determination of luminal and abluminal membrane distributions of transporters in porcine brain capillaries by plasma membrane fractionation and quantitative targeted proteomics. J Pharm Sci 104(9):3060–3068PubMedCrossRefGoogle Scholar
  75. 75.
    Devraj K, Klinger ME, Myers RL, Mokashi A, Hawkins RA, Simpson IA (2011) GLUT-1 glucose transporters in the blood-brain barrier: differential phosphorylation. J Neurosci Res 89(12):1913–1925PubMedCrossRefGoogle Scholar
  76. 76.
    Barros LF, Bittner CX, Loaiza A, Porras OH (2007) A quantitative overview of glucose dynamics in the gliovascular unit. Glia 55(12):1222–1237PubMedCrossRefGoogle Scholar
  77. 77.
    Kreft M, Lukšič M, Zorec TM, Prebil M, Zorec R (2013) Diffusion of D-glucose measured in the cytosol of a single astrocyte. Cell Mol Life Sci 70(8):1483–1492PubMedCrossRefGoogle Scholar
  78. 78.
    Pardridge WM (1983) Brain metabolism: a perspective from the blood-brain barrier. Physiol Rev 63(4):1481–1535PubMedGoogle Scholar
  79. 79.
    Aleshin AE, Zeng C, Bourenkov GP, Bartunik HD, Fromm HJ, Honzatko RB (1998) The mechanism of regulation of hexokinase: new insights from the crystal structure of recombinant human brain hexokinase complexed with glucose and glucose-6-phosphate. Structure 6(1):39–50PubMedCrossRefGoogle Scholar
  80. 80.
    Lund-Andersen H (1979) Transport of glucose from blood to brain. Physiol Rev 59(2):305–352PubMedGoogle Scholar
  81. 81.
    Blomqvist G, Grill V, Ingvar M, Widén L, Stone-Elander S (1998) The effect of hyperglycaemia on regional cerebral glucose oxidation in humans studied with [1-11C]-D-glucose. Acta Physiol Scand 163(4):403–415PubMedCrossRefGoogle Scholar
  82. 82.
    Gruetter R, Novotny EJ, Boulware SD, Rothman DL, Mason GF, Shulman GI, Shulman RG, Tamborlane WV (1992) Direct measurement of brain glucose concentrations in humans by 13C NMR spectroscopy. Proc Natl Acad Sci U S A 89(3):1109–1112PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Gruetter R, Ugurbil K, Seaquist ER (1998) Steady-state cerebral glucose concentrations and transport in the human brain. J Neurochem 70(1):397–408PubMedCrossRefGoogle Scholar
  84. 84.
    McNay EC, Gold PE (1999) Extracellular glucose concentrations in the rat hippocampus measured by zero-net-flux: effects of microdialysis flow rate, strain, and age. J Neurochem 72(2):785–790PubMedCrossRefGoogle Scholar
  85. 85.
    Reinstrup P, Stahl N, Mellergard P, Uski T, Ungerstedt U, Nordstrom CH (2000) Intracerebral microdialysis in clinical practice: baseline values for chemical markers during wakefulness, anesthesia, and neurosurgery. Neurosurgery 47(3):701–709PubMedGoogle Scholar
  86. 86.
    Wilson JE (1980) Brain hexokinase, the prototype ambiquitous enzyme. Curr Top Cell Regul 16:1–54PubMedCrossRefGoogle Scholar
  87. 87.
    McGowan KM, Long SD, Pekala PH (1995) Glucose transporter gene expression: regulation of transcription and mRNA stability. Pharmacol Ther 66(3):465–505PubMedCrossRefGoogle Scholar
  88. 88.
    Dwyer KJ, Boado RJ, Pardridge WM (1996) Cis-element/cytoplasmic protein interaction within the 3'-untranslated region of the glut1 glucose transporter mRNA. J Neurochem 66(2):449–458PubMedCrossRefGoogle Scholar
  89. 89.
    Devaskar S, Zahm DS, Holtzclaw L, Chundu K, Wadzinski BE (1991) Developmental regulation of the distribution of rat brain insulin-insensitive (Glut 1) glucose transporter. Endocrinology 129(3):1530–1540PubMedCrossRefGoogle Scholar
  90. 90.
    Kaiser N, Sasson S, Feener EP, Boukobza-Vardi N, Higashi S, Moller DE, Davidheiser S, Przybylski RJ et al (1993) Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells. Diabetes 42(1):80–89PubMedCrossRefGoogle Scholar
  91. 91.
    Zheng PP, Romme E, van der Spek PJ, Dirven CM, Willemsen R, Kros JM (2010) Glut1/SLC2A1 is crucial for the development of the blood-brain barrier in vivo. Ann Neurol 68(6):835–844PubMedCrossRefGoogle Scholar
  92. 92.
    Vannucci SJ, Seaman LB, Brucklacher RM, Vannucci RC (1994) Glucose transport in developing rat brain: glucose transporter proteins, rate constants and cerebral glucose utilization. Mol Cell Biochem 140(2):177–184PubMedCrossRefGoogle Scholar
  93. 93.
    Nualart F, Godoy A, Reinicke K (1999) Expression of the hexose transporters GLUT1 and GLUT2 during the early development of the human brain. Brain Res 824(1):97–104PubMedCrossRefGoogle Scholar
  94. 94.
    Virgintino D, Robertson D, Benagiano V, Errede M, Bertossi M, Ambrosi G, Roncali L (2000) Immunogold cytochemistry of the blood-brain barrier glucose transporter GLUT1 and endogenous albumin in the developing human brain. Brain Res Dev Brain Res 123(1):95–101PubMedCrossRefGoogle Scholar
  95. 95.
    Vannucci SJ, Simpson IA (2003) Developmental switch in brain nutrient transporter expression in the rat. Am J Physiol Endocrinol Metab 285(5):E1127–E1134PubMedCrossRefGoogle Scholar
  96. 96.
    Dormire SL (2009) The potential role of glucose transport changes in hot flash physiology: a hypothesis. Biol Res Nurs 10(3):241–247PubMedCrossRefGoogle Scholar
  97. 97.
    Morgello S, Uson RR, Schwartz EJ, Haber RS (1995) The human blood-brain barrier glucose transporter (GLUT1) is a glucose transporter of gray matter astrocytes. Glia 14(1):43–54PubMedCrossRefGoogle Scholar
  98. 98.
    Yu S, Ding WG (1998) The 45 kDa form of glucose transporter 1 (glut1) is localized in oligodendrocyte and astrocyte but not in microglia in the rat brain. Brain Res 797(1):65–72PubMedCrossRefGoogle Scholar
  99. 99.
    Birnbaum MJ, Haspel HC, Rosen OM (1986) Cloning and characterization of a cDNA encoding the rat brain glucose-transporter protein. Proc Natl Acad Sci U S A 83(16):5784–5788PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Asano T, Takata K, Katagiri H, Ishihara H, Inukai K, Anai M, Hirano H, Yazaki Y et al (1993) The role of N-glycosylation in the targeting and stability of GLUT1 glucose transporter. FEBS Lett 324(3):258–261PubMedCrossRefGoogle Scholar
  101. 101.
    Asano T, Katagiri H, Takata K, Lin JL, Ishihara H, Inukai K, Tsukuda K, Kikuchi M et al (1991) The role of N-glycosylation of GLUT1 for glucose transport activity. J Biol Chem 266(36):24632–24636PubMedGoogle Scholar
  102. 102.
    Onetti R, Baulida J, Bassols A (1997) Increased glucose transport in ras-transformed fibroblasts: a possible role for N-glycosylation of GLUT1. FEBS Lett 407(3):267–270PubMedCrossRefGoogle Scholar
  103. 103.
    McMahon RJ, Hwang JB, Frost SC (2000) Glucose deprivation does not affect GLUT1 targeting in 3T3-L1 adipocytes. Biochem Biophys Res Commun 273(3):859–864PubMedCrossRefGoogle Scholar
  104. 104.
    Maher F, Vannucci SJ, Simpson IA (1994) Glucose transporter proteins in brain. FASEB J 8(13):1003–1011PubMedGoogle Scholar
  105. 105.
    Maher F (1995) Immunolocalization of GLUT1 and GLUT3 glucose transporters in primary cultured neurons and glia. J Neurosci Res 42(4):459–469PubMedCrossRefGoogle Scholar
  106. 106.
    Maher F, Davies-Hill TM, Lysko PG, Henneberry RC, Simpson IA (1991) Expression of two glucose transporters, GLUT1 and GLUT3, in cultured cerebellar neurons: evidence for neuron-specific expression of GLUT3. Mol Cell Neurosci 2(4):351–360PubMedCrossRefGoogle Scholar
  107. 107.
    Mantych GJ, James DE, Chung HD, Devaskar SU (1992) Cellular localization and characterization of glut3 glucose transporter isoform in human brain. Endocrinology 131(3):1270–1278PubMedGoogle Scholar
  108. 108.
    Gerhart DZ, Broderius MA, Borson ND, Drewes LR (1992) Neurons and microvessels express the brain glucose transporter protein glut3. Proc Natl Acad Sci U S A 89(2):733–737PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Maher F, Davies-Hill TM, Simpson IA (1996) Substrate specificity and kinetic parameters of glut3 in rat cerebellar granule neurons. Biochem J 315(3):827–831PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Simpson IA, Carruthers A, Vannucci SJ (2007) Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J Cereb Blood Flow Metab 27(11):1766–1791PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Maher F, Simpson IA (1994) The GLUT3 glucose transporter is the predominant isoform in primary cultured neurons: assessment by biosynthetic and photoaffinity labelling. Biochem J 301(2):379–384PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Vannucci SJ, Maher F, Simpson IA (1997) Glucose transporter proteins in brain: delivery of glucose to neurons and glia. Glia 21(1):2–21PubMedCrossRefGoogle Scholar
  113. 113.
