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Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences

By Zoran Redzic

Abstract

Efficient processing of information by the central nervous system (CNS) represents an important evolutionary advantage. Thus, homeostatic mechanisms have developed that provide appropriate circumstances for neuronal signaling, including a highly controlled and stable microenvironment. To provide such a milieu for neurons, extracellular fluids of the CNS are separated from the changeable environment of blood at three major interfaces: at the brain capillaries by the blood-brain barrier (BBB), which is localized at the level of the endothelial cells and separates brain interstitial fluid (ISF) from blood; at the epithelial layer of four choroid plexuses, the blood-cerebrospinal fluid (CSF) barrier (BCSFB), which separates CSF from the CP ISF, and at the arachnoid barrier. The two barriers that represent the largest interface between blood and brain extracellular fluids, the BBB and the BCSFB, prevent the free paracellular diffusion of polar molecules by complex morphological features, including tight junctions (TJs) that interconnect the endothelial and epithelial cells, respectively. The first part of this review focuses on the molecular biology of TJs and adherens junctions in the brain capillary endothelial cells and in the CP epithelial cells. However, normal function of the CNS depends on a constant supply of essential molecules, like glucose and amino acids from the blood, exchange of electrolytes between brain extracellular fluids and blood, as well as on efficient removal of metabolic waste products and excess neurotransmitters from the brain ISF. Therefore, a number of specific transport proteins are expressed in brain capillary endothelial cells and CP epithelial cells that provide transport of nutrients and ions into the CNS and removal of waste products and ions from the CSF. The second part of this review concentrates on the molecular biology of various solute carrier (SLC) transport proteins at those two barriers and underlines differences in their expression between the two barriers. Also, many blood-borne molecules and xenobiotics can diffuse into brain ISF and then into neuronal membranes due to their physicochemical properties. Entry of these compounds could be detrimental for neural transmission and signalling. Thus, BBB and BCSFB express transport proteins that actively restrict entry of lipophilic and amphipathic substances from blood and/or remove those molecules from the brain extracellular fluids. The third part of this review concentrates on the molecular biology of ATP-binding cassette (ABC)-transporters and those SLC transporters that are involved in efflux transport of xenobiotics, their expression at the BBB and BCSFB and differences in expression in the two major blood-brain interfaces. In addition, transport and diffusion of ions by the BBB and CP epithelium are involved in the formation of fluid, the ISF and CSF, respectively, so the last part of this review discusses molecular biology of ion transporters/exchangers and ion channels in the brain endothelial and CP epithelial cells

Topics: Review
Publisher: BioMed Central
OAI identifier: oai:pubmedcentral.nih.gov:3045361
Provided by: PubMed Central

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Citations

  1. (1993). A: Differential expression of Na, K-ATPase alpha and beta subunit isoforms at the Redzic Fluids
  2. (2000). A: 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
  3. (2001). A: Molecular and functional identification of large neutral amino acid transporters LAT1 and LAT2 and their pharmacological relevance at the blood-brain barrier.
  4. (1993). Activation of hypoxia-inducible factor-1 in the rat cerebral cortex after transient global ischemia: potential role of insulin-like growth factor-1.
  5. (2009). Agrin, aquaporin-4, and astrocyte polarity as an important feature of the blood-brain barrier. Neuroscientist
  6. (1994). AL: Potassium cotransport at the rat choroid plexus.
  7. (1990). Alteration of atrial natriuretic peptide receptors in the choroid plexus of rats with induced or congenital hydrocephalus. Childs Nerv Syst
  8. (2010). AM: The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature. Circ Res
  9. (2001). Ambudkar SM: The mechanism of action of multidrug-resistance- linked P-glycoprotein.
  10. (2005). AT: ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood- tumor barrier. Cancer Res
  11. (2007). B: GLUT1 deficiency syndrome–2007 update. Dev Med Child Neurol
  12. (1983). Baker GL: Plasma amino acid concentrations in normal adults fed meals with added monosodium L-glutamate and aspartame.
  13. (2003). Balda MS: Holey barrier: claudins and the regulation of brain endothelial permeability.
