Anatomy and Physiology of the Blood–Brain Barriers

Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 10)

Abstract

This chapter covers the three main barrier layers separating blood and the central nervous system (CNS): the endothelium of the brain vasculature, the epithelium of the choroid plexus secreting cerebrospinal fluid (CSF) into the ventricles and the arachnoid epithelium forming the middle layer of the meninges on the brain surface. There are three key barrier features at each site that control the composition of brain fluids and regulate CNS drug permeation: (1) physical barriers result from features of the cell membranes and of the tight junctions restricting the paracellular pathway through intercellular clefts; (2) transport barriers result from membrane transporters mediating solute uptake and efflux, together with vesicular mechanisms mediating transcytosis of larger molecules such as peptides and proteins and (3) enzymatic barriers result from cell surface and intracellular enzymes that can modify molecules in transit. Brain fluids (CSF and brain interstitial fluid) are secreted, flow through particular routes and then drain back into the venous system; this fluid turnover aids central homeostasis and also affects CNS drug concentration. Several CNS pathologies involve changes in the barrier layers and the fluid systems. Many of these aspects of physiology and pathology have implications for drug delivery.

Keywords

Cholesterol Permeability Migration Luminal Hydrocephalus 

Notes

Acknowledgements

I am grateful to Dr Siti R. Yusof for help with artwork and many colleagues for discussions.