    Simpson IA, Dwyer D, Malide D, Moley KH, Travis A, Vannucci SJ (2008) The facilitative glucose transporter GLUT3: 20 years of distinction. Am J Physiol Endocrinol Metab 295(2):E242–E253PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Flavahan WA, Wu Q, Hitomi M, Rahim N, Kim Y, Sloan AE, Weil RJ, Nakano I et al (2013) Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake. Nat Neurosci 16(10):1373–1382PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Deng D, Sun P, Yan C, Ke M, Jiang X, Xiong L, Ren W, Hirata K et al (2015) Molecular basis of ligand recognition and transport by glucose transporters. Nature 526(7573):391–396PubMedCrossRefGoogle Scholar
  116. 116.
    Payne J, Maher F, Simpson I, Mattice L, Davies P (1997) Glucose transporter glut 5 expression in microglial cells. Glia 21(3):327–331PubMedCrossRefGoogle Scholar
  117. 117.
    Horikoshi Y, Sasaki A, Taguchi N, Maeda M, Tsukagoshi H, Sato K, Yamaguchi H (2003) Human GLUT5 immunolabeling is useful for evaluating microglial status in neuropathological study using paraffin sections. Acta Neuropathol 105(2):157–162PubMedGoogle Scholar
  118. 118.
    Mantych GJ, James DE, Devaskar SU (1993) Jejunal/kidney glucose transporter isoform (Glut-5) is expressed in the human blood-brain barrier. Endocrinology 132(1):35–40PubMedGoogle Scholar
  119. 119.
    Burant CF, Takeda J, Brot-Laroche E, Bell GI, Davidson NO (1992) Fructose transporter in human spermatozoa and small intestine is GLUT5. J Biol Chem 267(21):14523–14526PubMedGoogle Scholar
  120. 120.
    Kane S, Seatter MJ, Gould GW (1997) Functional studies of human GLUT5: effect of pH on substrate selection and an analysis of substrate interactions. Biochem Biophys Res Commun 238(2):503–505PubMedCrossRefGoogle Scholar
  121. 121.
    Douard V, Ferraris RP (2008) Regulation of the fructose transporter GLUT5 in health and disease. Am J Physiol Endocrinol Metab 295(2):E227–E237PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Barone S, Fussell SL, Singh AK, Lucas F, Xu J, Kim C, Wu X, Yu Y et al (2009) Slc2a5 (Glut5) is essential for the absorption of fructose in the intestine and generation of fructose-induced hypertension. J Biol Chem 284(8):5056–5066PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Nomura N, Verdon G, Kang HJ, Shimamura T, Nomura Y, Sonoda Y, Hussien SA, Qureshi AA et al (2015) Structure and mechanism of the mammalian fructose transporter GLUT5. Nature 526(7573):397–401PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Leloup C, Arluison M, Lepetit N, Cartier N, Marfaing-Jallat P, Ferre P, Penicaud L (1994) Glucose transporter 2 (GLUT 2): expression in specific brain nuclei. Brain Res 638(1–2):221–226PubMedCrossRefGoogle Scholar
  125. 125.
    Leloup C, Allard C, Carneiro L, Fioramonti X, Collins S, Pénicaud L (2015) Glucose and hypothalamic astrocytes: more than a fueling role? Neuroscience. doi: 10.1016/j.neuroscience.2015.06.007 PubMedGoogle Scholar
  126. 126.
    Arluison M, Quignon M, Nguyen P, Thorens B, Leloup C, Penicaud L (2004) Distribution and anatomical localization of the glucose transporter 2 (GLUT2) in the adult rat brain–an immunohistochemical study. J Chem Neuroanat 28(3):117–136PubMedCrossRefGoogle Scholar
  127. 127.
    Arluison M, Quignon M, Thorens B, Leloup C, Penicaud L (2004) Immunocytochemical localization of the glucose transporter 2 (GLUT2) in the adult rat brain. II. Electron microscopic study. J Chem Neuroanat 28(3):137–146PubMedCrossRefGoogle Scholar
  128. 128.
    Jurcovicova J (2014) Glucose transport in brain–effect of inflammation. Endocr Regul 48(1):35–48PubMedCrossRefGoogle Scholar
  129. 129.
    Marín-Juez R, Rovira M, Crespo D, van der Vaart M, Spaink HP, Planas JV (2015) GLUT2-mediated glucose uptake and availability are required for embryonic brain development in zebrafish. J Cereb Blood Flow Metab 35(1):74–85PubMedCrossRefGoogle Scholar
  130. 130.
    Forsyth R, Fray A, Boutelle M, Fillenz M, Middleditch C, Burchell A (1996) A role for astrocytes in glucose delivery to neurons? Dev Neurosci 18(5–6):360–370PubMedGoogle Scholar
  131. 131.
    McCall AL, van Bueren AM, Huang L, Stenbit A, Celnik E, Charron MJ (1997) Forebrain endothelium expresses GLUT4, the insulin-responsive glucose transporter. Brain Res 744(2):318–326PubMedCrossRefGoogle Scholar
  132. 132.
    Ngarmukos C, Baur EL, Kumagai AK (2001) Co-localization of glut1 and glut4 in the blood-brain barrier of the rat ventromedial hypothalamus. Brain Res 900(1):1–8PubMedCrossRefGoogle Scholar
  133. 133.
    Kobayashi M, Nikami H, Morimatsu M, Saito M (1996) Expression and localization of insulin-regulatable glucose transporter (glut4) in rat brain. Neurosci Lett 213(2):103–106PubMedCrossRefGoogle Scholar
  134. 134.
    El Messari S, Leloup C, Quignon M, Brisorgueil MJ, Penicaud L, Arluison M (1998) Immunocytochemical localization of the insulin-responsive glucose transporter 4 (glut4) in the rat central nervous system. J Comp Neurol 399(4):492–512PubMedCrossRefGoogle Scholar
  135. 135.
    Apelt J, Mehlhorn G, Schliebs R (1999) Insulin-sensitive glut4 glucose transporters are colocalized with glut3-expressing cells and demonstrate a chemically distinct neuron-specific localization in rat brain. J Neurosci Res 57(5):693–705PubMedCrossRefGoogle Scholar
  136. 136.
    Reagan LP, Rosell DR, Alves SE, Hoskin EK, McCall AL, Charron MJ, McEwen BS (2002) Glut8 glucose transporter is localized to excitatory and inhibitory neurons in the rat hippocampus. Brain Res 932(1–2):129–134PubMedCrossRefGoogle Scholar
  137. 137.
    Sankar R, Thamotharan S, Shin D, Moley KH, Devaskar SU (2002) Insulin-responsive glucose transporters-glut8 and glut4 are expressed in the developing mammalian brain. Brain Res Mol Brain Res 107(2):157–165PubMedCrossRefGoogle Scholar
  138. 138.
    Gomez O, Ballester-Lurbe B, Mesonero JE, Terrado J (2011) Glucose transporters glut4 and glut8 are upregulated after facial nerve axotomy in adult mice. J Anat 219(4):525–530PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Schmidt S, Joost HG, Schürmann A (2009) GLUT8, the enigmatic intracellular hexose transporter. Am J Physiol Endocrinol Metab 296(4):E614–E618PubMedCrossRefGoogle Scholar
  140. 140.
    Doege H, Bocianski A, Joost HG, Schürmann A (2000) Activity and genomic organization of human glucose transporter 9 (GLUT9), a novel member of the family of sugar-transport facilitators predominantly expressed in brain and leucocytes. Biochem J 350(3):771–776PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Stuart CA, Ross IR, Howell ME, McCurry MP, Wood TG, Ceci JD, Kennel SJ, Wall J (2011) Brain glucose transporter (Glut3) haploinsufficiency does not impair mouse brain glucose uptake. Brain Res 1384:15–22PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Nishizaki T, Kammesheidt A, Sumikawa K, Asada T, Okada Y (1995) A sodium- and energy-dependent glucose transporter with similarities to sglt1-2 is expressed in bovine cortical vessels. Neurosci Res 22(1):13–22PubMedCrossRefGoogle Scholar
  143. 143.
    Nishizaki T, Matsuoka T (1998) Low glucose enhances Na+/glucose transport in bovine brain artery endothelial cells. Stroke 29(4):844–849PubMedCrossRefGoogle Scholar
  144. 144.
    Elfeber K, Köhler A, Lutzenburg M, Osswald C, Galla HJ, Witte OW, Koepsell H (2004) Localization of the Na+-D-glucose cotransporter SGLT1 in the blood-brain barrier. Histochem Cell Biol 121(3):201–207PubMedCrossRefGoogle Scholar
  145. 145.
    Vemula S, Roder KE, Yang T, Bhat GJ, Thekkumkara TJ, Abbruscato TJ (2009) A functional role for sodium-dependent glucose transport across the blood-brain barrier during oxygen glucose deprivation. J Pharmacol Exp Ther 328(2):487–495PubMedCrossRefGoogle Scholar
  146. 146.
    Poppe R, Karbach U, Gambaryan S, Wiesinger H, Lutzenburg M, Kraemer M, Witte OW, Koepsell H (1997) Expression of the Na+-D-glucose cotransporter SGLT1 in neurons. J Neurochem 69(1):84–94PubMedCrossRefGoogle Scholar
  147. 147.
    O'Malley D, Reimann F, Simpson AK, Gribble FM (2006) Sodium-coupled glucose cotransporters contribute to hypothalamic glucose sensing. Diabetes 55(12):3381–3386PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Yu AS, Hirayama BA, Timbol G, Liu J, Diez-Sampedro A, Kepe V, Satyamurthy N, Huang SC et al (2013) Regional distribution of SGLT activity in rat brain in vivo. Am J Physiol Cell Physiol 304(3):C240–C247PubMedCrossRefGoogle Scholar
  149. 149.
    Wright EM, Hirayama BA, Loo DF (2007) Active sugar transport in health and disease. J Intern Med 261(1):32–43PubMedCrossRefGoogle Scholar
  150. 150.
    Chen XZ, Coady MJ, Jackson F, Berteloot A, Lapointe JY (1995) Thermodynamic determination of the Na+: glucose coupling ratio for the human SGLT1 cotransporter. Biophys J 69(6):2405–2414PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Mackenzie B, Loo DD, Wright EM (1998) Relationships between Na+/glucose cotransporter (SGLT1) currents and fluxes. J Membr Biol 162(2):101–106PubMedCrossRefGoogle Scholar
  152. 152.