  14. (2009). Banks WA: Isolation of peptide transport system-6 from brain endothelial cells: therapeutic effects with antisense inhibition in Alzheimer and stroke models. J Cereb Blood Flow Metab
  15. (2010). Barrand MA: ABC efflux transporters in brain vasculature of Alzheimer’s subjects. Brain Res
  16. (1993). Birnbaum MJ: Kinetics of GLUT1 and GLUT4 glucose transporters expressed in Xenopus oocytes.
  17. (2008). Blasig IE: Formation of tight junction: determinants of homophilic interaction between classic claudins.
  18. (2004). Blesch A: Nerve growth factor: from animal models of cholinergic neuronal degeneration to gene therapy in Alzheimer’s disease. Prog Brain Res
  19. (2007). Bogdanovic N: Occludin is overexpressed in Alzheimer’s disease and vascular dementia.
  20. (1987). Bourrer J-M: Evidence for alanine, serine, and cystine system of transport in isolated brain capillaries.
  21. (1983). Brain metabolism: a perspective from the blood-brain barrier. Physiol Rev
  22. (2003). Brain-targeted drug delivery: experiences to date.
  23. (2005). Cadherin-10 is a novel blood-brain barrier adhesion molecule in human and mouse. Brain Res
  24. (2008). Carro E: Megalin mediates the transport of leptin across the blood-CSF barrier. Neurobiol Aging
  25. (2010). Carro EM: Clearance of amyloid- peptide across the choroid plexus in Alzheimer’s disease. Curr Aging Sci
  26. (2003). CD: Constitutive expression of various xenobiotic and endobiotic transporter mRNAs in the choroid plexus of rats. Drug Metab Dispos
  27. (1998). CE: Vasopressin mediates the inhibitory effect of central angiotensin II on cerebrospinal fluid formation.
  28. (2007). CE: Vitamin transport and homeostasis in mammalian brain: focus on Vitamins
  29. (1995). Cerebrovascular permeability to peptides: manipulations of transport systems at the blood-brain barrier. Pharm Res
  30. (1993). CH: Peptidases, peptides, and the mammalian blood-brain barrier.
  31. (2006). Chodobski A: Chronic hypernatremia increases the expression of vasopressin and voltage-gated Na channels in the rat choroid plexus. Neuroendocrinology
  32. (2010). Chodobski A: Vasopressin amplifies the production of proinflammatory mediators in traumatic brain injury.
  33. (1999). Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci USA
  34. (2000). CL: Differential regulation of leptin transport by the choroid plexus and blood-brain barrier and high affinity transport systems for entry into hypothalamus and across the blood-cerebrospinal fluid barrier. Endocrinology
  35. (2003). CL: Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible.
  36. (2001). Claudin- 1, claudin-2 and claudin-11 are present in tight junctions of choroid plexus epithelium of the mouse. Neurosci Lett
  37. (1997). Cloning and functional expression of a brain peptide/ histidine transporter.
  38. (2009). CR: 17betaestradiol induces transthyretin expression in murine choroid plexus via an oestrogen receptor dependent pathway. Cell Mol Neurobiol
  39. (2008). CR: 5Alphadihydrotestosterone up-regulates transthyretin levels in mice and rat choroid plexus via an androgen receptor independent pathway. Brain Res
  40. (2010). CR: Progesterone enhances transthyretin expression in the rat choroid plexus in vitro and in vivo via progesterone receptor.
  41. (1967). Curl F: Secretion of cerebrospinal fluid by the ventricular ependyma of the rabbit.
  42. (1990). Davson H: Kinetics of arginine-vasopressin uptake at the blood-brain barrier. Biochim Biophys Acta
  43. (2008). de Leon MJ: Hippocampal hypometabolism predicts cognitive decline from normal aging. Neurobiol Aging
  44. (1993). De Vivo DC: A mouse model for Glut-1 haploinsufficiency. Hum Mol Genet
  45. (2010). De Vivo DC: Glut1 deficiency: Inheritance pattern determined by haploinsufficiency. Ann Neurol
  46. (2008). De Waziers I, Declèves X: ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood-brain barrier.
  47. (2007). Dejana E: Adherens junctions in endothelial cells regulate vessel maintenance and angiogenesis. Thromb Res
  48. (2004). Dejana E: Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev
  49. (1998). Dejana E: Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration.