References

  1. Aänismaa P, Gatlik-Landwojtowicz E, Seelig A (2008) P-glycoprotein senses its substrates and the lateral membrane packing density: consequences for the catalytic cycle. Biochemistry 47:10197–10207PubMedCrossRefGoogle Scholar
  2. Abbott NJ (1992) Comparative physiology of the blood–brain barrier. In: Bradbury MWB (ed) Physiology and pharmacology of the blood–brain barrier, vol 103, Handb Exp Pharmacol. Springer, Heidelberg, pp 371–396CrossRefGoogle Scholar
  3. Abbott NJ, Mendonça LL, Dolman DE (2003) The blood-brain barrier in systemic lupus erythematosus. Lupus 12:908–915PubMedCrossRefGoogle Scholar
  4. Abbott NJ (2004) Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int 45:545–552PubMedCrossRefGoogle Scholar
  5. Abbott NJ (2013) Blood–brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis 36:437–449PubMedCrossRefGoogle Scholar
  6. Abbott NJ, Friedman A (2012) Overview and introduction: the blood–brain barrier in health and disease. Epilepsia 53 (Suppl 6):1–6PubMedCentralPubMedCrossRefGoogle Scholar
  7. Abbott NJ, Rönnbäck L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7:41–53PubMedCrossRefGoogle Scholar
  8. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood–brain barrier. Neurobiol Dis 37:13–25PubMedCrossRefGoogle Scholar
  9. Alvarez JI, Dodelet-Devillers A, Kebir H, Ifergan I, Fabre PJ, Terouz S, Sabbagh M, Wosik K, Bourbonnière L, Bernard M, van Horssen J, de Vries HE, Charron F, Prat A (2011) The Hedgehog pathway promotes blood–brain barrier integrity and CNS immune quiescence. Science 334:1727–1731PubMedCrossRefGoogle Scholar
  10. Armulik A, Genové G, Mäe M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C (2010) Pericytes regulate the blood–brain barrier. Nature 468:557–561PubMedCrossRefGoogle Scholar
  11. Bazan NG, Eady TN, Khoutorova L, Atkins KD, Hong S, Lu Y, Zhang C, Jun B, Obenaus A, Fredman G, Zhu M, Winkler JW, Petasis NA, Serhan CN, Belayev L (2012) Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke. Exp Neurol 236:122–130PubMedCentralPubMedCrossRefGoogle Scholar
  12. Becker NH, Novikoff AB, Zimmerman HM (1967) Fine structure observations of the uptake of intravenously injected peroxidase by the rat choroid plexus. J Histochem Cytochem 15:160–165PubMedCrossRefGoogle Scholar
  13. Bodor N, Buchwald P (2003) Brain targeted drug delivery; experiences to date. Am J Drug Deliv 1:13–26CrossRefGoogle Scholar
  14. Bundgaard M, Abbott NJ (2008) All vertebrates started out with a glial blood–brain barrier 4–500 million years ago. Glia 56:699–708PubMedCrossRefGoogle Scholar
  15. Caporali A, Emanueli C (2011) MicroRNA regulation in angiogenesis. Vascul Pharmacol 55:79–86PubMedCrossRefGoogle Scholar
  16. Cayrol R, Haqqani AS, Ifergan I, Dodelet-Devillers A, Prat A (2011) Isolation of human brain endothelial cells and characterization of lipid raft-associated proteins by mass spectroscopy. Methods Mol Biol 686:275–295PubMedCrossRefGoogle Scholar
  17. Cording J, Berg J, Käding N, Bellmann C, Tscheik C, Westphal JK, Milatz S, Günzel D, Wolburg H, Piontek J, Huber O, Blasig IE (2013) In tight junctions, claudins regulate the interactions between occludin, tricellulin and marvelD3, which, inversely, modulate claudin oligomerization. J Cell Sci 26:554–564CrossRefGoogle Scholar
  18. Cristante E, McArthur S, Mauro C, Maggioli E, Romero IA, Wylezinska-Arridge M, Couraud PO, Lopez-Tremoleda J, Christian HC, Weksler BB, Malaspina A, Solito E (2013) Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications. Proc Natl Acad Sci U S A 110:832–841PubMedCentralPubMedCrossRefGoogle Scholar
  19. Cserr HF, Cooper DN, Suri PK, Patlak CS (1981) Efflux of radiolabeled polyethylene glycols and albumin from rat brain. Am J Physiol 240:F319–F328PubMedGoogle Scholar