    Lee WJ, Peterson DR, Sukowski EJ, Hawkins RA (1997) Glucose transport by isolated plasma membranes of the bovine blood-brain barrier. Am J Physiol 272(5):C1552–C1557PubMedGoogle Scholar
  153. 153.
    Kanai Y, Lee WS, You G, Brown D, Hediger MA (1994) The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest 93(1):397–404PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    You G, Lee WS, Barros EJ, Kanai Y, Huo TL, Khawaja S, Wells RG, Nigam SK et al (1995) Molecular characteristics of Na+-coupled glucose transporters in adult and embryonic rat kidney. J Biol Chem 270(49):29365–29371PubMedCrossRefGoogle Scholar
  155. 155.
    Yu AS, Hirayama BA, Timbol G, Liu J, Basarah E, Kepe V, Satyamurthy N, Huang SC et al (2010) Functional expression of SGLTs in rat brain. Am J Physiol Cell Physiol 299(6):C1277–C1284PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Kumagai AK, Kang YS, Boado RJ, Pardridge WM (1995) Upregulation of bloodbrain barrier GLUT1 glucose transporter protein and mRNA in experimental chronic hypoglycemia. Diabetes 44(12):1399–1404PubMedCrossRefGoogle Scholar
  157. 157.
    Simpson IA, Appel NM, Hokari M, Oki J, Holman GD, Maher F, Koehler-Stec EM, Vannucci SJ et al (1999) Blood-brain barrier glucose transporter: effects of hypo- and hyperglycemia revisited. J Neurochem 72(1):238–247PubMedCrossRefGoogle Scholar
  158. 158.
    Sajja RK, Prasad S, Cucullo L (2014) Impact of altered glycaemia on blood-brain barrier endothelium: an in vitro study using the hCMEC/D3 cell line. Fluids Barriers CNS 11:8PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Uehara Y, Nipper V, McCall AL (1997) Chronic insulin hypoglycemia induces GLUT-3 protein in rat brain neurons. Am J Physiol 272(4):E716–E719PubMedGoogle Scholar
  160. 160.
    Lee DH, Chung MY, Lee JU, Kang DG, Paek YW (2000) Changes of glucose transporters in the cerebral adaptation to hypoglycemia. Diabetes Res Clin Pract 47(1):15–23PubMedCrossRefGoogle Scholar
  161. 161.
    Sahin K, Tuzcu M, Orhan C, Ali S, Sahin N, Gencoglu H, Ozkan Y, Hayirli A et al (2013) Chromium modulates expressions of neuronal plasticity markers and glial fibrillary acidic proteins in hypoglycemia-induced brain injury. Life Sci 93(25–26):1039–1048PubMedCrossRefGoogle Scholar
  162. 162.
    Zhao F, Deng J, Yu X, Li D, Shi H, Zhao Y (2015) Protective effects of vascular endothelial growth factor in cultured brain endothelial cells against hypoglycemia. Metab Brain Dis 30(4):999–1007PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    (2012) Standards of medical care in diabetes. Diabetes Care 35(1):S11–S63Google Scholar
  164. 164.
    Pardridge WM, Triguero D, Farrell CR (1990) Downregulation of blood-brain barrier glucose transporter in experimental diabetes. Diabetes 39(9):1040–1044PubMedCrossRefGoogle Scholar
  165. 165.
    Hou WK, Xian YX, Zhang L, Lai H, Hou XG, Xu YX, Yu T, Xu FY et al (2007) Influence of blood glucose on the expression of glucose trans-porter proteins 1 and 3 in the brain of diabetic rats. Chin Med J (Engl) 120(19):1704–1709Google Scholar
  166. 166.
    Hasselbalch SG, Knudsen GM, Capaldo B, Postiglione A, Paulson OB (2001) Blood-brain barrier transport and brain metabolism of glucose during acute hyperglycemia in humans. J Clin Endocrinol Metab 86(5):1986–1990PubMedGoogle Scholar
  167. 167.
    Jacob RJ, Fan X, Evans ML, Dziura J, Sherwin RS (2002) Brain glucose levels are elevated in chronically hyperglycemic diabetic rats: no evidence for protective adaptation by the blood brain barrier. Metabolism 51(12):1522–1524PubMedCrossRefGoogle Scholar
  168. 168.
    Seaquist ER, Tkac I, Damberg G, Thomas W, Gruetter R (2005) Brain glucose concentrations in poorly controlled diabetes mellitus as measured by high-field magnetic resonance spectroscopy. Metabolism 54(8):1008–1013PubMedCrossRefGoogle Scholar
  169. 169.
    www.alz.org/downloads/ facts_Fig.s_2012.pdf
  170. 170.
    Luchsinger JA, Reitz C, Patel B, Tang MX, Manly JJ, Mayeux R (2007) Relation of diabetes to mild cognitive impairment. Arch Neurol 64(4):570–575PubMedCrossRefGoogle Scholar
  171. 171.
    Iadecola C, Davisson RL (2008) Hypertension and cerebrovascular dysfunction. Cell Metab 7(6):476–484PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K (2008) Central obesity and increased risk of dementia more than three decades later. Neurology 71(14):1057–1064PubMedCrossRefGoogle Scholar
  173. 173.
    Knopman DS, Roberts R (2010) Vascular risk factors: imaging and neuropathologic correlates. J Alzheimers Dis 20(3):699–709PubMedPubMedCentralGoogle Scholar
  174. 174.
    Naderali EK, Ratcliffe SH, Dale MC (2009) Obesity and Alzheimer's disease: a link between body weight and cognitive function in old age. Am J Alzheimers Dis Other Demen 24(6):445–449PubMedCrossRefGoogle Scholar
  175. 175.
    Dolan H, Crain B, Troncoso J, Resnick SM, Zonderman AB, O’brien RJ (2010) Atherosclerosis, dementia, and Alzheimer’s disease in the BLSA cohort. Ann Neurol 68(2):231–240PubMedPubMedCentralGoogle Scholar
  176. 176.
    Suemoto CK, Nitrini R, Grinberg LT, Ferretti RE, Farfel JM, Leite RE, Menezes PR, Fregni F et al (2011) Atherosclerosis and dementia: a cross-sectional study with pathological analysis of the carotid arteries. Stroke 42(12):3614–3615PubMedCrossRefGoogle Scholar
  177. 177.
    Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356PubMedCrossRefGoogle Scholar
  178. 178.
    Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10(9):698–712PubMedCrossRefGoogle Scholar
  179. 179.
    Reitz C (2012) Alzheimer's disease and the amyloid cascade hypothesis: a critical review. Int J Alzheimers Dis 2012:369808PubMedPubMedCentralGoogle Scholar
  180. 180.
    Armstrong RA (2014) A critical analysis of the 'amyloid cascade hypothesis'. Folia Neuropathol 52(3):211–225PubMedCrossRefGoogle Scholar
  181. 181.
    Drachman DA (2014) The amyloid hypothesis, time to move on: amyloid is the downstream result, not cause, of Alzheimer's disease. Alzheimers Dement 10(3):372–380PubMedCrossRefGoogle Scholar
  182. 182.
    Morris GP, Clark IA, Vissel B (2014) Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer's disease. Acta Neuropathol Commun 2:135PubMedPubMedCentralGoogle Scholar
  183. 183.
    Zlokovic BV (2005) Neurovascular mechanisms of Alzheimer’s neurodegeneration. Trends Neurosci 28(4):202–208PubMedCrossRefGoogle Scholar
  184. 184.
    Zlokovic BV (2010) Neurodegeneration and the neurovascular unit. Nat Med 16(12):1370–1371PubMedCrossRefGoogle Scholar
  185. 185.
    de la Torre JC (2010) Vascular risk factor detection and control may prevent Alzheimer’s disease. Aging Res Rev 9(3):218–225CrossRefGoogle Scholar
  186. 186.
    Marchesi VT (2011) Alzheimer’s dementia begins as a disease of small blood vessels, damaged by oxidative-induced inflammation and dysregulated amyloid metabolism: implications for early detection and therapy. FASEB J 25(1):5–13PubMedCrossRefGoogle Scholar
  187. 187.
    Sagare AP, Bell RD, Zlokovic BV (2012) Neurovascular dysfunction and faulty amyloid β-peptide clearance in Alzheimer disease. Cold Spring Harb Perspect Med 2(10):a011452PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Lyros E, Bakogiannis C, Liu Y, Fassbender K (2014) Molecular links between endothelial dysfunction and neurodegeneration in Alzheimer's disease. Current Alzheimer Res 11(1):18–26CrossRefGoogle Scholar
  189. 189.
    Harik SI, LaManna JC (1991) Altered glucose metabolism in microvessels from patients with Alzheimer’s disease. Ann Neurol 29(5):573PubMedCrossRefGoogle Scholar
  190. 190.
    Meneilly GS, Hill A (1993) Alterations in glucose metabolism in patients with Alzheimer’s disease. J Am Geriatr Soc 41(7):710–714PubMedCrossRefGoogle Scholar
  191. 191.
    Casadesus G, Moreira PI, Nunomura A, Siedlak SL, Bligh-Glover W, Balraj E, Petot G, Smith MA et al (2007) Indices of metabolic dysfunction and oxidative stress. Neurochem Res 32(4–5):717–722PubMedCrossRefGoogle Scholar
  192. 192.
    Hunt A, Schonknecht P, Henze M, Seidl U, Haberkorn U, Schroder J (2007) Reduced cerebral glucose metabolism in patients at risk for Alzheimer’s disease. Psychiatry Res 155(2):147–154PubMedCrossRefGoogle Scholar
  193. 193.
    Mosconi L, Pupi A, De Leon MJ (2008) Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann N Y Acad Sci 1147:180–195PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Furst AJ, Lal RA (2011) Amyloid-beta and glucose metabolism in Alzheimer’s disease. J Alzheimers Dis 26(3):105–116PubMedGoogle Scholar
  195. 195.
    Chen Z, Zhong C (2013) Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. Prog Neurobiol 108:21–43PubMedCrossRefGoogle Scholar
  196. 196.