  50. (2009). Delivery of peptide and protein drugs over the blood-brain barrier. Prog Neurobiol
  51. (2008). Delivery of peptides to the brain: emphasis on therapeutic development. Biopolymers
  52. (1999). Devaskar SU: Distribution of glucose transporter isoform-3 and hexokinase I in the postnatal murine brain. Brain Res
  53. (1983). DG: Blood-brain barrier permeability to dipeptides and their constituent amino acids. Brain Res
  54. (1984). Diemer NH: Elevations of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis.
  55. (2004). Distribution and anatomical localization of the glucose transporter 2 (GLUT2) in the adult rat brain–an immunohistochemical study.
  56. (2006). Distribution of sodium transporters and aquaporin-1 in the human choroid plexus.
  57. (2004). Do multidrug resistance-associated protein-1 and -2 play any role in the elimination of estradiol-17 betaglucuronide and 2, 4-dinitrophenyl-S-glutathione across the bloodcerebrospinal fluid barrier? J Pharm Sci
  58. (1998). DR: Glutamine transport by the blood-brain barrier: a possible mechanism for nitrogen removal.
  59. (2006). Drewes LR: The rat blood-brain barrier transcriptome.
  60. (2008). DS: Diesel exhaust particles induce oxidative stress, proinflammatory signaling, and P-glycoprotein up-regulation at the blood-brain barrier.
  61. (2006). DS: In vivo activation of human pregnane × receptor tightens the blood-brain barrier to methadone through P-glycoprotein up-regulation. Mol Pharmacol
  62. (2004). DS: Pregnane × receptor up-regulation of Pglycoprotein expression and transport function at the blood-brain barrier. Mol Pharmacol
  63. (2006). DS: Rapid modulation of Pglycoprotein-mediated transport at the blood-brain barrier by tumor necrosis factor-alpha and lipopolysaccharide. Mol Pharmacol
  64. (2007). DS: Tumor necrosis factor alpha and endothelin1 increase P-glycoprotein expression and transport activity at the bloodbrain barrier. Mol Pharmacol
  65. (2007). E: Hypoxia disrupts the barrier function of neural blood vessels through changes in the expression of claudin-5 in endothelial cells.
  66. (2010). EA: Low density lipoprotein receptor related protein-1: A serial clearance homeostatic mechanism controlling Alzheimer’s amyloid β-peptide elimination from the brain.
  67. (2008). Ejsing T: A review on the impact of P-glycoprotein on the penetration of drugs into the brain. Focus on psychotropic drugs. Eur Neuropsychopharmacol
  68. (1981). Electrical resistance of a capillary endothelium.
  69. (2003). Endou H: Expression of human organic anion transporters in the choroid plexus and their interactions with neurotransmitter metabolites.
  70. (2010). Epithelial pathways in choroid plexus electrolyte transport. Physiology (Bethesda)
  71. (2004). Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int
  72. (2002). Expression and functional characterization of rat organic anion transporter 3 (rOat3) in the choroid plexus. Mol Pharmacol
  73. (2003). Expression and functional involvement of organic anion transporting polypeptide subtype 3 (Slc21a7) in rat choroid plexus. Pharm Res
  74. (2004). Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain. Neuroscience
  75. (2009). Expression of EAAT-1 distinguishes choroid plexus tumors from normal and reactive choroid plexus epithelium. Acta Neuropathol
  76. (2008). Expression of the thyroid hormone transporters monocarboxylate transporter-8 (SLC16A2) and organic ion transporter-14 (SLCO1C1) at the blood-brain barrier. Endocrinology
  77. (2001). Factor (s) released by glucose-deprived astrocytes enhance glucose transporter expression and activity in rat brain endothelial cells. Biochim Biophys Acta
  78. Features of the choroid plexus of the cat, studied in vitro.
  79. (1994). Frelin C: Na+-K+-Cl- cotransporter of brain capillary endothelial cells.
  80. (1996). function, and regulation of the mammalian facilitative glucose transporter gene family. Annu Rev Nutr
  81. (2004). Ghersi-Egea JF: Detoxification systems, passive and specific transport for drugs at the blood-CSF barrier in normal and pathological situations. Adv Drug Deliv Rev
  82. (2008). Ghersi-Egea JF: Differential expression of the multidrug resistance-related proteins ABCb1 and ABCc1 between blood-brain interfaces.
