Abstract
All organisms with a complex nervous system have a well-developed blood-central nervous system barrier. In the vertebrates the central nervous system (CNS) lies behind the protective blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). In all mammals the BBB is formed at the level of the cerebral capillary endothelial cells and the BCSFB by the choroid plexus epithelium.
Key words
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Abbreviations
- 4F2hc:
-
unbiquitous cell surface antigen (CD98) heavy chain
- A/ATA:
-
amino acid transporter (preferring small neutral amino acids and an N-methyl group)
- ABC:
-
ATP binding cassette
- ACE:
-
angiotensin converting enzyme
- AMT:
-
adsorptive-mediated transcytosis
- ASC:
-
neutral amino acid transporter (preferring alanine, serine and cysteine)
- ATP:
-
adenosine triphosphate
- β:
-
β-amino acid transporter
- BBB:
-
blood-brain barrier
- BCRP:
-
breast cancer-resistance protein
- BCSFB:
-
blood-cerebrospinal fluid barrier
- bFGF:
-
basic fibroblastic growth factor
- B0,+ :
-
neutral/cationic amino acid transporter
- BUI:
-
brain uptake index
- cAMP:
-
cyclic adenosine monophosphate
- CAT1:
-
cationic amino acid transporter
- cGMP:
-
cyclic guanine mono phosphate
- cib:
-
concentrative nucleoside transporter (broad spectrum of substrates)
- cif:
-
concentrative nucleoside transporter (formycin-b preferring)
- cit:
-
consentrative nucleoside transporter (thymidine preferring
- CNS:
-
central nervous system
- CNT:
-
consentrative nucleoside trasnporter
- CSF:
-
cerebrospinal fluid
- DNA:
-
desoxyribose nucleic acid
- EAE:
-
experimental allergic encephalitis
- ECF:
-
extracellular fluid
- ei:
-
equilibrative nucleoside transporter (insensitive to NBMPR)
- ENT:
-
equilibrative nucleoside transporter
- es:
-
equilibrative nucleoside transporter (sensitive to NBMPR
- F-actin:
-
filamentous actin
- GLUT:
-
glucose transporter
- gp120:
-
glyco-protein 120
- GSH:
-
glutathione
- HIV-1:
-
human immunodeficiency virus-1
- HRP:
-
horseradish peroxidase
- ICAM-1:
-
intercellular adhesion molecule
- IFN-γ:
-
gamma interferon
- IL-1β:
-
interleukin 1β
- IL-3:
-
interleukin-3
- ISF:
-
interstitial fluid
- JAM:
-
junction associated molecule
- kDa:
-
kilo-Daltons
- Km :
-
Michaelis-Menten constant
- L:
-
large neutral amio acid transporter
- LAT:
-
large neutral amino acid transporter
- LNAA:
-
large neutral amino acid
- MCT:
-
monocarboxylic acid transporters
- MDR:
-
multidrug resistance
- mM:
-
millimolar
- mRNA:
-
messenger RNA
- MRP:
-
multidrug resistance-associated protein
- MXR1:
-
mitoxantrone-resistance protein=BCRP
- NBMPR:
-
nitrobenzylmercatopurine riboside
- NGF:
-
nerve growth factor
- OAT:
-
organic anion transporter
- Oatp:
-
organic anion transporting polypeptide
- OCT:
-
organic cation transporter
- OCTN:
-
organic caion transporter-novel
- PEPT2:
-
peptide transporter protein-2
- Pgp:
-
P-glycoprotein
- RMT:
-
receptor-mediated transcytosis
- RNA:
-
ribose nucleic acid
- SGLT1:
-
sodium-dependent glucose transporter-1
- SVCT2:
-
nucleobase transporter-2
- system β:
-
amino acid transporter (preferring β amino acids)
- system L:
-
large neutral amino acid transporter
- TER:
-
transendothelial/epithelial resistance
- TGF-β:
-
transforming growth factor β
- TNFα:
-
tumour necrosis factor α
- UDP:
-
uridine diphosphateglucuronosyltransferase
- VCAM-1:
-
vascular cell adhesion molecule
- VLA-4:
-
very late antigen-4
- WGA:
-
wheat-germ agglutinin
- X- AG :
-
amino acid transporter (preferring glutamic acid and aspartic acid)
- y+ :
-
cationic amino acid transporter
- ZO:
-
zona occludentes
- ZO1/2/3:
-
zona occudentes protein 1/2/3
References
Kniesel U, Wolburg H (2000) Tight junctions of the blood-brain barrier. Cell Mol Neurobiol 20: 57–76
Wolburg H, Wolburg-Buckholz K, Liebner S, Engelhardt B (2001) Claudin-1, claudin-2 and claudin 11 are present in tight junctions of choroid plexus epithelium of the mouse. Neurosci Lett 307: 77–80
Begley DJ (1996) The blood-brain barrier: principles for targeting peptides and drugs to the central nervous system. J Pharm Pharmacol 48: 136–146
Levin VA (1980) Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 23: 682–684
Sugiyama Y, Kusuhara H, Suzuki H (1999) Kinetic and biochemical analysis of carrier-mediated efflux of drugs through the blood-brain and blood-cerebrospinal fluid barriers: importance in the drug delivery to the brain. J Control Rel 62: 179–186
Tamai I, Tsuji A (2000) Transport-mediated permeation of drugs across the blood-brain barrier. J Pharm Sci 89: 1371–1388
Mertsch K, Maas J (2002) Blood-brain barrier penetration and drug development from an industrial point of view. Curr Med Chem (Central Nervous System Agents) 2: 187–201
Reese TS and Karnovsky MJ (1967) Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 34: 207–217