    Friedland RP, Jagust WJ, Huesman RH, Koss E, Knittel B, Mathis CA, Ober BA, Mazoyer BM et al (1989) Regional cerebral glucose transport and utilization in Alzheimer’s disease. Neurology 39(11):1427–1434PubMedCrossRefGoogle Scholar
  197. 197.
    Jagust WJ, Seab JP, Huesman RH, Valk PE, Mathis CA, Reed BR, Coxson PG, Budinger TF (1991) Diminished glucose transport in Alzheimer’s disease: dynamic pet studies. J Cereb Blood Flow Metab 11(2):323–330PubMedCrossRefGoogle Scholar
  198. 198.
    Piert M, Koeppe RA, Giordani B, Berent S, Kuhl DE (1996) Diminished glucose transport and phosphorylation in Alzheimer’s disease determined by dynamic FDG-PET. J Nucl Med 37(2):201–208PubMedGoogle Scholar
  199. 199.
    Samuraki M, Matsunari I, Chen WP, Yajima K, Yanase D, Fujikawa A, Takeda N, Nishimura S et al (2007) Partial volume effect-corrected FDG PET and grey matter volume loss in patients with mild Alzheimer’s disease. Eur J Nucl Med Mol Imaging 34(10):1658–1669PubMedCrossRefGoogle Scholar
  200. 200.
    Nobili F, Morbelli S (2010) [18F]FDG-PET as a biomarker for early Alzheimer’s disease. Open Nucl Med J 2:46–52Google Scholar
  201. 201.
    Mosconi L, Berti V, Glodzik L, Pupi A, De Santi S, de Leon MJ (2010) Pre-clinical detection of Alzheimer's disease using FDG-PET, with or without amyloid imaging. J Alzheimers Dis 20(3):843–854PubMedPubMedCentralGoogle Scholar
  202. 202.
    Mosconi L, McHugh PF (2011) FDG- and amyloid-PET in Alzheimer's disease: is the whole greater than the sum of the parts? Q J Nucl Med Mol Imaging 55(3):250–264PubMedPubMedCentralGoogle Scholar
  203. 203.
    Ishii K (2014) PET approaches for diagnosis of dementia. AJNR Am J Neuroradiol 35(11):2030–2038PubMedCrossRefGoogle Scholar
  204. 204.
    Perani D, Schillaci O, Padovani A, Nobili FM, Iaccarino L, Della Rosa PA, Frisoni G, Caltagirone C (2014) A survey of FDG- and amyloid-PET imaging in dementia and GRADE analysis. Biomed Res Int 2014:785039PubMedCrossRefGoogle Scholar
  205. 205.
    Shokouhi S, Claassen D, Riddle W (2014) Imaging brain metabolism and pathology in Alzheimer's disease with positron emission tomography. J Alzheimers Dis Parkinsonism 4(2):143PubMedPubMedCentralGoogle Scholar
  206. 206.
    Kalaria RN, Harik SI (1989) Reduced glucose transporter at the blood-brain barrier and in cerebral cortex in Alzheimer disease. J Neurochem 53(4):1083–1088PubMedCrossRefGoogle Scholar
  207. 207.
    Simpson IA, Chundu KR, Davies-Hill T, Honer WG, Davies P (1994) Decreased concentrations of glut1 and glut3 glucose transporters in the brains of patients with Alzheimer’s disease. Ann Neurol 35(5):546–551PubMedCrossRefGoogle Scholar
  208. 208.
    Harr SD, Simonian NA, Hyman BT (1995) Functional alterations in Alzheimer’s disease: decreased glucose transporter 3 immunoreactivity in the perforant pathway terminal zone. J Neuropathol Exp Neurol 54(1):38–41PubMedCrossRefGoogle Scholar
  209. 209.
    Mooradian AD, Chung HC, Shah GN (1997) Glut-1 expression in the cerebra of patients with Alzheimer’s disease. Neurobiol Aging 18(5):469–474PubMedCrossRefGoogle Scholar
  210. 210.
    Bailey TL, Rivara CB, Rocher AB, Hof PR (2004) The nature and effects of cortical microvascular pathology in aging and Alzheimer’s disease. Neurol Res 26(5):573–578PubMedCrossRefGoogle Scholar
  211. 211.
    Liu Y, Liu F, Iqbal K, Grundke-Iqbal I, Gong CX (2008) Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease. FEBS Lett 582(2):359–364PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Li X, Lu F, Wang JZ, Gong CX (2006) Concurrent alterations of O-GlcNAcylation and phosphorylation of tau in mouse brains during fasting. Eur J Neurosci 23(8):2078–2086PubMedCrossRefGoogle Scholar
  213. 213.
    Dias WB, Hart GW (2007) O-GlcNAc modification in diabetes and Alzheimer's disease. Mol Biosyst 3(11):766–772PubMedCrossRefGoogle Scholar
  214. 214.
    Liu F, Shi J, Tanimukai H, Gu J, Gu J, Grundke-Iqbal I, Iqbal K, Gong CX (2009) Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain 132(7):1820–1832PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2009) Brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer’s disease. J Neurochem 111(1):242–249PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Lee CW, Shih YH, Wu SY, Yang T, Lin C, Kuo YM (2013) Hypoglycemia induces tau hyperphosphorylation. Curr Alzheimer Res 10(3):298–308PubMedCrossRefGoogle Scholar
  217. 217.
    Yuzwa SA, Vocadlo DJ (2014) O-GlcNAc and neurodegeneration: biochemical mechanisms and potential roles in Alzheimer's disease and beyond. Chem Soc Rev 43(19):6839–6858PubMedCrossRefGoogle Scholar
  218. 218.
    Zhu Y, Shan X, Yuzwa SA, Vocadlo DJ (2014) The emerging link between O-GlcNAc and Alzheimer disease. J Biol Chem 289(50):34472–34481PubMedPubMedCentralCrossRefGoogle Scholar
  219. 219.
    Winkler EA, Nishida Y, Sagare AP, Rege SV, Bell RD, Perlmutter D, Sengillo JD, Hillman S et al (2015) GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration. Nat Neurosci 18(4):521–530PubMedPubMedCentralCrossRefGoogle Scholar
  220. 220.
    Akter K, Lanza EA, Martin SA, Myronyuk N, Rua M, Raffa RB (2011) Diabetes mellitus and Alzheimer’s disease: shared pathology and treatment? Br J Clin Pharmacol 71(3):365–376PubMedPubMedCentralCrossRefGoogle Scholar
  221. 221.
    Correia SC, Santos RX, Carvalho C, Cardoso S, Candeias E, Santos MS, Oliveira CR, Moreira PI (2012) Insulin signaling, glucose metabolism and mitochondria: major players in Alzheimer's disease and diabetes interrelation. Brain Res 1441:64–78PubMedCrossRefGoogle Scholar
  222. 222.
    Adeghate E, Donáth T, Adem A (2013) Alzheimer disease and diabetes mellitus: do they have anything in common? Curr Alzheimer Res 10(6):609–617PubMedCrossRefGoogle Scholar
  223. 223.
    Ahmad W (2013) Overlapped metabolic and therapeutic links between Alzheimer and diabetes. Mol Neurobiol 47(1):399–424PubMedCrossRefGoogle Scholar
  224. 224.
    De Felice FG (2013) Connecting type 2 diabetes to Alzheimer's disease. Expert Rev Neurother 13(12):1297–1299PubMedCrossRefGoogle Scholar
  225. 225.
    Jayaraman A, Pike CJ (2014) Alzheimer's disease and type 2 diabetes: multiple mechanisms contribute to interactions. Curr Diab Rep 14(4):476PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Mushtaq G, Khan JA, Kamal MA (2014) Biological mechanisms linking Alzheimer's disease and type-2 diabetes mellitus. CNS Neurol Disord Drug Targets 13(7):1192–1201PubMedCrossRefGoogle Scholar
  227. 227.
    Verdile G, Fuller SJ, Martins RN (2015) The role of type 2 diabetes in neurodegeneration. Neurobiol Dis. doi: 10.1016/j.nbd.2015.04.008 PubMedGoogle Scholar
  228. 228.
    de la Monte SM, Wands JR (2008) Alzheimer's disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2(6):1101–1113PubMedPubMedCentralCrossRefGoogle Scholar
  229. 229.
    Kroner Z (2009) The relationship between Alzheimer’s disease and diabetes: type 3 diabetes? Altern Med Rev 14(4):373–379PubMedGoogle Scholar
  230. 230.
    Accardi G, Caruso C, Colonna-Romano G, Camarda C, Monastero R, Candore G (2012) Can Alzheimer disease be a form of type 3 diabetes? Rejuvenation Res 15(2):217–221PubMedCrossRefGoogle Scholar
  231. 231.
    Ahmed S, Mahmood Z, Zahid S (2015) Linking insulin with Alzheimer's disease: emergence as type III diabetes. Neurol Sci 36(10):1763–1769PubMedCrossRefGoogle Scholar
  232. 232.
    Shah K, Desilva S, Abbruscato T (2012) The role of glucose transporters in brain disease: diabetes and Alzheimer’s disease. Int J Mol Sci 13(10):12629–12655PubMedPubMedCentralCrossRefGoogle Scholar
  233. 233.
    Thompson BJ, Ronaldson PT (2014) Drug delivery to the ischemic brain. Adv Pharmacol 71:165–202PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Shah K, Abbruscato T (2014) The role of blood-brain barrier transporters in pathophysiology and pharmacotherapy of stroke. Curr Pharm Des 20(10):1510–1522PubMedCrossRefGoogle Scholar
  235. 235.
    Alluri H, Anasooya Shaji C, Davis ML, Tharakan B (2015) Oxygen-glucose deprivation and reoxygenation as an in vitro ischemia-reperfusion injury model for studying blood-brain barrier dysfunction. J Vis Exp 99:e52699Google Scholar
  236. 236.
    McCall AL, Van Bueren AM, Nipper V, Moholt-Siebert M, Downes H, Lessov N (1996) Forebrain ischemia increases GLUT1 protein in brain microvessels and parenchyma. J Cereb Blood Flow Metab 16(1):69–76PubMedCrossRefGoogle Scholar
  237. 237.