  83. (1988). GI: Evidence for a family of human glucose transporter-like proteins. Sequence and gene localization of a protein expressed in fetal skeletal muscle and other tissues.
  84. (1993). GN: GLUT-1 expression in the cerebra of patients with Alzheimer’s disease. Neurobiol Aging
  85. (1978). Goldstein GW: Polarity of the blood-brain barrier: neutral amino acid transport into isolated brain capillaries. Science
  86. (2000). H: Phorbol ester induced changes in tight and adherens junctions in the choroid plexus epithelium and in the ependyma. Brain Res
  87. (1993). Halestrap AP: Transport of lactate and other monocarboxylates across mammalian plasma membranes.
  88. (1997). Hamprecht B: Expression of the surface antigen 4F2hc affects system-L-like neutral-amino-acid-transport activity in mammalian cells.
  89. (1990). HC: A morphometric study on the development of the lateral ventricle choroid plexus, choroid plexus capillaries and ventricular ependyma in the rat. Dev Brain Res
  90. (1999). Hediger MA: Distribution of peptide transporter PEPT2 mRNA in the rat nervous system. Anat Embryol (Berl)
  91. (2000). HG: Glucose transporter 8 (GLUT8): a novel sugar facilitator with glucose transport activity.
  92. (2000). HIF-1: mediator of physiological and pathophysiological responses to hypoxia.
  93. (2005). Hladky SB: Polarized distribution of nucleoside transporters in rat brain endothelial and choroid plexus epithelial cells.
  94. (2008). Hladky SB: Transport activities involved in intracellular pH recovery following acid and alkali challenges in rat brain microvascular endothelial cells. Pflugers Arch
  95. (2006). Hladky SB: Transporters involved in regulation of intracellular pH in primary cultured rat brain endothelial cells.
  96. HN: Transsynaptic control of neuronal protein synthesis. In The Neurosciences: Fourth Study Program. Edited by: Schmitt FO, Norden FG.
  97. (2000). Homophilic interaction of junctional adhesion molecule.
  98. (2006). HS: Atrial natriuretic peptide: its putative role in modulating the choroid plexus-CSF system for intracranial pressure regulation. Acta Neurochir Suppl
  99. (2007). Hübner CA: Mice with targeted Slc4a10 gene disruption have small brain ventricles and show reduced neuronal excitability. Proc Natl Acad Sci USA
  100. (2002). IA: Expression, regulation, and functional role of glucose transporters (GLUTs) in brain. Int Rev Neurobiol
  101. (1994). IA: Glucose transporter proteins in brain.
  102. (2009). IA: P-Glycoprotein and breast cancer resistance protein restrict apical-to-basolateral permeability of human brain endothelium to amyloid-beta. J Cereb Blood Flow Metab
  103. (1990). Immunocytochemical localization of the erythroid glucose transporter: abundance in tissues with barrier functions.
  104. (2007). Is lactate food for neurons? Comparison of monocarboxylate transporter subtypes in brain and muscle. Neuroscience
  105. (2009). Isakovic AJ: Blood-brain barrier efflux transport of pyrimidine nucleosides and nucleobases in the rat. Neurochem Res
  106. (2006). JC: Dietinduced ketosis increases capillary density without altered blood flow in rat brain.
  107. (2001). JE: Intravenous human interleukin1alpha impairs memory processing in mice: dependence on blood-brain barrier transport into posterior division of the septum. J Pharmacol Exp Ther
  108. (2004). JM: The role of claudins in determining paracellular charge selectivity. Proc Am Thorac Soc
  109. (1984). Kastin AJ: A brain-to-blood carrier-mediated transport system for small, N-tyrosinated peptides. Pharmacol Biochem Behav
  110. (1983). Kastin AJ: CSF-plasma relationships for DSIP and some other neuropeptides. Pharmacol Biochem Behav
  111. (1990). Kastin AJ: Editorial review: Peptide transport systems for opiates across the blood- brain barrier.
  112. (2008). KB: A critical overview of the influence of inflammation and infection on P-glycoprotein expression and activity in the brain. Expert Opin Drug Metab Toxicol
  113. Kinetic analysis of leucineenkephalin cellular uptake at the luminal side of the blood-brain barrier in an in situ perfused guinea-pig brain. JN e u r o c h e m1989,
  114. (1987). Kinetics of neutral amino acid transport across the blood-brain barrier.