  20. Daneman R (2012) The blood–brain barrier in health and disease. Ann Neurol 72:648–672PubMedCrossRefGoogle Scholar
  21. Daneman R, Agalliu D, Zhou L, Kuhnert F, Kuo CJ, Barres BA (2009) Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc Natl Acad Sci U S A 106:641–646PubMedCentralPubMedCrossRefGoogle Scholar
  22. Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468:562–566PubMedCentralPubMedCrossRefGoogle Scholar
  23. Dean M, Annilo T (2005) Evolution of the ATP-binding cassette (ABC) transporter superfamily in vertebrates. Annu Rev Genomics Hum Genet 6:123–142PubMedCrossRefGoogle Scholar
  24. Declèves X, Jacob A, Yousif S, Shawahna R, Potin S, Scherrmann JM (2011) Interplay of drug metabolizing CYP450 enzymes and ABC transporters in the blood–brain barrier. Curr Drug Metab 12:732–741PubMedCrossRefGoogle Scholar
  25. Demel MA, Krämer O, Ettmayer P, Haaksma EE, Ecker GF (2009) Predicting ligand interactions with ABC transporters in ADME. Chem Biodivers 6:1960–1969PubMedCrossRefGoogle Scholar
  26. Dodelet-Devillers A, Cayrol R, van Horssen J, Haqqani AS, de Vries HE, Engelhardt B, Greenwood J, Prat A (2009) Functions of lipid raft membrane microdomains at the blood–brain barrier. J Mol Med (Berl) 87:765–774CrossRefGoogle Scholar
  27. Dolman D, Drndarski S, Abbott NJ, Rattray M (2005) Induction of aquaporin 1 but not aquaporin 4 messenger RNA in rat primary brain microvessel endothelial cells in culture. J Neurochem 93:825–833PubMedCrossRefGoogle Scholar
  28. Engelhardt B, Coisne C (2011) Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle. Fluids Barriers CNS 8:4. doi: 10.1186/2045-8118-8-4 PubMedCentralPubMedCrossRefGoogle Scholar
  29. Fraser PA (2011) The role of free radical generation in increasing cerebrovascular permeability. Free Radic Biol Med 51:967–977PubMedCrossRefGoogle Scholar
  30. Friedman A (2011) Blood–brain barrier dysfunction, status epilepticus, seizures, and epilepsy: a puzzle of a chicken and egg? Epilepsia 52(Suppl 8):19–20PubMedCentralPubMedCrossRefGoogle Scholar
  31. Gatlik-Landwojtowicz E, Aänismaa P, Seelig A (2006) Quantification and characterization of P-glycoprotein-substrate interactions. Biochemistry 45:3020–3032PubMedCrossRefGoogle Scholar
  32. Ge S, Song L, Pachter JS (2005) Where is the blood–brain barrier … really? J Neurosci Res 79:421–427PubMedCrossRefGoogle Scholar
  33. Greenwood J, Heasman SJ, Alvarez JI, Prat A, Lyck R, Engelhardt B (2011) Review: Leucocyte-endothelial cell crosstalk at the blood–brain barrier: a prerequisite for successful immune cell entry to the brain. Neuropathol Appl Neurobiol 37:24–39PubMedCrossRefGoogle Scholar
  34. Groothuis DR, Vavra MW, Schlageter KE, Kang EW, Itskovich AC, Hertzler S, Allen CV, Lipton HL (2007) Efflux of drugs and solutes from brain: the interactive roles of diffusional transcapillary transport, bulk flow and capillary transporters. J Cereb Blood Flow Metab 27:43–56PubMedCrossRefGoogle Scholar
  35. György B, Szabó TG, Pásztói M, Pál Z, Misják P, Aradi B, László V, Pállinger E, Pap E, Kittel A, Nagy G, Falus A, Buzás EI (2011) Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 68:2667–2688PubMedCentralPubMedCrossRefGoogle Scholar
  36. Hackel D, Krug SM, Sauer RS, Mousa SA, Böcker A, Pflücke D, Wrede EJ, Kistner K, Hoffmann T, Niedermirtl B, Sommer C, Bloch L, Huber O, Blasig IE, Amasheh S, Reeh PW, Fromm M, Brack A, Rittner HL (2012) Transient opening of the perineurial barrier for analgesic drug delivery. Proc Natl Acad Sci U S A 109:E2018–E2027PubMedCentralPubMedCrossRefGoogle Scholar
  37. Hamel E (2006) Perivascular nerves and the regulation of cerebrovascular tone. J Appl Physiol 100:1059–1064PubMedCrossRefGoogle Scholar