    Vannucci SJ, Seaman LB, Vannucci RC (1996) Effects of hypoxia-ischemia on GLUT1 and GLUT3 glucose transporters in immature rat brain. J Cereb Blood Flow Metab 16(1):77–81PubMedCrossRefGoogle Scholar
  238. 238.
    Vannucci SJ, Reinhart R, Maher F, Bondy CA, Lee WH, Vannucci RC, Simpson IA (1998) Alterations in GLUT1 and GLUT3 glucose transporter gene expression following unilateral hypoxia-ischemia in the immature rat brain. Brain Res Dev Brain Res 107(2):255–264PubMedCrossRefGoogle Scholar
  239. 239.
    Yeh WL, Lin CJ, Fu WM (2008) Enhancement of glucose transporter expression of brain endothelial cells by vascular endothelial growth factor derived from glioma exposed to hypoxia. Mol Pharmacol 73(1):170–177PubMedCrossRefGoogle Scholar
  240. 240.
    Cura AJ, Carruthers A (2010) Acute modulation of sugar transport in brain capillary endothelial cell cultures during activation of the metabolic stress pathway. J Biol Chem 285(20):15430–15439PubMedPubMedCentralCrossRefGoogle Scholar
  241. 241.
    Zhang WW, Zhang L, Hou WK, Xu YX, Xu H, Lou FC, Zhang Y, Wang Q (2009) Dynamic expression of glucose transporters 1 and 3 in the brain of diabetic rats with cerebral ischemia reperfusion. Chin Med J (Engl) 122(17):1996–2001Google Scholar
  242. 242.
    Zovein A, Flowers-Ziegler J, Thamotharan S, Shin D, Sankar R, Nguyen K, Gambhir S, Devaskar SU (2004) Postnatal hypoxic-ischemic brain injury alters mechanisms mediating neuronal glucose transport. Am J Physiol Regul Integr Comp Physiol 286(2):R273–R282PubMedCrossRefGoogle Scholar
  243. 243.
    Iwabuchi S, Kawahara K (2011) Inducible astrocytic glucose transporter-3 contributes to the enhanced storage of intracellular glycogen during reperfusion after ischemia. Neurochem Int 59(2):319–325PubMedCrossRefGoogle Scholar
  244. 244.
    Espinoza-Rojo M, Iturralde-Rodríguez KI, Chánez-Cárdenas ME, Ruiz-Tachiquín ME, Aguilera P (2010) Glucose transporters regulation on ischemic brain: possible role as therapeutic target. Cent Nerv Syst Agents Med Chem 10(4):317–325PubMedCrossRefGoogle Scholar
  245. 245.
    Zhang S, Zuo W, Guo XF, He WB, Chen NH (2014) Cerebral glucose transporter: the possible therapeutic target for ischemic stroke. Neurochem Int 70:22–29PubMedCrossRefGoogle Scholar
  246. 246.
    Shah KK, Boreddy PR, Abbruscato TJ (2015) Nicotine pre-exposure reduces stroke-induced glucose transporter-1 activity at the blood-brain barrier in mice. Fluids Barriers CNS 12:10PubMedPubMedCentralCrossRefGoogle Scholar
  247. 247.
    Yamazaki Y, Harada S, Tokuyama S (2012) Post-ischemic hyperglycemia exacerbates the development of cerebral ischemic neuronal damage through the cerebral sodium-glucose transporter. Brain Res 1489:113–120PubMedCrossRefGoogle Scholar
  248. 248.
    Yamazaki Y, Harada S, Tokuyama S (2014) Sodium-glucose transporter type 3-mediated neuroprotective effect of acetylcholine suppresses the development of cerebral ischemic neuronal damage. Neuroscience 269:134–142PubMedCrossRefGoogle Scholar
  249. 249.
    Yamazaki Y, Harada S, Tokuyama S (2015) Relationship between cerebral sodium-glucose transporter and hyperglycemia in cerebral ischemia. Neurosci Lett 604:134–139PubMedCrossRefGoogle Scholar
  250. 250.
    De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI (1991) Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. New Eng J Med 325(10):703–709PubMedCrossRefGoogle Scholar
  251. 251.
    Klepper J, Willemsen M, Verrips A, Guertsen E, Herrmann R, Kutzick C, Flörcken A, Voit T (2001) Autosomal dominant transmission of GLUT1 deficiency. Hum Mol Genet 10(1):63–68PubMedCrossRefGoogle Scholar
  252. 252.
    Klepper J, Scheffer H, Elsaid MF, Kamsteeg EJ, Leferink M, Ben-Omran T (2009) Autosomal recessive inheritance of GLUT1 deficiency syndrome. Neuropediatrics 40(5):207–210PubMedCrossRefGoogle Scholar
  253. 253.
    Rotstein M, Engelstad K, Yang H, Wang D, Levy B, Chung WK, De Vivo DC (2010) Glut1 deficiency: inheritance pattern determined by haploinsufficiency. Ann Neurol 68(6):955–958PubMedPubMedCentralCrossRefGoogle Scholar
  254. 254.
    Wang BY, Kalir T, Sabo E, Sherman DE, Cohen C, Burstein DE (2000) Immunohistochemical staining of GLUT1 in benign, hyperplastic and malignant endometrial epithelia. Cancer 88(12):2774–2781PubMedCrossRefGoogle Scholar
  255. 255.
    Klepper J, Leiendecker B, Bredahl R, Athanassopoulos S, Heinen F, Gertsen E, Flörcken A, Metz A et al (2002) Introduction of a ketogenic diet in young infants. J Inherit Metab Dis 25(6):449–460PubMedCrossRefGoogle Scholar
  256. 256.
    Brockmann K (2009) The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev 31(7):545–552PubMedCrossRefGoogle Scholar
  257. 257.
    De Giorgis V, Veggiotti P (2013) GLUT1 deficiency syndrome 2013: current state of the art. Seizure 22(10):803–811PubMedCrossRefGoogle Scholar
  258. 258.
    Pearson TS, Akman C, Hinton VJ, Engelstad K, De Vivo DC (2013) Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS). Curr Neurol Neurosci Rep 13(4):342PubMedCrossRefGoogle Scholar
  259. 259.
    Gras D, Roze E, Caillet S, Méneret A, Doummar D, Billette de Villemeur T, Vidailhet M, Mochel F (2014) GLUT1 deficiency syndrome: an update. Rev Neurol (Paris) 170(2):91–99CrossRefGoogle Scholar
  260. 260.
    Leen WG, Taher M, Verbeek MM, Kamsteeg EJ, van de Warrenburg BP, Willemsen MA (2014) GLUT1 deficiency syndrome into adulthood: a follow-up study. J Neurol 261(3):589–599PubMedCrossRefGoogle Scholar
  261. 261.
    Ragona F, Matricardi S, Castellotti B, Patrini M, Freri E, Binelli S, Granata T (2014) Refractory absence epilepsy and glut1 deficiency syndrome: a new case report and literature review. Neuropediatrics 45(5):328–332PubMedCrossRefGoogle Scholar
  262. 262.
    Tzadok M, Nissenkorn A, Porper K, Matot I, Marcu S, Anikster Y, Menascu S, Bercovich D et al (2014) The many faces of Glut1 deficiency syndrome. J Child Neurol 29(3):349–359PubMedCrossRefGoogle Scholar
  263. 263.
    Suls A, Mullen SA, Weber YG, Verhaert K, Ceulemans B, Guerrini R, Wuttke TV, Salvo-Vargas A et al (2009) Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1. Ann Neurol 66(3):415–419PubMedCrossRefGoogle Scholar
  264. 264.
    Mullen SA, Suls A, De Jonghe P, Berkovic SF, Scheffer IE (2010) Absence epilepsies with widely variable onset are a key feature of familial GLUT1 deficiency. Neurology 75(5):432–440PubMedCrossRefGoogle Scholar
  265. 265.
    Arsov T, Mullen SA, Damiano JA, Lawrence KM, Huh LL, Nolan M, Young H, Thouin A et al (2012) Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency. Epilepsia 53(12):e204–e207PubMedCrossRefGoogle Scholar
  266. 266.
    Arsov T, Mullen SA, Rogers S, Phillips AM, Lawrence KM, Damiano JA, Goldberg-Stern H, Afawi Z et al (2012) Glucose transporter 1 deficiency in the idiopathic generalized epilepsies. Ann Neurol 72(5):807–815PubMedCrossRefGoogle Scholar
  267. 267.
    Striano P, Weber YG, Toliat MR, Schubert J, Leu C, Chaimana R, Baulac S, Guerrero R et al (2012) GLUT1 mutations are a rare cause of familial idiopathic generalized epilepsy. Neurology 78(8):557–562PubMedCrossRefGoogle Scholar
  268. 268.
    Weber YG, Storch A, Wuttke TV, Brockmann K, Kempfle J, Maljevic S, Margari L, Kamm C et al (2008) GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. J Clin Invest 118(6):2157–2168PubMedPubMedCentralGoogle Scholar
  269. 269.
    Suls A, Dedeken P, Goffin K, Van Esch H, Dupont P, Cassiman D, Kempfle J, Wuttke TV et al (2008) Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain 131(7):1831–1844PubMedPubMedCentralCrossRefGoogle Scholar
  270. 270.
    Schneider SA, Paisan-Ruiz C, Garcia-Gorostiaga I, Quinn NP, Weber YG, Lerche H, Hardy J, Bhatia KP (2009) GLUT1 gene mutations cause sporadic paroxysmal exercise-induced dyskinesias. Mov Disord 24(11):1684–1688PubMedCrossRefGoogle Scholar
  271. 271.
    Weber YG, Kamm C, Suls A, Kempfle J, Kotschet K, Schüle R, Wuttke TV, Maljevic S et al (2011) Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect. Neurology 77(10):959–964PubMedCrossRefGoogle Scholar
  272. 272.
    Verrotti A, D'Egidio C, Agostinelli S, Gobbi G (2012) Glut1 deficiency: when to suspect and how to diagnose? Eur J Paediatr Neurol 16(1):3–9PubMedCrossRefGoogle Scholar
  273. 273.