  115. (2008). KK: Subcellular localization of transporters along the rat blood-brain barrier and blood-cerebral-spinal fluid barrier by in vivo biotinylation. Neuroscience
  116. (2001). KM: Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters.
  117. (1998). Landschulz WH: Monocarboxylate transporter expression in mouse brain.
  118. (2005). Lavie A: Structure of the conserved cytoplasmic C-terminal domain of occludin: identification of the ZO-1 binding surface.
  119. (2010). Lead-induced accumulation of beta-amyloid in the choroid plexus: role of low density lipoprotein receptor protein-1 and protein kinase C. Neurotoxicology
  120. (2010). LG: Regulation and role of organic anion-transporting polypeptides (OATPs) in drug delivery at the choroid plexus.
  121. (1985). Lodish HF: Sequence and structure of human glucose transporter. Science
  122. (2006). LQ: Estradiol reduces activity of the bloodbrain barrier Na-K-Cl cotransporter and decreases edema formation in permanent middle cerebral artery occlusion. J Cereb Blood Flow Metab
  123. (2000). LR: Expression of large amino acid transporter LAT1 in rat brain endothelium.
  124. (1989). LR: Glucose transporter localization in brain using light and electron immunocytochemistry.
  125. (1999). LR: Monocarboxylate transporter (MCT1) abundance in brains of suckling and adult rats: a quantitative electron microscopic immunogold study. Brain Res Dev Brain Res
  126. (2003). Lysosomal amino acid transporter LYAAT-1 in the rat central nervous system: an in situ hybridization and immunohistochemical study.
  127. (2003). Magistretti PJ: Food for thought: challenging the dogmas.
  128. (1996). Magistretti PJ: Metabolic coupling between glia and neurons.
  129. (2003). Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview:. Adv Drug Deliv Rev
  130. (2010). Mastrobattista E: Identification of peptide ligands for targeting to the blood-brain barrier. Pharm Res
  131. (2006). MB: Uneven distribution of nucleoside transporters and intracellular enzymatic degradation prevent transport of intact [ 14C] adenosine across the sheep choroid plexus epithelium as a monolayer in primary culture. Cerebrospinal Fluid Res
  132. (1997). MHM: Transthyretin is not essential for thyroxine to reach the brain and other tissues in transthyretin-null mice.
  133. (1999). Minato N: 4F2 (CD98) heavy chain is associated covalently with an amino acid transporter and controls intracellular trafficking and membrane topology of 4F2 heterodimer.
  134. (1974). MN: Scanning electron microscopy in the ultrastructural analysis of the mammalian cerebral ventricular system. Int Rev Cytol
  135. (2002). Molecular aspects of renal anionic drug transport. Ann Rev Physiol
  136. (1997). Monfils PR: The presence of arginine vasopressin and its mRNA in rat choroid plexus epithelium. Brain Res Mol Brain Res
  137. (2005). MP: Occludin: structure, function and regulation. Adv Drug Deliv Rev
  138. (1995). MR: The ependyma: a protective barrier between brain and cerebrospinal fluid. Glia
  139. (1978). MV: Junctional complexes and variations in gap junctions between spinal cord ependymal cells of a teleost Sternarchus albifrons (Gymnotoidei). Brain Res
  140. (2003). MW: Insulin and the bloodbrain barrier. Curr Pharm Des
  141. (2003). MW: Structural and functional aspects of the bloodbrain barrier. Prog Drug Res
  142. (1995). N-system amino acid transport at the blood–CSF barrier.
  143. (1999). Na (+)-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal.
  144. (2008). Nałecz KA: Localization of organic cation/carnitine transporter (OCTN2) in cells forming the blood-brain barrier.
  145. (2006). Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: the role of microglia, phagocytosis, and NADPH oxidase.
  146. (1995). Neutral amino acid transport characterization of isolated luminal and abluminal membranes of the blood-brain barrier.
  147. (2009). Nhe1 is a luminal Na+/H+ exchanger in mouse choroid plexus and is targeted to the basolateral membrane in Ncbe/Nbcn2-null mice.
  148. (1997). Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA
  149. (1987). NR: Cell junctions and membrane specializations in the ventricular zone (germinal matrix) of the developing sheep brain: a CSF-brain barrier.