  38. Haqqani AS, Hill JJ, Mullen J, Stanimirovic DB (2011) Methods to study glycoproteins at the blood–brain barrier using mass spectrometry. Methods Mol Biol 686:337–353PubMedCrossRefGoogle Scholar
  39. Haqqani AS, Delaney CE, Tremblay TL, Sodja C, Sandhu JK, Stanimirovic DB (2013) Method for isolation and molecular characterization of extracellular microvesicles released from brain endothelial cells. Fluids Barriers CNS 10:4. doi: 10.1186/2045-8118-10-4 PubMedCentralPubMedCrossRefGoogle Scholar
  40. Hartmann D, Thum T (2011) MicroRNAs and vascular (dys)function. Vascul Pharmacol 55:92–105PubMedCrossRefGoogle Scholar
  41. Iadecola C, Nedergaard M (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10:1369–1376PubMedCrossRefGoogle Scholar
  42. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4:147ra111. doi: 10.1126/scitranslmed.3003748 PubMedCentralPubMedCrossRefGoogle Scholar
  43. Janson C, Romanova L, Hansen E, Hubel A, Lam C (2011) Immortalization and functional characterization of rat arachnoid cell lines. Neuroscience 177:23–34PubMedCrossRefGoogle Scholar
  44. Johanson CE, Duncan JA 3rd, Klinge PM, Brinker T, Stopa EG, Silverberg GD (2008) Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Cerebrospinal Fluid Res 5:10. doi: 10.1186/1743-8454-5-10 PubMedCentralPubMedCrossRefGoogle Scholar
  45. Kim SY, Buckwalter M, Soreq H, Vezzani A, Kaufer D (2013) Blood–brain barrier dysfunction-induced inflammatory signaling in brain pathology and epileptogenesis. Epilepsia 53(Suppl 6):37–44Google Scholar
  46. Kodaira H, Kusuhara H, Ushiki J, Fuse E, Sugiyama Y (2010) Kinetic analysis of the cooperation of P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp/Abcg2) in limiting the brain and testis penetration of erlotinib, flavopiridol, and mitoxantrone. J Pharmacol Exp Ther 333:788–796PubMedCrossRefGoogle Scholar
  47. Krämer SD, Schütz YB, Wunderli-Allenspach H, Abbott NJ, Begley DJ (2002) Lipids in blood–brain barrier models in vitro II: influence of glial cells on lipid classes and lipid fatty acids. In Vitro Cell Dev Biol 38:566–571CrossRefGoogle Scholar
  48. Lam CH, Hansen EA, Hubel A (2011) Arachnoid cells on culture plates and collagen scaffolds: phenotype and transport properties. Tissue Eng Part A 17:1759–1766PubMedCrossRefGoogle Scholar
  49. Lam CH, Hansen EA, Janson C, Bryan A, Hubel A (2012) The characterization of arachnoid cell transport II: paracellular transport and blood-cerebrospinal fluid barrier formation. Neuroscience 222:228–238PubMedCrossRefGoogle Scholar
  50. Liebner S, Corada M, Bangsow T, Babbage J, Taddei A, Czupalla CJ, Reis M, Felici A, Wolburg H, Fruttiger M, Taketo MM, von Melchner H, Plate KH, Gerhardt H, Dejana E (2008) Wnt/beta-catenin signaling controls development of the blood–brain barrier. J Cell Biol 183:409–417PubMedCrossRefGoogle Scholar
  51. Liebner S, Czupalla CJ, Wolburg H (2011) Current concepts of blood–brain barrier development. Int J Dev Biol 55:467–476PubMedCrossRefGoogle Scholar
  52. Liu DZ, Ander BP, Xu H, Shen Y, Kaur P, Deng W, Sharp FR (2010) Blood–brain barrier breakdown and repair by Src after thrombin-induced injury. Ann Neurol 67:526–533PubMedCentralPubMedCrossRefGoogle Scholar
  53. MacAulay N, Zeuthen T (2010) Water transport between CNS compartments: contributions of aquaporins and cotransporters. Neuroscience 168:941–956PubMedCrossRefGoogle Scholar
  54. Mäe M, Armulik A, Betsholtz C (2011) Getting to know the cast–cellular interactions and signaling at the neurovascular unit. Curr Pharm Des 17:2750–2754PubMedCrossRefGoogle Scholar
  55. Mathiisen TM, Lehre KP, Danbolt NC, Ottersen OP (2010) The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction. Glia 58:1094–1103PubMedCrossRefGoogle Scholar
  56. Mayor S, Pagano RE (2007) Pathways of clathrin-independent endocytosis. Nat Rev Mol Cell Biol 8:603–612PubMedCrossRefGoogle Scholar