    Leen WG, Wevers RA, Kamsteeg EJ, Scheffer H, Verbeek MM, Willemsen MA (2013) Cerebrospinal fluid analysis in the workup of GLUT1 deficiency syndrome: a systematic review. JAMA Neurol 70(11):1440–1444PubMedCrossRefGoogle Scholar
  274. 274.
    Klepper J, Garcia-Alvarez M, O'Driscoll KR, Parides MK, Wang D, Ho YY, De Vivo DC (1999) Erythrocyte 3-O-methyl-D-glucose uptake assay for diagnosis of glucose-transporter-protein syndrome. J Clin Lab Anal 13(3):116–121PubMedCrossRefGoogle Scholar
  275. 275.
    Yang H, Wang D, Engelstad K, Bagay L, Wei Y, Rotstein M, Aggarwal V, Levy B et al (2011) Glut1 deficiency syndrome and erythrocyte glucose uptake assay. Ann Neurol 70(6):996–1005PubMedCrossRefGoogle Scholar
  276. 276.
    Wang D, Pascual JM, De Vivo D. Glucose transporter type 1 deficiency syndrome. In Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K (eds). GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2015Google Scholar
  277. 277.
    Pascual JM, Van Heertum RL, Wang D, Engelstad K, De Vivo DC (2002) Imaging the metabolic footprint of Glut1 deficiency on the brain. Ann Neurol 52(4):458–464PubMedCrossRefGoogle Scholar
  278. 278.
    Klepper J, Diefenbach S, Kohlschütter A, Voit T (2004) Effects of the ketogenic diet in the glucose transporter 1 deficiency syndrome. Prostaglandins Leukot Essent Fatty Acids 70(3):321–327PubMedCrossRefGoogle Scholar
  279. 279.
    Klepper J (2008) Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic diet. Epilepsia 49(8):46–49PubMedCrossRefGoogle Scholar
  280. 280.
    Klepper J, Leiendecker B (2013) Glut1 deficiency syndrome and novel ketogenic diets. J Child Neurol 28(8):1045–1048PubMedCrossRefGoogle Scholar
  281. 281.
    Bertoli S, Trentani C, Ferraris C, De Giorgis V, Veggiotti P, Tagliabue A (2014) Long-term effects of a ketogenic diet on body composition and bone mineralization in GLUT-1 deficiency syndrome: a case series. Nutrition 30(6):726–728PubMedCrossRefGoogle Scholar
  282. 282.
    Veggiotti P, De Giorgis V (2014) Dietary treatments and new therapeutic perspective in GLUT1 deficiency syndrome. Curr Treat Options Neurol 16(5):291PubMedCrossRefGoogle Scholar
  283. 283.
    Chenouard A, Vuillaumier-Barrot S, Seta N, Kuster A (2015) A cause of permanent ketosis: GLUT-1 deficiency. JIMD Rep 18:79–83PubMedCrossRefGoogle Scholar
  284. 284.
    Singh LD, Singh SP, Handa RK, Ehmann S, Snyder AK (1996) Effects of ethanol on GLUT1 protein and gene expression in rat astrocytes. Metab Brain Dis 11(4):343–357PubMedCrossRefGoogle Scholar
  285. 285.
    Hu IC, Singh SP, Snyder AK (1995) Effects of ethanol on glucose transporter expression in cultured hippocampal neurons. Alcohol Clin Exp Res 19(6):1398–1402PubMedCrossRefGoogle Scholar
  286. 286.
    Handa RK, DeJoseph MR, Singh LD, Hawkins RA, Singh SP (2000) Glucose transporters and glucose utilization in rat brain after acute ethanol administration. Metab Brain Dis 15(3):211–222PubMedGoogle Scholar
  287. 287.
    Abdul Muneer PM, Alikunju S, Szlachetka AM, Haorah J (2011) Inhibitory effects of alcohol on glucose transport across the blood-brain barrier leads to neurodegeneration: preventive role of acetyl-L-carnitine. Psychopharmacology (Berlin) 214(3):707–718CrossRefGoogle Scholar
  288. 288.
    Duelli R, Staudt R, Grünwald F, Kuschinsky W (1998) Increase of glucose transporter densities (Glut1 and Glut3) during chronic administration of nicotine in rat brain. Brain Res 782(1–2):36–42PubMedCrossRefGoogle Scholar
  289. 289.
    Canis M, Mack B, Gires O, Maurer MH, Kuschinsky W, Duembgen L, Duelli R (2009) Increased densities of monocarboxylate transport protein MCT1 after chronic administration of nicotine in rat brain. Neurosci Res 64(4):429–435PubMedCrossRefGoogle Scholar
  290. 290.
    Abdul Muneer PM, Alikunju S, Szlachetka AM, Murrin LC, Haorah J (2011) Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction. Mol Neurodegener 6:23PubMedPubMedCentralCrossRefGoogle Scholar
  291. 291.
    Abdul Muneer PM, Alikunju S, Szlachetka AM, Haorah J (2011) Methamphetamine inhibits the glucose uptake by human neurons and astrocytes: stabilization by acetyl-L-carnitine. PLoS One 6(4):e19258PubMedPubMedCentralCrossRefGoogle Scholar
  292. 292.
    Rask-Andersen M, Masuram S, Fredriksson R, Schiöth HB (2013) Solute carriers as drug targets: current use, clinical trials and prospective. Mol Asp Med 34(2–3):702–710CrossRefGoogle Scholar
  293. 293.
    Pardridge WM (2003) Blood-brain barrier drug targeting: the future of brain drug development. Mol Interv 3(2):90–105PubMedCrossRefGoogle Scholar
  294. 294.
    Pardridge WM (2005) Molecular biology of the blood-brain barrier. Mol Biotechnol 30(1):57–70PubMedCrossRefGoogle Scholar
  295. 295.
    Pardridge WM (2007) Blood-brain barrier delivery. Drug Discov Today 12(1–2):54–61PubMedCrossRefGoogle Scholar
  296. 296.
    Ohtsuki S, Terasaki T (2007) Contribution of carrier-mediated transport systems to the blood-brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development. Pharm Res 24(9):1745–1758PubMedCrossRefGoogle Scholar
  297. 297.
    Patel MM, Goyal BR, Bhadada SV, Bhatt JS, Amin AF (2009) Getting into the brain: approaches to enhance brain drug delivery. CNS Drugs 23(1):35–58PubMedCrossRefGoogle Scholar
  298. 298.
    Stenehjem DD, Hartz AM, Bauer B, Anderson GW (2009) Novel and emerging strategies in drug delivery for overcoming the blood-brain barrier. Future Med Chem 1(9):1623–1641PubMedCrossRefGoogle Scholar
  299. 299.
    Ronaldson PT (2014) Targeting transporters for CNS drug delivery. Curr Pharm Des 20(10):1419–1421PubMedCrossRefGoogle Scholar
  300. 300.
    Alyautdin R, Khalin I, Nafeeza MI, Haron MH, Kuznetsov D (2014) Nanoscale drug delivery systems and the blood-brain barrier. Int J Nanomedicine 9:795–811PubMedPubMedCentralGoogle Scholar
  301. 301.
    On NH, Miller DW (2014) Transporter-based delivery of anticancer drugs to the brain: improving brain penetration by minimizing drug efflux at the blood-brain barrier. Curr Pharm Des 20(10):1499–1509PubMedCrossRefGoogle Scholar
  302. 302.
    Tashima T (2015) Intriguing possibilities and beneficial aspects of transporter-conscious drug design. Bioorg Med Chem 23(15):4119–4131PubMedCrossRefGoogle Scholar
  303. 303.
    Pardridge WM (2015) Blood-brain barrier endogenous transporters as therapeutic targets: a new model for small molecule CNS drug discovery. Expert Opin Ther Targets 19(8):1059–1072PubMedCrossRefGoogle Scholar
  304. 304.
    Yang C, Tirucherai GS, Mitra AK (2001) Prodrug based optimal drug delivery via membrane transporter/receptor. Expert Opin Biol Ther 1(2):159–175PubMedCrossRefGoogle Scholar
  305. 305.
    Prokai-Tatrai K, Prokai L (2003) Modifying peptide properties by prodrug design for enhanced transport into the CNS. Prog Drug Res 61:155–188PubMedGoogle Scholar
  306. 306.
    Stella VJ, Nti-Addae KW (2007) Prodrug strategies to overcome poor water solubility. Adv Drug Deliv Rev 59(7):677–694PubMedCrossRefGoogle Scholar
  307. 307.
    Huttunen KM, Rautio J (2011) Prodrugs–an efficient way to breach delivery and targeting barriers. Curr Top Med Chem 11(18):2265–2287PubMedCrossRefGoogle Scholar
  308. 308.
    Pavan B, Dalpiaz A, Ciliberti N, Biondi C, Manfredini S, Vertuani S (2008) Progress in drug delivery to the central nervous system by the prodrug approach. Molecules 13(5):1035–1065PubMedCrossRefGoogle Scholar
  309. 309.
    Pavan B, Dalpiaz A (2011) Prodrugs and endogenous transporters: are they suitable tools for drug targeting into the central nervous system? Curr Pharm Des 17(32):3560–3576PubMedCrossRefGoogle Scholar
  310. 310.
    Peura L, Malmioja K, Huttunen K, Leppänen J, Hämäläinen M, Forsberg MM, Gynther M, Rautio J et al (2013) Design, synthesis and brain uptake of LAT1-targeted amino acid prodrugs of dopamine. Pharm Res 30(10):2523–2537PubMedCrossRefGoogle Scholar
  311. 311.
    Tamai I, Tsuji A (2000) Transporter-mediated permeation of drugs across the blood-brain barrier. J Pharm Sci 89(11):1371–1388PubMedCrossRefGoogle Scholar
  312. 312.
    Guo X, Geng M, Du G (2005) Glucose transporter 1, distribution in the brain and in neural disorders: its relationship with transport of neuroactive drugs through the blood-brain barrier. Biochem Genet 43(3–4):175–187PubMedGoogle Scholar
  313. 313.
    Halmos T, Santarromana M, Antonakis K, Scherman D (1996) Synthesis of glucose-chlorambucil derivatives and their recognition by the human GLUT1 glucose transporter. Eur J Pharmacol 318(2–3):477–484PubMedCrossRefGoogle Scholar
  314. 314.