  150. (2000). Nterminal tripeptide of IGF-1 (GPE) prevents the loss of TH positive neurons after 6-OHDA induced nigral lesion in rats. Brain Res
  151. (2007). O: Cortical consequences of in vivo blockade of monocarboxylate transport during brain development in mice. Pediatr Res
  152. (2002). Ohno S: aPKC kinase activity is required for the asymmetric differentiation of the premature junctional complex during epithelial cell polarization.
  153. (2008). Organic aniontransporting polypeptides at the blood-brain and blood-cerebrospinal fluid barriers. Curr Top Dev Biol
  154. (2001). Ottersen OP: A novel postsynaptic density protein: the monocarboxylate transporter MCT2 is colocalized with delta 2 glutamate receptors in postsynaptic densities of parallel fiber-Purkinje cell synapses. Exp Brain Res
  155. (2007). Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. Biochem J
  156. (1994). Pardridge WM: Differential glycosylation of the GLUT1 glucose transporter in brain capillaries and choroid plexus. Biochim Biophys Acta
  157. (2009). Pardridge WM: Engineering and expression of a chimeric transferrin receptor monoclonal antibody for bloodbrain barrier delivery in the mouse. Biotechnol Bioeng
  158. (2001). Pasternak GW: Transport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs.
  159. (1992). Paulson OB: Capillary circulation in the brain. Cerebrovasc Brain Metab Rev
  160. (2010). Paulus W: Choroid plexus: biology and pathology. Acta Neuropathol
  161. (2008). PD: NBCe2 exhibits a 3 HCO3-:1 Na+ stoichiometry in mouse choroid plexus epithelial cells. Biochem Biophys Res Commun
  162. (2010). PD: Regulatory volume increase in epithelial cells isolated from the mouse fourth ventricle choroid plexus involves Na+-H+ exchange but not Na+-K+-2Cl-cotransport. Brain Res
  163. (2008). Peptide transporters and their roles in physiological processes and drug disposition. Xenobiotica
  164. (1999). PJ: Localization of the organic anion transporting polypeptide 2 (Oatp2) in capillary endothelium and choroid plexus epithelium of rat brain.
  165. (1999). PN: AVP V1 receptor-mediated decrease in Cl- efflux and increase in dark cell number in choroid plexus epithelium.
  166. (1993). QR: Identification of the cationic amino acid transporter (System y+) of the rat blood-brain barrier.
  167. (1987). Rakic L: Transport of leucine-enkephalin across the blood-brain barrier in the perfused guinea pig brain.
  168. Reduced cerebral glucose metabolism in patients at risk for Alzheimer’s disease.
  169. (2004). Redzic ZB: Brain to blood efflux transport of adenosine: blood-brain barrier studies in the rat.
  170. (2008). Redzic ZB: Transport of [ 14C] hypoxanthine by sheep choroid plexus epithelium as a monolayer in primary culture: Na +-dependent and Na +-independent uptake by the apical membrane and rapid intracellular metabolic conversion to nucleotides. Neurosci Lett
  171. (1984). Regulation of bicarbonate transport across the brush border membrane of the bull-frog choroid plexus.
  172. (2010). Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier. Trends Pharmacol Sci
  173. (1980). Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability.
  174. (1989). RGL: Convection of cerebral interstitial fluid and its role in brain volume regulation.
  175. (1999). Risau W: A dominant mutant of occludin disrupts tight junction structure and function.
  176. (2005). Role and relevance of peptide transporter 2 (PEPT2) in the kidney and choroid plexus: in vivo studies with glycylsarcosine in wild-type and PEPT2 knockout mice. J Pharmacol Exp Ther
  177. (2002). Role of PEPT2 in peptide/mimetic trafficking at the blood-cerebrospinal fluid barrier: studies in rat choroid plexus epithelial cells in primary culture. J Pharmacol Exp Ther
  178. (2004). Role of PEPT2 in the choroid plexus uptake of glycylsarcosine and 5-aminolevulinic acid: studies in wild-type and null mice. Pharm Res
  179. (2002). RS: Striking differences in glucose and lactate levels between brain extracellular
  180. (1998). RT: Glut1 glucose transporter in the primate choroid plexus endothelium.
  181. (2004). S: A SCL4A10 gene product maps selectively to the basolateral plasma membrane of choroid plexus epithelial cells.