Brightman MW (1968) The intracerebral movement of proteins injected into blood and cerebrospinal fluid of mice. Prog Brain Res 29: 19–37
Brightman MW and Reese TS (1969) Junctions between intimately apposed cell mem-branes in the vertebrate brain. J Cell Biol 40: 648–677
Butt AM (1995) Effect of inflammatory agents on electrical resistance across the blood-brain barrier in pial microvessels of anaesthetized rats. Brain Res 696: 145–150
Brightman MW, Tao-Cheng J-H (1993) Tight junctions of brain endothelium and epithelium. In: WM Pardridge (ed): The blood-brain barrier cellular and molecular biology. Raven Press, 107–125
Morita K, Sasaki H, Furuse M, Tsukita S (1999) Endothelial claudin: claudin 5 TMVCF, constitutes tight junction strands in endothelial cells. J Cell Biol 147: 185–194
Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S (1993) Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 123: 1777–1788
Saitou M, Fujimoto K, Doi Y, Itoh M, Fujimoto T, Furuse M, Takano H, Noda T, Tsukita S (1998) Occludin-deficient embryonic stem cells can differentiate into polarized epithelial cells bearing tight junctions. J Cell Biol 141: 397–408
Del Maschio A, de Luigi A, Marin-Padura I, Brockhaus M, Bartfai T, Fruscella P, Adorini L, Martino G, Furlan R, de Simoni MG et al (1999) Leukocyte recruitment in the cerebrospinal fluid of mice with experimental meningitis is inhibited by an antibody to junctional adhesion molecule UAM). J Exp Med 190: 1351–1356
Cordonensi M, D’Atri F, Hammar E, Parry DAD, Kendrick-Jones J, Shore D, Citi S (1999) Cingulin contains lobular and coiled-coil domains and interacts with ZO-1, ZO-2, ZO-3 and myosin. J Cell Biol 147: 1569–1581
Martinez-Palomo A, Erlij D (1975) Structure of tight junctions in epithelia with different permeability. Proc Natl Acad Sci USA 72: 4487–4491
Stevenson BR, Anderson JM, Goodenough DA, Mooseker MS (1988) Tight junction structure and ZO-1 content are identical in two strains of Madin-Darby canine kidney cells which differ in transepithelial resistance. J Cell Biol 107: 2401–2408
Yuan Y, Meng FY, Huang Q Hawker J, Mac Wu H (1998) Tyrosine phosphorylation of paxillin/pp125FAK and microvascular endothelial barrier function. Am J Physiol 275: (Heart Circ Physiol 44): H84–H93
Staddon JM, Herrenknecht K, Smales C, Rubin LL (1995) Evidence that tyrosine phosphorylation may increase tight junction permeability. J Cell Sci 108: 609–619
Fanning AS, Jameson BJ, Jesaitis LA, Anderson JM (1998) The tight junction protein ZO1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J Biol Chem 273: 29745–29753
Huber JD, Egleton RD, Davis TP (2001) Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends in Neurosci 24: 719–725
Trentin AG, Alvarez-Silva M, Moura Neto V (2001) Thyroid hormone induces cerebellar astrocytes and C6 glioma cells to secrete mitogenic growth factors. Am J Physiol 281: E1088–1094
Deli MA, Descamps L, Dehouck M-P, Ceccheli R, Joo F, Abraham CS, Torpier G (1995) Exposure of tumor necrosis factor to luminal membrane of bovine brain capillary endothelial cells cocultured with astrocytes induces a delayed increase of permeability and cytoplasmic stress fiber formation of actin. J Neurosci Res 41: 717–726
Ozaki H, Ishii K, Horiuchi H, Arai H, Kawamoto K, Okawa A, Iwamatsu A, Kita T (1999) Cutting edge: combined treatment of TNF-alpha and IFN-gamma causes redistribution of junctional adhesion molecule in human endothelial cells. J Immunol 163: 553–557
Hickey W (1999) Leukocyte traffic in the central nervous system: the participants and their roles. Semin Immunol 11: 125–137
Wong D, Prameya, R, Dorovini-Zis K (1999) In vitro adhesion and migration of T lympohocytes across monolayers of human brain microvesel and endothelial cells: regulation by ICAM-1, VCAM-1, E-selectin and PECAM-1. J Neuropathol Exp Neurol 58: 138–152
Burns AR, Bowden RA, MacDonell SD, Walker DC, Odebunmi TO, Donnachie EM, Simon SI, Entman ML, Smith CW (2000) Analysis of tight junctions during neutrophil transendothelial migration. J Cell Sci 113: 45–57
Faustman PM, Dermietzel R (1985) Extravasation of polymorphonuclear leukocytes from the cerebral microvasculature. Inflammatory response induced by alpha-bungaro-toxin. Cell Tissue Res 242: 399–407
Sixt M, Engelhardt B, Pausch F, Hallman R, Wendler O, Sorokin CM (2001) Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis. J Cell Biol 153: 933–946
Raub TJ, Newton CR. (1991) Membrane recycling, adsorptive and receptor-mediated endocytosis by bovine cerebral microvessel endothelial cell monolayers. In: G Wilson, A Zweibaum, L Ilium, S Davis (eds): Pharmaceutical Applications of Cell and Tissue Culture to Drug Transport. Plenum Press, New York, 203–216
Villegas JC, Broadwell RD (1993): Transcytosis of protein through the mammalian cerebral epithelium and endothelium. II Adsorptive transcytosis of WGA-HRP and the blood-brain and brain-blood barriers. J Neurocytol 22: 67–80.
Vorbrodt AW (1989) Ultracytochemical characterization of anionic sites in the wall of brain capillaries. J Neurocytol 18: 359–368
Pardridge WM, Triguero D, Buciak J, Yang J (1990) Evaluation of cationized rat albumin as a potential blood-brain barrier drug transport vector. J Pharmacol Exp Ther 255: 893–899
Pardridge WM, Eisenberg J, Cefalu WT (1985) Absence of albumin receptor on brain capillaries in vivo or in vitro. Am J Physiol 249 (3 Pt 1): E264–E267
Schnitzer JE (1992) gp60 is an albumin-binding glycoprotein expressed by continuous endothelium involved in albumin transcytosis. Am J Physiol 262 (Heart Circ Physiol 31): H246–H254
Friden PM, Walus LR, Musso GF, Taylor MA, Malfroy B, Starzyk RM (1991) Anti-trans-ferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier. Proc Natl Acad Sci USA 88: 4771–4775
Morgan EH, Moos T (2002) Mechanism and developmental changes in iron transport across the blood-brain barrier. Dev Neurosci 24: 106–113
Zhang Y, Pardridge WM (2001) Neuroprotection in transient focal brain ischemia after delayed intravenous administration of brain-derived neurotropic factor conjugated to a blood-brain barrier drug targeting system. Stroke 32: 1378–1384
Broadwell RD, Brightman MW (1976) Entry of peroxidase into neurons of the central and peripheral nervous system from extracerebral and cerebral blood. J Comp Neurol 166: 257–284
Fiala M, Looney DJ, Stins M, Way DD, Zhang X, Gan F, Chiappelli F, Schweitzer ES, Shap-Shak P, Weinand M et al (1997) TNF-alpha opens a paracellular route for HIV-1 invasion across the blood-brain barrier. Mol Med 3: 553–564
Banks WA, Freed EO, Wolf KM, Robinson SM, Franko M, Kumar VB (2001) Transport of human immunodeficiency virus type 1 pseudoviruses across the blood-brain barrier: role of envelope proteins and adsorptive endocytosis. J Virol 75: 4681–4691
Brightman MW, Ishihara S, Chang L (1995) Penetration of solutes viruses and cells across the blood-brain barrier. Curr Topics Microbiol Immun 202: 63–78
Broadwell RD, Balin BJ (1985) Endocytic and exocytic pathways of the neuronal secretory process and trans-synaptic transfer of wheat germ agglutinin-horseradish peroxidase in vivo. J Comp Neurol 242: 632–650
Rinaman L, Roesch MR, Card JP (1999) Retrograde transynaptic pseudorabies virus infection of central autonomic circuits in neonatal rats. Develop Brain Res 114: 207–216
Frey WH, Liu J, Chen X, Thorne RG, Fawcett JR, Ala TA, Rahman Y-E (1997) Delivery of 125I-NGF to the brain via the olfactory route. Drug Delivery 4: 87–92
Sakane T, Akizuki M, Taki Y, Yamashita S, Sezaki H, Nadai T (1995) Direct drug transport from the rat nasal cavity to the cerebrosoinal fluid: the relation to the molecular weight of drugs. J Pharm Pharmacol 47: 379–381
Pardridge WM (1991) Peptide Drug Delivery to the Brain. Raven Press. New York, 357
Bradbury M, Cserr HF, Westrop RJ (1981) Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. Am J Physiol 240: F329–F336
Jarolim KL, McCosh JK, Howard MJ, John DT (2000) A light microscopy study of the migration of Naegleria fowleri from the nasal submucosa to the central nervous system during the early stage of primary amebic meningoencephalitis in mice. J Parasitol 86: 50–55
Knopf PM, Cserr HF, Nolan SC, Wu T-Y, Harling-Berg CJ (1995) Physiology and immunology of lymphatic drainage of interstitial and cerebrospinal fluid from the brain. Neuropathol Appl Neurobiol 21: 175–180
Nadal A, Fuentes E, Pastor J, McNaughton PA (1995) Plasma albumin is a potent trigger of calcium signals and DNA synthesis in astrocytes. Proc Natl Acad Sci USA 92: 1426–1430
Tao-Cheng J-H, Nagy Z, Brightman MW (1987) Tight junctions of brain endothelium in vitro are enhanced by astroglia. J Neurosci 7: 3293–3299
Westergaard E, Brightman MW (1973) Transport of proteins across normal cerebral arterioles. J Comp Neurol 152: 17–44
Brightman MW (1999) Blood-brain barrier: penetration by solutes and cells. In: G Adel-man and BH Smith (eds): Encyclopedia of Neuroscience, 2nd ed., Elsevier Science, Amsterdam, 241–245
Betz AL, Firth JA, Goldstein GW (1980) Polarity of the blood-brain barrier: Distribution of enzymes between the luminal and abluminal membranes of brain capillary endothelial cells. Brain Res 192: 17–28
Zeuthan T, Wright EM (1981) Epithelial potassium transport: tracer and electrophysio-logical studies in choroids plexus. J Membrane Biol 60: 105–128
Johansen C E, Swenney SM, Parmalee JT, Epstein MH (1990) Cotransport of sodium and chloride by the adult mammalian choroid plexus. Am J Physiol 258: C211–C215
Speake T, Whitwell C, Kajita H, Majid A, Brown PD (2001) Mechanisms of CSF secretion by the choroid plexus. Microsc Res Tech 52: 49–52
Nielsen S, Smith BL, Christensen EI, Agre P (1993) Distribution of the aquaporin CHIP in secretory and resorptive epithelia and capillary endothelia. Proc Natl Acad Sci USA 90: 7275–7279
Wu Q Delpire E, Hebert SC, Strange K (1998) Functional demonstration of Na+-K+-2Cl-cotransporter activity in isolated, polarizedchoroid plexus cells. Am J Physiol 275: C1565–1572
Sobue K, Yamamoto N, Yoneda K, Fujita K, Miura Y, Asia K, Tsuda T, Katsuya H, Kato T (1999) Molecular cloning of two bovine aquaporin-4 cDNA isoforms and their expression in brain endothelial cells. Biochim Biophys Acta 1489: 393–398
Nielsen S, Nagelhus EA, Amiry-Moghadden M, Bourque C, Ottesen OP (1997) Specialised membrane domains for water transport in glial cells: High reolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 17: 171–180
Nico B, Frigeri A, Nicchia GP, Quondamatteo F, Herken R, Errede M, Ribatti D, Svelto M, Roncali L (2001) Role of aquaporin-4 water channel in the integrity of the blood brain barrier. J Cell Sci 114: 1297–1307
Badaut, J, Lasbennes F, Magistretti PJ, Luca R (2002) Aquaporins in Brain: Distribution, Physiology and Pathophysiology. J Cereb Blood Flow Metab 22: 367–378
Mann GE, Yudilevich DL, Sobrevia L (2003) Regulation of amino acid and glucose transporters in endothelial and smooth muscle cells. Physiol Rev 83: 183–252
Zhang EY, Knipp GT, Ekins S, Swann PW (2001) Structural biology and function of solute transporters: implications for identifying and designing substrates. Drug Metab Rev 34: 709–750
Farrel CL, Pardridge WM (1991) Blood-brain glucose transporter is asymmetrically distributed on brain capillary endothelial lumenal and ablumenal membranes: an electron microscope study. Proc Natl Acad Sci USA 88: 5779–5783
Pardridge W M, Boado RJ (1993) Molecular cloning and regulation of gene expression of blood brain barrier glucose transporter. In: WM Pardridge (ed): The blood-brain barrier. Raven Press, New York, 395–440
Cornford EM, Hyman S, and Swartz BE (1994) The human brain GLUT1 glucose transporter: Ultrastructural localization to the blood-brain barrier endothelia. J Cereb Blood Flow Metab 14: 106–112
Cornford EM, Hyman S, Cornford ME, Landaw EM, Delgado-Escueta AV (1998) Interictal seizure resections show two configurations of endothelial GLUT1 glucose transporter in the human blood brain barrier. J Cereb Blood Flow Metab 18: 26–42
McAllister MS, Krizanac-Bengez L, Macchia F, Naftalin RJ, Pedley KC, Mayberg MR, Marroni M, Leaman S, Stanness KA, Janigro D (2001) Mechanisms of glucose transport at the blood-brain barrier: an in vitro study. Brain Res 904: 20–30
Drewes LR (1998) Biology of the blood-brain glucose transporter. In: WM Pardridge (ed): Introduction to the blood-brain barrier. Cambridge University Press, Cambridge, 165–174
Maher F, Vannuchi S, Simpson IA (1993) Glucose transporter proteins in brain. FASEB J 8: 1003–1011
Livingstone C, Lyall H, Gould GW (1995) Hypothalamic Glut 4 expression: A glucose and insulin sensing mechanism. Mol Cell Endocrinol 107: 67–70
Lee WJ, Peterson DR, Sukowski EJ, Hawkins RA (1997) Glucose transport by isolated plasma membranes of the bovine blood-brain barrier. Am J Physiol Cell Physiol 272: C1552–C1557
Vannuchi SJ (1994) Developmental expression of GLUT1 and GLUT4 glucose transporters in brain. J Neurochem 62: 240–246
Pardridge WM (1995) Transport of small molecules through the blood-brain barrier; Biology and methodology. Adv Drug Delivery Rev 15: 5–36
Pardridge WM (1998) Blood-brain barrier carrier-mediated transport and brain metabolism of amino acids. Neurochem Res 23: 636–644
Smith QR, Stoll J (1998) Blood-brain barrier amino acid transport. In: WM Pardridge (ed): Introduction to the blood-brain barrier: Methodology, biology and pathology. Cambridge University Press, Cambridge, 188–197
Pardridge WM (1983) Brain metabolism a perspective from the blood-brain barrier. Physiol Rev 63: 1481–1535
Smith QR, Takasato Y (1986) Kinetics of amino acid transport at the blood-brain barrier studied using an in situ brain perfusion technique. Ann NY Acad Sci 481: 186–201
Smith QR (1995) Carrier-mediated drug transport at the blood-brain barrier and the potential for drug targeting to the brain. In: J Greenwood, DJ Begley, MB Segal (eds): New concepts of a blood-brain barrier. Plenum Press, New York and London, 265–276
Smith QR (2000) Transport of glutamate and other amino acids at the blood-brain barrier. J Nutr 130: 1016S–1022S
Kageyama T, Nakamura M, Matsuo A, Yamasaki Y, Takaura Y, Hashida M, Kanai Y, Naito M, Tsuro T, Minato N et al (2000) The 4F2hc/LAT1 complex transports L-DOPA across the blood-brain barrier. Brain Res 879: 115–121
Stoll J, Wadhwani KC, Smith QR (1993) Identification of the cationic amino acid transporter (system y+) of the rat blood-brain barrier. J Neurochem 60: 1956–1959
Wang H, Huang W, Sugawara M, Devoe LD, Leibach FH, Prasad PD, Ganpathy V (2000) Cloning and functional expression of ATA1 a subtype of amino acid transporter A, from human placenta. Biochem Biophys Res Comm 273: 1175–1179
Takanaga H, Tokuda S, Ohtsuki S, Hosoya K-I, Terasaki T (2002) ATA2 is predominantly expressed as system A at the blood-brain barrier and acts as brain to blood efflux transport for L-proline. Mol Pharmacol 61: 1289–1296
Betz AL, Goldstein GW (1978) Polarity of the blood-brain barrier: neutral amino acid transport into isolated brain capillaries. Science 202: 225–227
Lee WJ, Hawkins RA, Peterson DR,Vifia JR (1996) Role of oxoproline in the regulation of neutral amino acid transport across the blood-brain barrier. J Biol Chem 271: 19129–19133
Lee WJ, Hawkins RA, Vifia JR, Peterson DR (1998) Glutamine transport by the blood-brain barrier; a possible mechanism for nitrogen removal. Am J Physiol 274: C1101–C1107
Sánchez del Pino MM, Hawkins RA, Peterson DR (1995) Neutral amino acid transportcharaterization of isolated luminal and abluminal membranes of the blood-brain barrier. J Biol Chem 270: 1493–14918
Tayarani I, Lefauconnier JM, Roux F, Bourre JM (1987) Evidence for an alanine, serine and cysteine system of transport in isolated brain capillaries. J Cereb Blood Flow Metab 7: 585–591
Tayarani I, Cloez I, Lefauconnier JM, Bourre JM (1989) Sodium dependent high affinity uptake of taurine by isolated rat brain capillaries. Biochim Biophys Acta 985: 168–172
Guidotti G G, Gazzola GC (1992) Amino acid stransporters: systematic approach and principles of control. In: MS Kilberg, D Haussinger (eds): Mammalian amino acid transport. Plenum Press, New York, 3–30
Tamai I, Senmaru M, Teraskai T, Tsuji A (1995) Na+ and Cl-dependent transport of taurine at the blood-brain barrier. Biochem Pharmacol 50: 1783–1739
Al-Sarraf H, Preston J, Segal, MB (1995) The entry of acidic amino acids into brain and CSF during development using in situ brain perfusion in the rat. Dev Brain Res 90: 151–158
Al-Sarraf H, Preston J, Segal MB (1997) Changes in the kinetics of the acidic amino acid brain and CSF uptake during development in the rat. Dev Brain Res 102: 127–134
Benrabh H, Lefauconnier JM (1996) Glutamate is transported across the rat blood-brain barrier by a sodium-independent system. Neurosci Lett 210: 9–12
Oldendorf WH, Szabo J (1976) Amino acid assignment to one of three blood-brain barrier amino acid carriers. Am J Physiol 230: 94–98
Segal MB (2001) Transport of nutrients across the choroid plexus. Micros Res and Tech 52: 38–48
Preston J, Segal MB (1990) The steady-state amino acid fluxes across the perfused choroids plexus of the sheep. Brain Res 525: 275–279
Preston J, Segal MB (1992) The uptake of anionic and cationic amino acids by the perfused sheep choroid plexus. Brain Res 581: 35–355
Davson H, Hollingsworth JG, Carey MB, Fenstermacher JD (1982) Ventriculo-cisternal perfusion of twelve amino acids in the rabbit. J Neurobiol 13: 293–318
Redzic ZB, Segal MB, Gasic JM, Markovic ID, Vojvodic VP, Iskavic A, Thomas SA, Rakic Lj (2001) The characteristics of nucleobase transport and metabolism by the perfused sheep choroid plexus. Brain Res 888: 66–74
Fox IH, Kelly WH (1978) The role of adenosine and 2’-deoxyadenosine in mammalian cells. Ann Rev Biochem 47: 655–686
Cornford EM, Oldendorf WH (1975) Inedependant blood-brain barrier transport systems for nucleic acid precursors. Biochim Biophys Acta 394: 211–219
Lee G, Dallas S, Hong R, Bendayan R (2001) Drug transporters in the central nervous system: brain barriers and brain parenchymal considerations. Pharmacol Rev 53: 569–596
Chishty M, Begley DJ, Abbott NJ, Reichel A. (2003) Functional characterisation of nucleoside transport in rat brain endothelial cells. Neuro Report: 14: 1087–1090
Gerhart DZ, Enerson BE, Zhdakina OY, Leino RL, Drewes LR (1997) Expression of monocarboxylate transporter MCT1 by brain endothelium and glia in adult and suckling rats. Am J Physiol 273: E207–E213
Price NT, Jackson VN, Halestap AP (1998) Cloning and sequencing of four new mammalian monocarboxylic acid transporter (MCT) homlogues confirms the existence of a transporter family with an ancient past. Biochem J 329: 321–328
Cornford EM, Hyman S (1999) Blood-Brain barrier permeability to small and large molecules. Adv Drug Deliv Rev 36: 145–163
Kusuhara H, Sekine N, Utsunomiya-Tate M, Tsuda R, Kojima SH, Cha Y, Sugiyama Y, Kanai Y, Endou H (1999) Molecular cloningand charaterisation of a new multispecific organic anion transporter from rat brain J Biol Chem 274: 13575–13680
Burkhardt G, Wolf NA (2000) Structure of renal organic anion and cation transporters. Am J Physiol 278: F853–F866
Suzuki H, Sawada Y, Sugiyama Y, Iga T, Hanano M (1986) Transport of cimetidine by the rat choroid plexus in vitro. J Pharm Exp Ther 239: 927–935
Suzuki H, Sawada Y, Sugiyama Y, Iga T, Hanano M (1987) Transport of benzyl penicillin by the rat choroid plexus in vitro. J Pharm Exp Ther 242: 660–665
Prichard JB, Sweet DH, Miller DS, Walden R (1999) Mechanism of organic anion transport across the apical membrane of the choroids plexus. J Biol Chem 274: 33382–33387
Ghersi-Egea J-F, Strazielle N (2002) Choroid plexus transporters for drugs and other xeno-biotics. J Drug Targ11: 353–357
Hosoyamada M, Sekine T, Kanai Y, Endou H (1999) Molecular cloning and functional expression of a multi specific organic anion transporter from human kidney. Am J Physiol 276: F122–F128
Kusuhara H, Sugiyama Y (2001) Efflux transport systems for drugs at the blood-brain and blood cerebrosinal fluid barrier (Part 1). Drug Discov Today 6: 150–156
Kusuhara H, Sugiyama Y (2001) Efflux transport systems for drugs at the blood-brain and blood cerebrosinal fluid barrier (Part 2). Drug Discov Today 6: 206–212
Begley DJ (2003) Efflux mechanisms in the CNS: A powerful influence on drug distribution within the brain. In: HS Sharma, J Westman (eds): Blood-spinal cord and brain barriers in health and disease. Elsevier/Academic Press, San Diego, 83–96
Meier PJ, Eckhardt U, Schoeder A, Hagenbuch, Steiger, B (1997) Substrate specificity of sinusoidal bile acid and organic anin uptake systems in rat and human liver. Hepatology 26: 1667–1677
Noé B, Hagenbuch B, Stieger B, Meier PJ (1997) Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. Proc Natl Acad Sci USA 94: 10346–10350
Li L, Lee TK, Meier PJ, Ballatori N (1998) Identification of glutathione as a driving force and leukotriene C4 as a substrate for Oatpl, the hepatic sinusoidal organic solute transporter. J Biol Chem 273: 16184–16191
Reichel C, Gao B, van Monyfoort J, Cattori V, Rahner C, Hagenbuch B, Stieger B, Kamisako T, Meier PJ (1999) Localization and function of the organic anion transporting polypeptide Oatp2 in rat liver. Gastroenterology 117: 688–695
Kakyo M, Sakgami H, Nishio T, Naki D, Nakagomi R, Tokui T, Naitoh T, Matsuno S, Abe T, Yawo H (1999) Immunohistochemical distribution and functional characterisation of an organic anion transporting polypeptide 2 (Oatp2). FEBS Lett 445: 343–346
Gao B, Hagenbuch B, Kullak-Ublick GA, Benke D, Aguzzi A, and Meir PJ (2000) Organic anion transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J Pharmacol Exp Ther 294: 73–79
Kullak-Ublick GA, Ismair MG, Stieger B, Landmann L, Huber R, Pizzagalli F, Fattinger K, Meir PJ, Hagenbuch B (2001) Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology 120: 525–533
Satlin LM, Amin V, Wolkoff AW (1997) Organic anion transporting polypeptide mediates organic anion/HCO3-exchange. J Biol Chem 272: 26340–26345
Angeletti RH, Novikoff PM, Juvadi SR, Fritschy JM, Meir PJ, Wolkoff AW (1997) The choroid plexus is the site of the organic anio transport protein in the brain. Proc Natl Acad Sci USA 94: 283–286
Gao B, Stieger B, Noé B, Fritschy J-M, Meir PJ (1999) Localization of the organic anion transporting polypeptide 2 (Oatp2) in capillary endothelium and choroid plexus epithelium of rat brain. j Histochem Cytochem 47: 1255–1263
Gao B, Meier PJ (2001) Organic anion transport across the choroid plexus. Microsc Res Tech 52: 60–64
Sweet DH, Miller DS, Pritchard JB (2001) Ventricular choline transport: a role for organic cation transporter 2 expressed in choroid plexus. J Biol Chem 276: 41611–41619.
Kekuda R, Prasad PD, Wu X, Wang H, Fei Y-J, Leibach, FH, Ganapathy V (1998) Cloning and functional chacterisation of a potential sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta. J Biol Chem 272: 15971–15979
Miller DS, Villalobos AR, Pritchard JB (1999) Organic cation transport in rat choroids plexus cells studied by fluorescent microscopy. Am J Physiol 45: C955–C968
Tamai I, Ohashi R, Nezu J, Yabuuchi H, Oku A, Simane M, Sai Y, Tsuji A (1998) Molecular and functional indentification of sodium ion-dependent, high affinity human carnitine transporter OCTN2. J Biol Chem 272: 20378–20382
Wu X, Huang W, Prasad PD, Seth P, Rajan DP, Leobach FH, Chen J, Conway SJ, Ganapathy V (1999) Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter. J Pharm Exp Ther 290: 1482–1492
Wu X, George RL, Huang W, Wang H, Conway SJ, Leibach FH, Ganapathy V (2000) Structural and functional characteristics and tissue distribution of rat OCTN1 an organic cation transporter, cloned from placenta. Biochim Biophys Acta 1466: 315–327
Yabuuchi H, Tamai I, Nezu J, Sakamoto K, Oku A, Shimane M, Sai Y, Tsuji A (1999) Novel membrane transporter OCTN1 mediates multispecific, bi-directional and pH dependent transport of organic cations. J Pharmacol Exp Ther 289: 768–773
Kido Y, Tamai I, Ohnaraia A, Sai, Y, Kagami T, Nezu J, Nikaido H, Hashimoto N, Asano M, Tsuji A (2001) Functional relevance of carnitine transporter\octn2 to brain distribution of L-carnitine and acetyl-L- carnitine across the blood-brain barrier. J Neurochem 79: 959–969
Tamai I, Ohashi R, Nezu J, Sai, Y, Kobayashi, D, Oku A, Simane M, Tsuji, A (2000) Molecular and functional characterisation of organic cation/carnitine transporter family in mice. J Biol Chem 275: 40064–40072
Klien I, Sarkadi B, Váradi A (1999) An inventory of the human ABC proteins. Biochim Biophys Acta 1461: 237–262
Terasaki T, Hosoya K (1999) The blood-brain barrier efflux transporters as a detoxifying stsytem for the brain. Adv Drug Deliv Rev 5: 195–209
Sun H, Dai H, Shaik N, Elmquist WF (2003) Drug efflux transporters in the CNS. Adv Drug Deliv Rev 55: 83–105
Deely RG, Cole SP (1997) Function, evolution and structure of multidrug resistance protein (MRP). Seminars in Cancer Biol 8: 193–204
Chin JE, Soffir R, Noonan KE, Choi KY, Robinson IB (1989) Structure and expression of the human MDR (P-glycoprotein) gene family. Mol Cell Biol 9: 2808–3820
Hsu SIH, Cohen D, Kirchner LS, Hartstein M, Horwitz SB (1990) Structural analysis of the mouse mdrla (P-glycprotien) promoter reveals the basis for differential transcripts heterogeneity in multidrug resistant J774.2 cells. Mol Cell Biol 10: 3596–3606
Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR (1989) Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 86: 695–698
Tatsuta T, Naito M, Oh-hara T, Sugawara I, Tsuruo T, (1992) Functional involvement of P-glycoprotein in blood-brain barrier. J Biol Chem 267: 20383–20391
Stewart PA, Beliveau R, Rogers KA (1996) Cellular localisation of P-glycoprotein recog-nised by MRK16 monoclonal antibody in brain and spinal cord. J Histochem Cytochem 44: 679–685
Beaulieu E, Demeule M, Ghitescu L, Beliveau R (1997) P-glycoprotein is strongly expressed in the luminal membranes of the endothelium of blood-vessels in the brain. Biochem J 326: 301–307
Begley DJ, Khan EU, Rollison C, Abbott NJ, Regina A, Roux F (2000) The role of brain extracellular fluid production and efflux mechanisms in drug transprt to the brain. In: DJ Begley, MWB Bradbury, J Kreuter (eds): The blood-brain barrier and drug delivery to the CNS. Marcel Dekker, New York, 93–108
Rao VV, Dahlheimer JL, Bardgett ME, Snyder AZ, Finch RA, Sartorelli AC, Piwnica-Worms D (1999) Choriod plexus epithelial expression of MDR1 P-gycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal fluid drug-permeability barrier. Proc Natl Acad Sci USA 96: 3900–3905
Regina A, Koman A, Piciotti M, El Hafny B, Center MS, Bergman R, Couraud P-O, Roux F (1998) Mrpl multidrug resistance-associated protein and P-glycoprotein expression in rat brain microvessel endothelial cells. J Neurochem 71: 705–715
Kusuhara H, Sugiyama Y (2002) Role of transporters in the tissue-selective distribution and elimination of drugs: Transporters in the liver, small intestine, brain and kidney. J Control Ref 78: 43–54
Miller DS, Nobmann SN, Gutmann H, Toeroek J, Drewe G, Fricker G (2000) Xenobiotic transport across isolated brain microvessels studied by confocal microscopy. Mol Pharmacol 58: 1357–1367
Fricker G, Nobmann S, Miller DS (2002) Permeability of porcine blood-brain barrier to somatostatin analogues. Br J Pharmacol 135: 1308–1314
Zhang Y, Han H, Elmquist WF, Miller DW (2000) Expression of various multidrug resis-tance-associated protein (MRP) homologues in brain mircovessel endothelial cells. Brain Res 876: 148–153
Cisternino S, Rouselle C, Lorico A, Rappa G, and Scherrmann J-M (2003) Apparent lack of MRP1-mediated efflux at the luminal side of mouse BBB endothelial cells. Pharm Res 20: 904–909
Wijnholds J, De Lange EL, Scheffer GL, van den Berg DJ, Mol CA, van der Walk M, Schinkel AH, Scheper RJ, Briemer DD, Borst P (2000) Multidrug resistance protein protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier. J Clin Invest 105: 279–285
Eisenblätter T, Galla H-J (2002) A new multidrug resistance protein at the blood-brain barrier. Biochem Biophys Res Comm 293: 1273–1278
Cooray H, Blackmore CG, Maskell L, Barrand MA (2002) Localisation of breast cancer resistance protein in microvessel endothelium of human brain. Neuro Report 13: 2059–2063.
Zhang W, Cui H, Zhang H, Ball M, Stanimirovich D (2002) Expression and functional characterisation of the ABC transporter gene, ABCG2, in brain endothelial cells. Abstract: Human Genome Meeting 2002. Nature Publishing Group, Shanghai, China, 122
Litman T, Brangi M, Hudson E, Fetsch P, Abati A, Ross DD, Miyake K, Resau, JH, Bates SE (2000) The multidrug-resistant phenotype associated with over expression of the new ABC half transporter, MXR (ABCG2). J Cell Sci 113: 2011–2021
Banks WA, Kastin A (1996) Passage of peptides across the blood-brain barrier: Patho-physiological perspectives. Life Sci 59: 1923–1943
Pan W, Banks WA, Kastin AJ (1997) Permeability of the blood-brain barrier and spinal cord barriers to interferons. J Neuroimmunol 76: 105–111
Pan W, Banks WA, Kastin AJ (1990) Permeability of the blood-brain barrier to neurotrophins. Brain Res 788: 87–94
Kastin AJ (1999) Multiple direct actions of peptides on the CNS. Brain Res Bull 50: 361–362
Kastin AJ, Pan W, Maness LM, Banks WA (1999) Peptides crossing the blood-brain barrier: some unusual observations. Brain Res 848: 96–100
Teuscher NS, Novotny A, Keep R.F, Smith DE (2000) Functional evidence for presence of PEPT2 in rat choroid plexus: studies with glycylsarcosine. J Pharm Exp Ther 294: 494–499
Yamashita T, Shimada S, Guo W, Sato K, Kohmura E, Hayakawa T, Tahagi T, Tohyama M (1997) Cloning and functional expression of a brain peptide/histidine transporter. J Biol Chem 272: 10205–10211
Minn A, El-Bacha DS, Bayol-Denizot C, Lagrange P, Suleman FG (2000) Drug metabolism in the brain: benefits and risks. In: DJ Begley, MWB Bradbury, J Kreuter (eds): The blood-brain barrier and drug delivery to the CNS. Marcel Dekker, New York, 145–170
Minn A, Leclerc S, Heydel J-M, Minn A-L, Denizot C, Cattarelli M, Netter P, Gradinaru D (2002) Drug transport into the mammalian brain: the nasal pathway and its specific metabolic barrier. I Drug Targ 10: 285–296
Ghersi-Egea J-F, Strazielli N (2001) Brain drug delivery, drug metabolism, and multidrug resistance at the choroid plexus. Microsc Res Tech 52: 83–88
Rush and Hersh LB (1982) Multiple molecular forms of rat brain enkephalinase. Life Sci 21: 445–451
Turner AJ (1987) Endopeptidase-24.11 and neuropeptide metabolism. In: AJ Turner (ed): Neuropeptides and their peptidases. Ellis Horwood and UCH Verlagsgesellschaft, Chichester, UK, 310–315
Skidgel, RA, Defendini R, Erdos EG (1987) Angiotensin I converting enzyme and its role in neuropeptide metabolism. In: AJ Turner (ed): Neuropeptides and their peptidases. Ellis Horwood and UCH Verlagsgesellschaft, Chichester, UK, 165–182
Dyer SH, Slaughter CA, Orth, K, Moomaw, CR, Hersh LB (1990) Comparison of the soluble and membrane bound forms of the puromycin-sensitive enkephalin-degrading aminopeptidase from rat. J Neurochem 44: 1427–1435
Brownlees J, Williams CH (1993) Peptidases, peptides and the mammalian blood-brain barrier. J Neurochem 60: 793–803
Will KA, Gillespie TJ, Huber JD, Egleton RD, Davis TP (2001) Peptide drug modifications to enhance bioavailability and blood brain barrier permeability. Peptides 22: 2329–2343
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Begley, D.J., Brightman, M.W. (2003). Structural and functional aspects of the blood-brain barrier. In: Prokai, L., Prokai-Tatrai, K. (eds) Peptide Transport and Delivery into the Central Nervous System. Progress in Drug Research, vol 61. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8049-7_2
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