    Halmos T, Santarromana M, Antonakis K, Scherman D (1997) Synthesis of O-methylsulfonyl derivatives of D-glucose as potential alkylating agents for targeted drug delivery to the brain. Evaluation of their interaction with the human erythrocyte GLUT1 hexose transporter. Carbohydr Res 299(1–2):15–21PubMedCrossRefGoogle Scholar
  315. 315.
    Bilsky EJ, Egleton RD, Mitchell SA, Palian MM, Davis P, Huber JD, Jones H, Yamamura HI et al (2000) Enkephalin glycopeptide analogues produce analgesia with reduced dependence liability. J Med Chem 43(13):2586–2590PubMedCrossRefGoogle Scholar
  316. 316.
    Polt R, Porreca F, Szabò LZ, Bilsky EJ, Davis P, Abbruscato TJ, Davis TP, Harvath R et al (1994) Glycopeptide enkephalin analogues produce analgesia in mice: evidence for penetration of the blood-brain barrier. Proc Natl Acad Sci U S A 91(15):7114–7118PubMedPubMedCentralCrossRefGoogle Scholar
  317. 317.
    Elmagbari NO, Egleton RD, Palian MM, Lowery JJ, Schmid WR, Davis P, Navratilova E, Dhanasekaran M et al (2004) Antinociceptive structure-activity studies with enkephalin-based opioid glycopeptides. J Pharmacol Exp Ther 311(1):290–297PubMedCrossRefGoogle Scholar
  318. 318.
    Battaglia G, La Russa M, Bruno V, Arenare L, Ippolito R, Copani A, Bonina F, Nicoletti F (2000) Systematically administered D-glucose conjugates of 7-chlorokynurenic acid are centrally available and exert anticonvulsant activity in rodents. Brain Res 860(1–2):149–156PubMedCrossRefGoogle Scholar
  319. 319.
    Bonina F, Arenare L, Ippolito R, Boatto G, Battaglia G, Bruno V, de Caparariis P (2000) Synthesis, pharmacokinetics and anticonvulsant activity of 7-chlorokynurenic acid prodrugs. Int J Pharm 202(1–2):79–88PubMedCrossRefGoogle Scholar
  320. 320.
    Bonina F, Puglia C, Rimoli MG, Melisi D, Boatto G, Nieddu M, Malignano A, La Rana G et al (2003) Glycosyl derivatives of dopamine and L-dopa as antiparkinson prodrugs: synthesis, pharmacological activity and in vitro stability studies. J Drug Target 11(1):25–36PubMedGoogle Scholar
  321. 321.
    Dalpiaz A, Filosa R, de Caprariis P, Conte G, Bortolotti F, Biondi C, Scatturin A, Prasad PD et al (2007) Molecular mechanism involved in the transport of a prodrug dopamine glycosyl conjugate. Int J Pharm 336(1):133–139PubMedCrossRefGoogle Scholar
  322. 322.
    Gynther M, Ropponen J, Laine K, Leppänen J, Haapakoski P, Peura L, Järvinen T, Rautio J (2009) Glucose promoiety enables glucose transporter mediated brain uptake of ketoprofen and indomethacin prodrugs in rats. J Med Chem 52(10):3348–3353PubMedCrossRefGoogle Scholar
  323. 323.
    Chen Q, Gong T, Liu J, Wang X, Fu H, Zhang Z (2009) Synthesis, in vitro and in vivo characterization of glycosyl derivatives of ibuprofen as novel prodrugs for brain drug delivery. J Drug Target 17(4):318–328PubMedCrossRefGoogle Scholar
  324. 324.
    Zhao Y, Qu B, Wu X, Li X, Liu Q, Jin X, Guo L, Hai L et al (2014) Design, synthesis and biological evaluation of brain targeting l-ascorbic acid prodrugs of ibuprofen with "lock-in" function. Eur J Med Chem 82:314–323PubMedCrossRefGoogle Scholar
  325. 325.
    Jain KK (2012) Nanobiotechnology-based strategies for crossing the blood-brain barrier. Nanomedicine (London) 7(8):1225–1233CrossRefGoogle Scholar
  326. 326.
    Costantino L, Boraschi D, Eaton M (2014) Challenges in the design of clinically useful brain-targeted drug nanocarriers. Curr Med Chem 21(37):4227–4246PubMedCrossRefGoogle Scholar
  327. 327.
    Zhou X, Porter AL, Robinson DK, Shim MS, Guo Y (2014) Nano-enabled drug delivery: a research profile. Nanomedicine 10(5):889–896PubMedGoogle Scholar
  328. 328.
    Hwang SR, Kim K (2014) Nano-enabled delivery systems across the blood-brain barrier. Arch Pharm Res 37(1):24–30PubMedCrossRefGoogle Scholar
  329. 329.
    Ma J, Porter AL, Aminabhavi TM, Zhu D (2015) Nano-enabled drug delivery systems for brain cancer and Alzheimer's disease: research patterns and opportunities. Nanomedicine 11(7):1763–1771PubMedGoogle Scholar
  330. 330.
    Qin Y, Fan W, Chen H, Yao N, Tang W, Tang J, Yuan W, Kuai R et al (2010) In vitro and in vivo investigation of glucose-mediated brain-targeting liposomes. J Drug Target 18(7):536–549PubMedCrossRefGoogle Scholar
  331. 331.
    Lei F, Fan W, Li XK, Wang S, Hai L, Wu Y (2011) Design, synthesis and preliminary bio-evaluation of glucose-cholesterol derivatives as ligands for brain targeting liposomes. Chin Chem Lett 22(7):831–834CrossRefGoogle Scholar
  332. 332.
    Xie F, Yao N, Qin Y, Zhang Q, Chen H, Yuan M, Tang J, Li X et al (2012) Investigation of glucose-modified liposomes using polyethylene glycols with different chain lengths as the linkers for brain targeting. Int J Nanomedicine 7:163–175PubMedPubMedCentralCrossRefGoogle Scholar
  333. 333.
    Qu B, Li X, Guan M, Li X, Hai L, Wu Y (2014) Design, synthesis and biological evaluation of multivalent glucosides with high affinity as ligands for brain targeting liposomes. Eur J Med Chem 72:110–118PubMedCrossRefGoogle Scholar
  334. 334.
    Hao ZF, Cui YX, Li MH, Du D, Liu MF, Tao HQ, Li S, Cao FY et al (2013) Liposomes modified with P-aminophenyl-α-D-mannopyranoside: a carrier for targeting cerebral functional regions in mice. Eur J Pharm Biopharm 84(3):505–516PubMedCrossRefGoogle Scholar
  335. 335.
    Du D, Chang N, Sun S, Li M, Yu H, Liu M, Liu X, Wang G et al (2014) The role of glucose transporters in the distribution of p-aminophenyl-α-d-mannopyranoside modified liposomes within mice brain. J Control Release 182:99–110PubMedCrossRefGoogle Scholar
  336. 336.
    Zidan AS, Aldawsari H (2015) Ultrasound effects on brain-targeting mannosylated liposomes: in vitro and blood-brain barrier transport investigations. Drug Des Devel Ther 9:3885–3898PubMedPubMedCentralCrossRefGoogle Scholar
  337. 337.
    Shao K, Zhang Y, Ding N, Huang S, Wu J, Li J, Yang C, Leng Q et al (2015) Functionalized nanoscale micelles with brain targeting ability and intercellular microenvironment biosensitivity for anti-intracranial infection applications. Adv Healthc Mater 4(2):291–300PubMedCrossRefGoogle Scholar
  338. 338.
    Shao K, Ding N, Huang S, Ren S, Zhang Y, Kuang Y, Guo Y, Ma H et al (2014) Smart nanodevice combined tumor-specific vector with cellular microenvironment-triggered property for highly effective antiglioma therapy. ACS Nano 8(2):1191–1203PubMedCrossRefGoogle Scholar
  339. 339.
    Guo Y, Zhang Y, Li J, Zhang Y, Lu Y, Jiang X, He X, Ma H et al (2015) Cell microenvironment-controlled antitumor drug releasing-nanomicelles for GLUT1-targeting hepatocellular carcinoma therapy. ACS Appl Mater Interfaces 7(9):5444–5453PubMedCrossRefGoogle Scholar
  340. 340.
    Niu J, Wang A, Ke Z, Zheng Z (2014) Glucose transporter and folic acid receptor-mediated Pluronic P105 polymeric micelles loaded with doxorubicin for brain tumor treating. J Drug Target 22(8):712–723PubMedCrossRefGoogle Scholar
  341. 341.
    Gromnicova R, Davies HA, Sreekanthreddy P, Romero IA, Lund T, Roitt IM, Phillips J, Male DK (2013) Glucose-coated gold nanoparticles transfer across human brain endothelium and enter astrocytes in vitro. PLoS One 8(12):e81043PubMedPubMedCentralCrossRefGoogle Scholar
  342. 342.
    Jiang X, Xin H, Ren Q, Gu J, Zhu L, Du F, Feng C, Xie Y et al (2014) Nanoparticles of 2-deoxy-D-glucose functionalized poly(ethylene glycol)-co-poly(trimethylene carbonate) for dual-targeted drug delivery in glioma treatment. Biomaterials 35(1):518–529PubMedCrossRefGoogle Scholar
  343. 343.
    Naik P, Cucullo L (2012) In vitro blood-brain barrier models: current and perspective technologies. J Pharm Sci 101(4):1337–1354PubMedCrossRefGoogle Scholar
  344. 344.
    Abbott NJ (2002) Astrocyte‐endothelial interactions and the blood‐brain barrier permeability. J Anat 200(6):629–638PubMedPubMedCentralCrossRefGoogle Scholar
  345. 345.
    Parkinson FE, Hacking C (2005) Pericyte abundance affects sucrose permeability in cultures of rat brain microvascular endothelial cells. Brain Res 1049(1):8–14PubMedCrossRefGoogle Scholar
  346. 346.
    He Y, Yao Y, Tsirka SE, Cao Y (2014) Cell-culture models of the blood-brain barrier. Stroke 45(8):2514–2526PubMedPubMedCentralCrossRefGoogle Scholar
  347. 347.