  182. (2000). S: Increased survival of dopaminergic neurons in striatal grafts of fetal ventral mesencephalic cells exposed to neurotrophin-3 or glial cell line-derived neurotrophic factor. Cell Transplant
  183. (2005). Salmaggi A: Expression of drug resistance proteins Pgp, MRP1, MRP3, MRP5 and GST-pi in human glioma.
  184. (1997). Segal MB: Acidic amino acid accumulation by rat choroid plexus during development. Brain Res Dev Brain Res
  185. (1985). Segal MB: The transport of sugars across the perfused choroid plexus of the sheep.
  186. (1992). Segal MB: The uptake of anionic and cationic amino acids by the isolated perfused sheep choroid plexus. Brain Res
  187. (1996). Selkoe DJ: Amyloid beta-peptide is transported on lipoproteins and albumin in human plasma.
  188. (2008). Silverberg GD: Multiplicity of cerebrospinal fluid functions: New challenges in health and disease. Cerebrospinal Fluid Res
  189. (2004). Simultaneous activation of several second messengers in hypoxia-induced hyperpermeability of brain derived endothelial cells.
  190. (2004). Sisk CL: Estrogen increases brain expression of the mRNA encoding transthyretin, an amyloid beta scavenger protein. J Alzheimers Dis
  191. (2003). SJ: Neurotrophins and neurodegeneration.
  192. (2007). SJ: Supply and demand in cerebral energy metabolism: the role of nutrient transporters.
  193. (2001). SL: A conserved family of prolyl-4-hydroxylases that modify HIF. Science
  194. (2002). Soto C: Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer’s disease by treatment with a beta-sheet breaker peptide.
  195. (2003). Stanimirovic D: The expression and functional characterization of ABCG2 in brain endothelial cells and vessels.
  196. (2009). Steadystate brain glucose transport kinetics re-evaluated with a four-state conformational model. Front Neuroenergetics
  197. (2006). Structure of the blood-brain barrier and its role in the transport of amino acids.
  198. (2003). System L: heteromeric exchangers of large, neutral amino acids involved in directional transport. Pflugers Arch
  199. (2009). Takeichi M: Adherens junction: molecular architecture and regulation. Cold Spring Harb Perspect Biol
  200. (2006). Takeo S: Cerebral ischemia enhances tyrosine phosphorylation of occludin in brain capillaries. Biochem Biophys Res Commun
  201. (2007). Teichberg VI: Brain neuroprotection by scavenging blood glutamate. Exp Neurol
  202. (2005). Terasaki T: Distinct spatio-temporal expression of ABCA and ABCG transporters in the developing and adult mouse brain.
  203. (2010). Terasaki T: Lack of brain-to-blood efflux transport activity of low-density lipoprotein receptor-related protein-1 (LRP-1) for amyloid-b peptide(1-40) in mouse: involvement of an LRP-1-independent pathway.
  204. (2004). Terasaki T: Organic anion transporter 3 is involved in the brain-to-blood efflux transport of thiopurine nucleobase analogs.
  205. (1998). The amino acid transport system y+L/4F2hc is a heteromultimeric complex.
  206. (2009). The blood-brain barrier and glutamate.
  207. (2004). The C-terminal cytoplasmic tail of claudins 1 and 5 but not its PDZ-binding motif is required for apical localization at epithelial and endothelial tight junctions.
  208. (2006). The CNS as a target for peptides and peptide-based drugs. Expert Opin Drug Deliv
  209. (1979). The Concept of a Blood-Brain Barrier Chichester:
  210. (2002). The evolution of transthyretin synthesis in the choroid plexus. Clin Chem Lab Med
  211. (2009). The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev
  212. (2001). The human ATP-binding cassette (ABC) transporter superfamily.