  57. McArthur S, Cristante E, Paterno M, Christian H, Roncaroli F, Gillies GE, Solito E (2010) Annexin A1: a central player in the anti-inflammatory and neuroprotective role of microglia. J Immunol 185:317–328CrossRefGoogle Scholar
  58. Miller DS (2010) Regulation of P-glycoprotein and other ABC drug transporters at the blood brain barrier. Trends Pharmacol Sci 31:246–254PubMedCentralPubMedCrossRefGoogle Scholar
  59. Mishra R, Singh SK (2013) HIV-1 Tat C modulates expression of miRNA-101 to suppress VE-cadherin in human brain microvascular endothelial cells. J Neurosci 33:5992–6000PubMedCrossRefGoogle Scholar
  60. Nabeshima S, Reese TS, Landis DMD, Brightman MW (1975) Junctions in the meninges and marginal glia. J Comp Neurol 164:127–169PubMedCrossRefGoogle Scholar
  61. Neuwelt EA, Bauer B, Fahlke C, Fricker G, Iadecola C, Janigro D, Leybaert L, Molnár Z, O’Donnell ME, Povlishock JT, Saunders NR, Sharp F, Stanimirovic D, Watts RJ, Drewes LR (2011) Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci 12:169–182PubMedCentralPubMedCrossRefGoogle Scholar
  62. Paolinelli R, Corada M, Orsenigo F, Dejana E (2011) The molecular basis of the blood brain barrier differentiation and maintenance. Is it still a mystery? Pharmacol Res 63:165–171PubMedCrossRefGoogle Scholar
  63. Parkinson FE, Damaraju VL, Graham K, Yao SY, Baldwin SA, Cass CE, Young JD (2011) Molecular biology of nucleoside transporters and their distributions and functions in the brain. Curr Top Med Chem 11:948–972PubMedCrossRefGoogle Scholar
  64. Patabendige A, Skinner RA, Morgan L, Abbott NJ (2013) A detailed method for preparation of a functional and flexible blood–brain barrier model using porcine brain endothelial cells. Brain Res 1521:16–30, doi:pii: S0006-8993(13)00519-2.  10.1016/j.brainres.2013.04.006 PubMedCentralPubMedCrossRefGoogle Scholar
  65. Potschka H (2012) Role of CNS efflux drug transporters in antiepileptic drug delivery: overcoming CNS efflux drug transport. Adv Drug Deliv Rev 64:943–952PubMedCrossRefGoogle Scholar
  66. Pottiez G, Duban-Deweer S, Deracinois B, Gosselet F, Camoin L, Hachani J, Couraud PO, Cecchelli R, Dehouck MP, Fenart L, Karamanos Y, Flahaut C (2011) A differential proteomic approach identifies structural and functional components that contribute to the differentiation of brain capillary endothelial cells. J Proteomics 75:628–641PubMedCrossRefGoogle Scholar
  67. Ransohoff RM, Brown MA (2012) Innate immunity in the central nervous system. J Clin Invest 122:1164–1171PubMedCentralPubMedCrossRefGoogle Scholar
  68. Ransohoff RM, Engelhardt B (2012) The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol 12:623–635PubMedCrossRefGoogle Scholar
  69. Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145PubMedCrossRefGoogle Scholar
  70. Redzic Z (2011) Molecular biology of the blood–brain and the blood-cerebrospinal fluid barriers: similarities and differences. Fluids Barriers CNS 8:3. doi: 10.1186/2045-8118-8-3 PubMedCentralPubMedCrossRefGoogle Scholar
  71. Reese TS, Karnovsky MJ (1967) Fine structural localization of a blood–brain barrier to exogenous peroxidase. J Cell Biol 34:207–217PubMedCrossRefGoogle Scholar
  72. Reijerkerk A, Lopez-Ramirez MA, van Het Hof B, Drexhage JA, Kamphuis WW, Kooij G, Vos JB, van der Pouw Kraan TC, van Zonneveld AJ, Horrevoets AJ, Prat A, Romero IA, de Vries HE (2013) MicroRNAs regulate human brain endothelial cell-barrier function in inflammation: implications for Multiple Sclerosis. J Neurosci 33:6857–6863PubMedCrossRefGoogle Scholar
  73. Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11:775–787PubMedCrossRefGoogle Scholar
  74. Saunders NR, Daneman R, Dziegielewska KM, Liddelow SA (2013) Transporters of the blood–brain and blood-CSF interfaces in development and in the adult. Mol Aspects Med 34:742–752PubMedCrossRefGoogle Scholar
  75. Seelig A (2007) The role of size and charge for blood–brain barrier permeation of drugs and fatty acids. J Mol Neurosci 33:32–41PubMedCrossRefGoogle Scholar
  76. Serot JM, Zmudka J, Jouanny P (2012) A possible role for CSF turnover and choroid plexus in the pathogenesis of late onset alzheimer’s disease. J Alzheimers Dis 30:17–26PubMedGoogle Scholar
  77. Shawahna R, Uchida Y, Declèves X, Ohtsuki S, Yousif S, Dauchy S, Jacob A, Chassoux F, Daumas-Duport C, Couraud PO, Terasaki T, Scherrmann JM (2011) Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. Mol Pharm 8:1332–1341PubMedCrossRefGoogle Scholar
  78. Shen L, Weber CR, Turner JR (2008) The tight junction protein complex undergoes rapid and continuous molecular remodeling at steady state. J Cell Biol 181:683–695PubMedCrossRefGoogle Scholar
  79. Shlosberg D, Benifla M, Kaufer D, Friedman A (2010) Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol 6:393–403PubMedCentralPubMedCrossRefGoogle Scholar
  80. Silverberg GD, Mayo M, Saul T, Rubenstein E, McGuire D (2003) Alzheimer’s disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis. Lancet Neurol 2:506–511PubMedCrossRefGoogle Scholar
  81. Smith JA, Das A, Ray SK, Banik NL (2012) Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull 87:10–20PubMedCrossRefGoogle Scholar
  82. Somjen GG (2004) Ions in the brain: normal function, seizures and stroke. Oxford University Press, OxfordGoogle Scholar
  83. Stanimirovic DB, Friedman A (2012) Pathophysiology of the neurovascular unit: disease cause or consequence? J Cereb Blood Flow Metab 32:1207–1221PubMedCrossRefGoogle Scholar
  84. Strazielle N, Ghersi-Egea JF (2013) Physiology of blood–brain interfaces in relation to brain disposition of small compounds and macromolecules. Mol Pharm 10:1473–1491PubMedCrossRefGoogle Scholar
  85. Sykova E, Nicholson C (2008) Diffusion in brain extracellular space. Physiol Rev 88:1277–1340PubMedCentralPubMedCrossRefGoogle Scholar
  86. Thorne RG, Nicholson C (2006) In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc Natl Acad Sci U S A 103:5567–5572PubMedCentralPubMedCrossRefGoogle Scholar
  87. Tian W, Sawyer A, Kocaoglu FB, Kyriakides TR (2011) Astrocyte-derived thrombospondin-2 is critical for the repair of the blood–brain barrier. Am J Pathol 179:860–868PubMedCrossRefGoogle Scholar
  88. Weerasuriya A, Spangler RA, Rapoport SI, Taylor RE (1984) AC impedance of the perineurium of the frog sciatic nerve. Biophys J 46:167–174PubMedCentralPubMedCrossRefGoogle Scholar
  89. Weller RO, Subash M, Preston SD, Mazanti I, Carare RO (2008) Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol 18:253–266PubMedCrossRefGoogle Scholar
  90. Weller RO, Djuanda E, Yow HY, Carare RO (2009) Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathol 117:1–14PubMedCrossRefGoogle Scholar
  91. Wolak DJ, Thorne RG (2013) Diffusion of macromolecules in the brain: implications for drug delivery. Mol Pharm 10:1492–1504PubMedCrossRefGoogle Scholar
  92. Yang L, Kress BT, Weber HJ, Thiyagarajan M, Wang B, Deane R, Benveniste H, Iliff JJ, Nedergaard M (2013) Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J Transl Med 11:107, [Epub ahead of print] PubMed PMID: 23635358PubMedCentralPubMedCrossRefGoogle Scholar
  93. Yasuda K, Cline C, Vogel P, Onciu M, Fatima S, Sorrentino BP, Thirumaran RK, Ekins S, Urade Y, Fujimori K, Schuetz EG (2013) Drug transporters on arachnoid barrier cells contribute to the blood-cerebrospinal fluid barrier. Drug Metab Dispos 41:923–931PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  1. 1.Institute of Pharmaceutical Science, Blood–Brain Barrier GroupKing’s College LondonLondonUK

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