    Weksler BB, Subileau EA, Perriere N, Charneau P, Holloway K, Leveque M, Tricoire-Leignel H, Nicotra A et al (2005) Blood-brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J 19(13):1872–1874PubMedGoogle Scholar
  348. 348.
    Tarbell JM (2010) Shear stress and the endothelial transport barrier. Cardiovasc Res 87(2):320–330PubMedPubMedCentralCrossRefGoogle Scholar
  349. 349.
    Bussolari SR, Dewey CF Jr, Gimbrone MA Jr (1982) Apparatus for subjecting living cells to fluid shear stress. Rev Sci Instrum 53(12):1851–1854PubMedCrossRefGoogle Scholar
  350. 350.
    Stanness KA, Guatteo E, Janigro D (1996) A dynamic model of the blood-brain barrier “in vitro”. Neurotoxicology 17(2):481–496PubMedGoogle Scholar
  351. 351.
    Janigro D, Leaman SM, Stanness KA (1999) Dynamic modeling of the blood-brain barrier: a novel tool for studies of drug delivery to the brain. Pharm Sci Technol Today 2(1):7–12PubMedCrossRefGoogle Scholar
  352. 352.
    Cucullo L, McAllister MS, Kight K, Krizanac-Bengez L, Marroni M, Mayberg MR, Stanness KA, Janigro D (2002) A new dynamic in vitro model for the multidimensional study of astrocyte-endothelial cell interactions at the blood-brain barrier. Brain Res 951(2):243–254PubMedCrossRefGoogle Scholar
  353. 353.
    Santaguida S, Janigro D, Hossain M, Oby E, Rapp E, Cucullo L (2006) Side by side comparison between dynamic versus static models of blood-brain barrier in vitro: a permeability study. Brain Res 1109(1):1–13PubMedCrossRefGoogle Scholar
  354. 354.
    Cucullo L, Couraud PO, Weksler B, Romero IA, Hossain M, Rapp E, Janigro D (2008) Immortalized human brain endothelial cells and flow-based vascular modeling: a marriage of convenience for rational neurovascular studies. J Cereb Blood Flow Metab 28(2):312–328PubMedCrossRefGoogle Scholar
  355. 355.
    Booth R, Kim H (2011) A multi-layered microfluidic device for in vitro bloodbrain barrier permeability studies. In: International conference on miniaturized systems for chemistry and life sciences. Red Hook: Curran Associates, Inc. pp 1388–1390Google Scholar
  356. 356.
    Booth R, Kim H (2012) Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB). Lab Chip 12(10):1784–1792PubMedCrossRefGoogle Scholar
  357. 357.
    Yeon JH, Na D, Choi K, Ryu SW, Choi C, Park JK (2012) Reliable permeability assay system in a microfluidic device mimicking cerebral vasculatures. Biomed Microdevices 14(6):1141–1148PubMedCrossRefGoogle Scholar
  358. 358.
    Griep LM, Wolbers F, de Wagenaar B, ter Braak PM, Weksler BB, Romero IA, Couraud PO, Vermes I et al (2013) BBB on chip: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function. Biomed Microdevices 15(1):145–150PubMedCrossRefGoogle Scholar
  359. 359.
    Prabhakarpandian B, Shen MC, Nichols JB, Mills IR, Sidoryk-Wegrzynowicz M, Aschner M, Pant K (2013) SyM-BBB: a microfluidic blood brain barrier model. Lab Chip 13(6):1093–1101PubMedPubMedCentralCrossRefGoogle Scholar
  360. 360.
    Gumbleton M, Audus KL (2001) Progress and limitations in the use of in vitro cell cultures to serve as a permeability screen for the blood-brain barrier. J Pharm Sci 90(11):1681–1698PubMedCrossRefGoogle Scholar
  361. 361.
    Deli MA, Abrahám CS, Kataoka Y, Niwa M (2005) Permeability studies on in vitro blood-brain barrier models: physiology, pathology, and pharmacology. Cell Mol Neurobiol 25(1):59–127PubMedCrossRefGoogle Scholar
  362. 362.
    Deli E (2007) Blood–brain barrier models (chapter 2). In: Abel L (ed) Handbook of neurochemistry and molecular neurobiology (3rd edition). Springer, Berlin, pp 29–55CrossRefGoogle Scholar
  363. 363.
    Ogunshola OO (2011) In vitro modeling of the blood-brain barrier: simplicity versus complexity. Curr Pharm Des 17(26):2755–2761PubMedCrossRefGoogle Scholar
  364. 364.
    Tóth A, Veszelka S, Nakagawa S, Niwa M, Deli MA (2011) Patented in vitro blood-brain barrier models in CNS drug discovery. Recent Pat CNS Drug Discov 6(2):107–118PubMedCrossRefGoogle Scholar
  365. 365.
    Wilhelm I, Fazakas C, Krizbai IA (2011) In vitro models of the blood-brain barrier. Acta Neurobiol Exp (Wars) 71(1):113–128Google Scholar
  366. 366.
    Shawahna R, Decleves X, Scherrmann JM (2013) Hurdles with using in vitro models to predict human blood-brain barrier drug permeability: a special focus on transporters and metabolizing enzymes. Curr Drug Metab 14(1):120–136PubMedCrossRefGoogle Scholar
  367. 367.
    Shityakov S, Salvador E, Förster C (2013) In silico, in vitro and in vivo methods to analyse drug permeation across the blood brain barrier: a critical review. OA Anaesthetics 1:13CrossRefGoogle Scholar
  368. 368.
    Abbott NJ, Dolman DEM, Yusof SR, Reichel A (2014) In vitro models of CNS barriers. In Drug delivery to the brain. New York: Springer pp 163–197Google Scholar
  369. 369.
    Bicker J, Alves G, Fortuna A, Falcão A (2014) Blood-brain barrier models and their relevance for a successful development of CNS drug delivery systems: a review. Eur J Pharm Biopharm 87(3):409–432PubMedCrossRefGoogle Scholar
  370. 370.
    Czupalla CJ, Liebner S, Devraj K (2014) In vitro models of the blood-brain barrier. Methods Mol Biol 1135:415–437PubMedCrossRefGoogle Scholar
  371. 371.
    Palmiotti CA, Prasad S, Naik P, Abul KM, Sajja RK, Achyuta AH, Cucullo L (2014) In vitro cerebrovascular modeling in the 21st century: current and prospective technologies. Pharm Res 31(12):3229–3250PubMedPubMedCentralCrossRefGoogle Scholar
  372. 372.
    Wilhelm I, Krizbai IA (2014) In vitro models of the blood–brain barrier for the study of drug delivery to the brain. Mol Pharm 11(7):1949–1963PubMedCrossRefGoogle Scholar
  373. 373.
    Wolff A, Antfolk M, Brodin B, Tenje M (2015) In vitro blood-brain barrier models–an overview of established models and new microfluidic approaches. J Pharm Sci 104(9):2727–2746PubMedCrossRefGoogle Scholar
  374. 374.
    Weksler B, Romero IA, Couraud PO (2013) The hCMEC/D3 cell line as a model of the human blood brain barrier. Fluids Barriers CNS 10(1):16PubMedPubMedCentralCrossRefGoogle Scholar
  375. 375.
    Poller B, Gutmann H, Krähenbühl S, Weksler B, Romero I, Couraud PO, Tuffin G, Drewe J et al (2008) The human brain endothelial cell line hCMEC/D3 as a human blood-brain barrier model for drug transport studies. J Neurochem 107(5):1358–1368PubMedCrossRefGoogle Scholar
  376. 376.
    Carl SM, Lindley DJ, Das D, Couraud PO, Weksler BB, Romero I, Mowery SA, Knipp GT (2010) ABC and SLC transporter expression and proton oligopeptide transporter (POT) mediated permeation across the human blood-brain barrier cell line, hCMEC/D3 [corrected]. Mol Pharm 7(4):1057–1068PubMedPubMedCentralCrossRefGoogle Scholar
  377. 377.
    Eigenmann DE, Xue G, Kim KS, Moses AV, Hamburger M, Oufir M (2013) Comparative study of four immortalized human brain capillary endothelial cell lines, hCMEC/D3, hBMEC, TY10, and BB19, and optimization of culture conditions, for an in vitro blood-brain barrier model for drug permeability studies. Fluids Barriers CNS 10(1):33PubMedPubMedCentralCrossRefGoogle Scholar
  378. 378.
    Urich E, Lazic SE, Molnos J, Wells I, Freskgård PO (2012) Transcriptional profiling of human brain endothelial cells reveals key properties crucial for predictive in vitro blood-brain barrier models. PLoS One 7(5):e38149PubMedPubMedCentralCrossRefGoogle Scholar
  379. 379.
    Ohtsuki S, Ikeda C, Uchida Y, Sakamoto Y, Miller F, Glacial F, Decleves X, Scherrmann JM et al (2013) Quantitative targeted absolute proteomic analysis of transporters, receptors and junction proteins for validation of human cerebral microvascular endothelial cell line hCMEC/D3 as a human blood-brain barrier model. Mol Pharm 10(1):289–296PubMedCrossRefGoogle Scholar
  380. 380.
    Meireles M, Martel F, Araújo J, Santos-Buelga C, Gonzalez-Manzano S, Dueñas M, de Freitas V, Mateus N et al (2013) Characterization and modulation of glucose uptake in a human blood-brain barrier model. J Membr Biol 246(9):669–677PubMedCrossRefGoogle Scholar
  381. 381.
    Lippmann ES, Azarin SM, Kay JE, Nessler RA, Wilson HK, Al-Ahmad A, Palecek SP, Shusta EV (2012) Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells. Nat Biotechnol 30(8):783–791PubMedPubMedCentralCrossRefGoogle Scholar
  382. 382.
    Cecchelli R, Aday S, Sevin E, Almeida C, Culot M, Dehouck L, Coisne C, Engelhardt B et al (2014) A stable and reproducible human blood-brain barrier model derived from hematopoietic stem cells. PLoS One 9(6):e99733PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Astbury Centre for Structural Molecular Biology and School of Biomedical SciencesUniversity of LeedsLeedsUK

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