  213. (2007). The MCT8 thyroid hormone transporter and Allan-Herndon-Dudley syndrome. Best Pract Res Clin Endocrinol Metab
  214. (2010). The physiological significance of the cardiotonic steroid/ ouabain-binding site of the Na, K-ATPase. Annu Rev Physiol
  215. (2001). The roles of claudin superfamily proteins in paracellular transport. Traffic
  216. (2004). The SLC16 gene family: from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch
  217. (2009). Thekkumkara TJ, Abbruscato TJ: A functional role for sodium-dependent glucose transport across the blood-brain barrier during oxygen glucose deprivation. J Pharmacol Exp Ther
  218. (2006). Thekkumkara TJ, Abbruscato TJ: Protein kinase C family members as a target for regulation of blood-brain barrier Na, K, 2Cl-cotransporter during in vitro stroke conditions and nicotine exposure. Pharm Res
  219. (1980). Thiesson D: Tight junctions in the ependyma of the spinal cord of the urodele Pleurodeles waltlii. Anat Embryol
  220. (2003). Tight junction proteins. Prog Biophys Mol Biol
  221. (2010). Torres-Aleman I: Neuronal activity drives localized blood-brain-barrier transport of serum insulin-like growth factor-I into the CNS. Neuron
  222. (2002). TP: Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation.
  223. (2001). TP: Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci
  224. (2010). TP: Oxidative stress increases blood-brain barrier permeability and induces alterations in occludin during hypoxia-reoxygenation. J Cereb Blood Flow Metab
  225. (2010). TP: Protein kinase C activation modulates reversible increase in cortical blood-brain barrier permeability and tight junction protein expression during hypoxia and posthypoxic reoxygenation. J Cereb Blood Flow Metab
  226. (2005). TP: The blood-brain barrier neurovascular unit in health and disease. Pharmacol Rev
  227. (2009). TP: Transforming growth factor-beta signaling alters substrate permeability and tight junction protein expression at the blood-brain barrier during inflammatory pain. J Cereb Blood Flow Metab
  228. (1989). Transcytosis of macromolecules through the blood-brain barrier: a cell biological perspective and critical appraisal. Acta Neuropathol
  229. (1996). Transcytosis of protein through the mammalian cerebral epithelium and endothelium. III. Receptor-mediated transcytosis through the bloodbrain barrier of blood-borne transferrin and antibody against the transferrin receptor. Exp Neurol
  230. (2010). Traumatic brain injury and recovery mechanisms: peptide modulation of periventricular neurogenic regions by the choroid plexus-CSF nexus.
  231. (2000). Tsukita S: Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol Biol Cell
  232. (2001). Tsukita S: Junctional adhesion molecule (JAM) binds to PAR-3: a possible mechanism for the recruitment of PAR-3 to tight junctions.
  233. (1998). Tsukita S: Occludin-deficient embryonic stem cells can differentiate into polarized epithelial cells bearing tight junctions.
  234. (2003). Tsukita S: Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice.
  235. (1988). Ultrastructural cytochemistry of blood-brain barrier endothelia. Prog Histochem Cytochem
  236. (2009). Unadkat JD: Drug interactions at the blood-brain barrier: fact or fantasy? Pharmacol Ther
  237. (2006). Utepbergenov DI: Assembly of tight junction is regulated by the antagonism of conventional and novel protein kinase C isoforms.
  238. (2008). VE-cadherin: the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation. Arterioscler Thromb Vasc Biol
  239. (2009). Verrey F: Culture-induced changes in blood-brain barrier transcriptome: implications for amino-acid transporters in vivo.
  240. (1913). Vitalfarbung am Zentralnervensystem. Abh preuss Akad Wiss Phys-Math
  241. (2007). Volk C: Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res
  242. (2002). Warzok RW: Deposition of Alzheimer’s beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics
  243. (2009). Zhang W: ABCG2 is upregulated in Alzheimer’s brain with cerebral amyloid angiopathy and may act as a gatekeeper at the blood-brain barrier for Ab(1-40) peptides.
  244. (2007). Zlokovic BV: Clearance of amyloid-beta by circulating lipoprotein receptors. Nat Med
  245. (2009). Zlokovic BV: Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer’s disease. CNS Neurol Disord Drug Targets
  246. (2005). Zlokovic BV: IgG-assisted age-dependent clearance of Alzheimer’s amyloid beta peptide by the blood-brain barrier neonatal Fc receptor.
  247. (1990). Zlokovic BV: Kinetics and Na independence of amino acid uptake by blood side of perfused sheep choroid plexus.
  248. (2004). Zlokovic BV: LRP/amyloid b-peptide interaction mediates differential brain efflux of Ab isoforms. Neuron
  249. (2007). Zlokovic BV: Transport pathways for clearance of human Alzheimer’s amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab