Journal of Inherited Metabolic Disease

, Volume 36, Issue 3, pp 437–449 | Cite as

Blood–brain barrier structure and function and the challenges for CNS drug delivery

Review

Abstract

The neurons of the central nervous system (CNS) require precise control of their bathing microenvironment for optimal function, and an important element in this control is the blood–brain barrier (BBB). The BBB is formed by the endothelial cells lining the brain microvessels, under the inductive influence of neighbouring cell types within the ‘neurovascular unit’ (NVU) including astrocytes and pericytes. The endothelium forms the major interface between the blood and the CNS, and by a combination of low passive permeability and presence of specific transport systems, enzymes and receptors regulates molecular and cellular traffic across the barrier layer. A number of methods and models are available for examining BBB permeation in vivo and in vitro, and can give valuable information on the mechanisms by which therapeutic agents and constructs permeate, ways to optimize permeation, and implications for drug discovery, delivery and toxicity. For treating lysosomal storage diseases (LSDs), models can be included that mimic aspects of the disease, including genetically-modified animals, and in vitro models can be used to examine the effects of cells of the NVU on the BBB under pathological conditions. For testing CNS drug delivery, several in vitro models now provide reliable prediction of penetration of drugs including large molecules and artificial constructs with promising potential in treating LSDs. For many of these diseases it is still not clear how best to deliver appropriate drugs to the CNS, and a concerted approach using a variety of models and methods can give critical insights and indicate practical solutions.

Abbreviations

AAV

adeno-associated virus

ABC

ATP-binding cassette

ABCG2

BCRP

ADME

absorption, distribution, metabolism, excretion

AMT

adsorptive-mediated transcytosis

BBB

blood–brain barrier

BBEC

bovine brain endothelial cells (primary)

BCRP

breast cancer resistance protein

bEND3

mouse immortalised brain endothelial cell line

CNS

central nervous system

CSF

cerebrospinal fluid

CYP

cytochrome P450 enzyme

CVO

circumventricular organ

ERT

enzyme replacement therapy

GAGs

glycosaminoglycans

GLUT1

glucose carrier

hCMEC/D3

human immortalised brain endothelial cell line

hPSCs

human pluripotent stem cells

IL-1, IL17A

interleukins

INCL

infantile neuronal ceroid lipofuscinosis

IV

intravenous

Kp,uu

unbound drug brain:plasma concentration ratio

LAT1

large neutral amino acid carrier

LDL

low density lipoprotein

LogBB (or Kp)

total drug brain:plasma concentration ratio

LogDoctanol

log compound distribution coefficient octanol/buffer at given pH

LogPoctanol

log compound partition coefficient octanol/water, neutral species

LSD

lysosomal storage disease

MPR

mannose-6-phosphate receptor

MDR1 (or PgP)

P-glycoprotein

MMP

matrix metalloproteinase

MPS

mucopolysaccharidosis

MPSIIIA or B

Sanfilippo syndrome type A or B

MPSVII

Gaucher’s disease

miRNA

microRNA

NVU

neurovascular unit

PAMPA

parallel artificial membrane permeability assay

Papp

apparent permeability

PBEC

porcine brain endothelial cells (primary)

PBEC/As

PBEC co-cultured with rat astrocytes

PDGF-B

platelet-derived growth factor B

Pe

endothelial permeability

PgP

P-glycoprotein (or MDR1, ABCB1)

PS

permeability x surface area product

QSAR

quantitative structure-activity relationship

RBEC

rat brain endothelial cells (primary)

RBEC/As

RBEC co-cultured with rat astrocytes

RMT

receptor-mediated transcytosis

SAR

structure-activity relationship

SLC

small solute carrier

SRT

substrate-replacement therapy

TEER

transendothelial electrical resistance

XMET

xenobiotic metabolising enzymes and transporters

References

  1. Abbott NJ (1992) Comparative physiology of the blood–brain barrier. In: Bradbury MWB (ed) Physiology and pharmacology of the blood–brain barrier (Handbk Exp Pharmacol 103). Springer, Heidelberg, pp 371–396Google Scholar
  2. Abbott NJ (2004a) Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int 45:545–552PubMedCrossRefGoogle Scholar
  3. Abbott NJ (2004b) Prediction of blood–brain barrier permeation in drug discovery, from in vivo, in vitro and in silico models. Drug Discov Today: Technol 1:407–416CrossRefGoogle Scholar
  4. Abbott NJ, Friedman A (2012) Overview and introduction: the blood–brain barrier in health and disease. Epilepsia 53(Suppl 6:1–6)Google Scholar
  5. Abbott NJ, Rönnbäck L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7:41–53PubMedCrossRefGoogle Scholar
  6. Abbott NJ, Dolman DE, Patabendige AK (2008) Assays to predict drug permeation across the blood–brain barrier, and distribution to brain. Curr Drug Metab 9:901–910PubMedCrossRefGoogle Scholar
  7. 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
  8. Anson DS, McIntyre C, Byers S (2011) Therapies for neurological disease in the mucopolysaccharidoses. Curr Gene Ther 11:132–143PubMedCrossRefGoogle Scholar
  9. Arfi A, Richard M, Gandolphe C, Bonnefont-Rousselot D, Thérond P, Scherman D (2011) Neuroinflammatory and oxidative stress phenomena in MPS IIIA mouse model: the positive effect of long-term aspirin treatment. Mol Genet Metab 103:18–25PubMedCrossRefGoogle Scholar
  10. Armulik A, Genové G, Mäe M et al (2010) Pericytes regulate the blood–brain barrier. Nature 468:557–561PubMedCrossRefGoogle Scholar
  11. Armulik A, Genové G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21:193–215PubMedCrossRefGoogle Scholar
  12. Avdeef A (2011) How well can in vitro brain microcapillary endothelial cell models predict rodent in vivo blood–brain barrier permeability? Eur J Pharm Sci 43:109–124PubMedCrossRefGoogle Scholar
  13. Avdeef A (2012) Absorption and drug development: Solubility, permeability, and charge, 2nd edn. Wiley, Hoboken, p 698ppCrossRefGoogle Scholar
  14. Begley DJ, Brightman MW (2003) Structural and functional aspects of the blood–brain barrier. Progr Drug Res 61:39–78Google Scholar
  15. Begley DJ, Pontikis CC, Scarpa M (2008) Lysosomal storage diseases and the blood–brain barrier. Curr Pharm Des 14:1566–1580PubMedCrossRefGoogle Scholar
  16. Bell RD, Winkler EA, Sagare AP et al (2010) Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68:409–427PubMedCrossRefGoogle Scholar
  17. Bellettato CM, Scarpa M (2010) Pathophysiology of neuropathic lysosomal storage disorders. J Inherit Metab Dis 33:347–362PubMedCrossRefGoogle Scholar
  18. Benarroch EE (2011) Circumventricular organs: receptive and homeostatic functions and clinical implications. Neurology 77:1198–1204PubMedCrossRefGoogle Scholar
  19. Bikadi Z, Hazai I, Malik D et al (2011) Predicting P-glycoprotein-mediated drug transport based on support vector machine and three-dimensional crystal structure of P-glycoprotein. PLoS One 6:e25815PubMedCrossRefGoogle Scholar
  20. Cabrera-Salazar MA, Deriso M, Bercury SD et al (2012) Systemic delivery of a glucosylceramide synthase inhibitor reduces CNS substrates and increases lifespan in a mouse model of type 2 Gaucher disease. PLoS One 7:e43310PubMedCrossRefGoogle Scholar
  21. Calias P, Papisov M, Pan J et al (2012) CNS penetration of intrathecal-lumbar idursulfase in the monkey, dog and mouse: implications for neurological outcomes of lysosomal storage disorder. PLoS One 7:e30341PubMedCrossRefGoogle Scholar
  22. Candela P, Gosselet F, Miller F et al (2008) Physiological pathway for low-density lipoproteins across the blood–brain barrier: transcytosis through brain capillary endothelial cells in vitro. Endothelium 15:254–264PubMedCrossRefGoogle Scholar
  23. Candela P, Gosselet F, Saint-Pol J et al (2010) Apical-to-basolateral transport of amyloid-β peptides through blood–brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by P-glycoprotein. J Alzheimers Dis 22:849–859PubMedGoogle Scholar
  24. Carruthers A, DeZutter J, Ganguly A, Devaskar SU (2009) Will the original glucose transporter isoform please stand up! Am J Physiol Endocrinol Metab 297:E836–E848PubMedCrossRefGoogle Scholar
  25. Cecchelli R, Dehouck B, Descamps L et al (1999) In vitro model for evaluating drug transport across the blood–brain barrier. Adv Drug Deliv Rev 36:165–178PubMedCrossRefGoogle Scholar
  26. Cecchelli R, Berezowski V, Lundquist S et al (2007) Modelling of the blood–brain barrier in drug discovery and development. Nat Rev Drug Discov 6:650–661PubMedCrossRefGoogle Scholar
  27. Chen YH, Claflin K, Geoghegan JC, Davidson BL (2012) Sialic acid deposition impairs the utility of AAV9, but not peptide-modified AAVs for brain gene therapy in a mouse model of lysosomal storage disease. Mol Ther 20:1393–1399PubMedCrossRefGoogle Scholar
  28. Costantino L, Boraschi D (2012) Is there a clinical future for polymeric nanoparticles as brain-targeting drug delivery agents? Drug Discov Today 17:367–378PubMedCrossRefGoogle Scholar
  29. Dagenais C, Avdeef A, Tsinman O, Dudley A, Beliveau R (2009) P-glycoprotein deficient mouse in situ blood–brain barrier permeability and its prediction using an in combo PAMPA model. Eur J Pharm Sci 38:121–137PubMedCrossRefGoogle Scholar
  30. 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 106:641–646PubMedCrossRefGoogle Scholar
  31. Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468:562–566PubMedCrossRefGoogle Scholar
  32. Dauchy S, Dutheil F, Weaver RJ et al (2008) ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood–brain barrier. J Neurochem 107:1518–1528PubMedCrossRefGoogle Scholar
  33. Deli MA, Abrahám CS, Kataoka Y, Niwa M (2005) Permeability studies on in vitro blood–brain barrier models: physiology, pathology, and pharmacology. Cell Mol Neurobiol 25:59–127PubMedCrossRefGoogle Scholar
  34. Descamps L, Dehouck MP, Torpier G, Cecchelli R (1996) Receptor-mediated transcytosis of transferrin through blood–brain barrier endothelial cells. Am J Physiol 270:H1149–H1158PubMedGoogle Scholar
  35. Dickson PI, Chen AH (2011) Intrathecal enzyme replacement therapy for mucopolysaccharidosis I: translating success in animal models to patients. Curr Pharm Biotechnol 12:946–955PubMedCrossRefGoogle Scholar
  36. Dickson P, McEntee M, Vogler C et al (2007) Intrathecal enzyme replacement therapy: successful treatment of brain disease via the cerebrospinal fluid. Mol Genet Metab 91:61–68PubMedCrossRefGoogle Scholar
  37. Dohgu S, Ryerse JS, Robinson SM, Banks WA (2012) Human immunodeficiency virus-1 uses the mannose-6-phosphate receptor to cross the blood–brain barrier. PLoS One 7:e39565PubMedCrossRefGoogle Scholar
  38. Dutheil F, Jacob A, Dauchy S (2010) ABC transporters and cytochromes P450 in the human central nervous system: influence on brain pharmacokinetics and contribution to neurodegenerative disorders. Expert Opin Drug Metab Toxicol 6:1161–1174PubMedCrossRefGoogle Scholar
  39. Engelhardt B, Ransohoff RM (2012) Capture, crawl, cross: the T cell code to breach the blood–brain barriers. Trends Immunol 33:579–589PubMedCrossRefGoogle Scholar
  40. Farfel-Becker T, Vitner EB, Pressey SN, Eilam R, Cooper JD, Futerman AH (2011) Spatial and temporal correlation between neuron loss and neuroinflammation in a mouse model of neuronopathic Gaucher disease. Hum Mol Genet 20:1375–1386PubMedCrossRefGoogle Scholar
  41. Fillebeen C, Descamps L, Dehouck MP et al (1999) Receptor-mediated transcytosis of lactoferrin through the blood–brain barrier. J Biol Chem 274:7011–7017PubMedCrossRefGoogle Scholar
  42. Franke H, Galla HJ, Beuckmann CT (1999) An improved low-permeability in vitro-model of the blood–brain barrier: transport studies on retinoids, sucrose, haloperidol, caffeine and mannitol. Brain Res 818:65–71PubMedCrossRefGoogle Scholar
  43. Fu H, Dirosario J, Killedar S, Zaraspe K, McCarty DM (2011) Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood–brain barrier gene delivery. Mol Ther 19:1025–1033PubMedCrossRefGoogle Scholar
  44. Garbuzova-Davis S, Louis MK, Haller EM, Derasari HM, Rawls AE, Sanberg PR (2011) Blood–brain barrier impairment in an animal model of MPS III B. PLoS One 6:e16601PubMedCrossRefGoogle Scholar
  45. Garcia MA, Carrasco M, Godoy A et al (2001) Elevated expression of glucose transporter-1 in hypothalamic ependymal cells not involved in the formation of the brain-cerebrospinal fluid barrier. J Cell Biochem 80:491–503PubMedCrossRefGoogle Scholar
  46. Ghosh C, Puvenna V, Gonzalez-Martinez J, Janigro D, Marchi N (2011) Blood–brain barrier P450 enzymes and multidrug transporters in drug resistance: a synergistic role in neurological diseases. Curr Drug Metab 12:742–749PubMedCrossRefGoogle Scholar
  47. Gleeson MP (2008) Generation of a set of simple, interpretable ADMET rules of thumb. J Med Chem 51:817–834PubMedCrossRefGoogle Scholar
  48. Grubb JH, Vogler C, Levy B, Galvin N, Tan Y, Sly WS (2008) Chemically modified beta-glucuronidase crosses blood–brain barrier and clears neuronal storage in murine mucopolysaccharidosis VII. Proc Natl Acad Sci U S A 105:2616–2621PubMedCrossRefGoogle Scholar
  49. Grubb JH, Vogler C, Sly WS (2010) New strategies for enzyme replacement therapy for lysosomal storage diseases. Rejuvenation Res 13:229–236PubMedCrossRefGoogle Scholar
  50. Guffon N, Bin-Dorel S, Decullier E, Paillet C, Guitton J, Fouilhoux A (2011) Evaluation of miglustat treatment in patients with type III mucopolysaccharidosis: a randomized, double-blind, placebo-controlled study. J Pediatr 159:838–844PubMedCrossRefGoogle Scholar
  51. Hamilton NB, Attwell D, Hall CN (2011) Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. Front Neuroenergetics 2:pii5 doi:10.3389/fnene.2010.00005
  52. Hammarlund-Udenaes M, Fridén M, Syvänen S, Gupta A (2008) On the rate and extent of drug delivery to the brain. Pharm Res 25:1737–1750PubMedCrossRefGoogle Scholar
  53. Haqqani AS, Stanimirovic DB (2011) Intercellular interactomics of human brain endothelial cells and th17 lymphocytes: a novel strategy for identifying therapeutic targets of CNS inflammation. Cardiovasc Psychiatry Neurol 2011:175364PubMedGoogle Scholar
  54. Hemsley KM, Hopwood JJ (2010) Lessons learnt from animal models: pathophysiology of neuropathic lysosomal storage disorders. J Inherit Metab Dis 33:363–371PubMedCrossRefGoogle Scholar
  55. Hervé F, Ghinea N, Scherrmann JM (2008) CNS delivery via adsorptive transcytosis. AAPS J 10:455–472PubMedCrossRefGoogle Scholar
  56. Iadecola C, Nedergaard M (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10:1369–1376PubMedCrossRefGoogle Scholar
  57. Ishikawa T, Saito H, Hirano H, Inoue Y, Ikegami Y (2012) Human ABC transporter ABCG2 in cancer chemotherapy: drug molecular design to circumvent multidrug resistance. Meth Mol Biol 910:267–278CrossRefGoogle Scholar
  58. Jolly RD, Marshall NR, Perrott MR, Dittmer KE, Hemsley KM, Beard H (2011) Intracisternal enzyme replacement therapy in lysosomal storage diseases: routes of absorption into brain. Neuropathol Appl Neurobiol 37:414–422PubMedCrossRefGoogle Scholar
  59. Jones AR, Shusta EV (2007) Blood–brain barrier transport of therapeutics via receptor-mediation. Pharm Res 24:1759–1771PubMedCrossRefGoogle Scholar
  60. Kandel ER, Schwartz J, Jessel T (2000) Principles of neural science, 4th edn. McGraw Hill, New YorkGoogle Scholar
  61. Katona RL, Sinkó I, Holló G et al (2008) A combined artificial chromosome-stem cell therapy method in a model experiment aimed at the treatment of Krabbe’s disease in the Twitcher mouse. Cell Mol Life Sci 65:3830–3838PubMedCrossRefGoogle Scholar
  62. Killedar S, Dirosario J, Divers E, Popovich PG, McCarty DM, Fu H (2010) Mucopolysaccharidosis IIIB, a lysosomal storage disease, triggers a pathogenic CNS autoimmune response. J Neuroinflammation 7:39. doi:10.1186/1742-2094-7-39 PubMedCrossRefGoogle Scholar
  63. Kloska A, Narajczyk M, Jakóbkiewicz-Banecka J et al (2012) Synthetic genistein derivatives as modulators of glycosaminoglycan storage. J Transl Med 10:153. doi:10.1186/1479-5876-10-153 PubMedCrossRefGoogle Scholar
  64. Koshiba S, An R, Saito H, Wakabayashi K, Tamura A, Ishikawa T (2008) Human ABC transporters ABCG2 (BCRP) and ABCG4. Xenobiotica 38:863–888PubMedCrossRefGoogle Scholar
  65. Kovács R, Papageorgiou I, Heinemann U (2011) Slice cultures as a model to study neurovascular coupling and blood brain barrier in vitro. Cardiovasc Psychiatry Neurol 2011:646958. doi:10.1155/2011/646958 PubMedGoogle Scholar
  66. Liddelow SA, Temple S, Møllgård K et al (2012) Molecular characterisation of transport mechanisms at the developing mouse blood-CSF interface: a transcriptome approach. PLoS One 7:e33554PubMedCrossRefGoogle Scholar
  67. Lippmann ES, Azarin SM, Kay JE et al (2012) Derivation of blood–brain barrier endothelial cells from human pluripotent stem cells. Nat Biotechnol 30:783–791PubMedCrossRefGoogle Scholar
  68. Liu M, Hou T, Feng Z, Li Y (2012) The flexibility of P-glycoprotein for its poly-specific drug binding from molecular dynamics simulations. J Biomol Struct Dyn Aug 13. [Epub ahead of print] PubMed PMID: 22888853Google Scholar
  69. Lockman PR, Mittapalli RK, Taskar KS et al (2010) Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res 16:5664–5678PubMedCrossRefGoogle Scholar
  70. Lohmann C, Hüwel S, Galla HJ (2002) Predicting blood–brain barrier permeability of drugs: evaluation of different in vitro assays. J Drug Target 10:263–276PubMedCrossRefGoogle Scholar
  71. Lundquist S, Renftel M, Brillault J, Fenart L, Cecchelli R, Dehouck MP (2002) Prediction of drug transport through the blood–brain barrier in vivo: a comparison between two in vitro cell models. Pharm Res 19:976–981PubMedCrossRefGoogle Scholar
  72. Malinowska M, Wilkinson FL, Langford-Smith KJ et al (2010) Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease. PLoS One 5:e14192PubMedCrossRefGoogle Scholar
  73. Markoutsa E, Pampalakis G, Niarakis A et al (2011) Uptake and permeability studies of BBB-targeting immunoliposomes using the hCMEC/D3 cell line. Eur J Pharm Biopharm 77:265–274PubMedCrossRefGoogle Scholar
  74. Markoutsa E, Papadia K, Clemente C, Flores O, Antimisiaris SG (2012) Anti-Aβ-MAb and dually decorated nanoliposomes: effect of Aβ1-42 peptides on interaction with hCMEC/D3 cells. Eur J Pharm Biopharm 81:49–56PubMedCrossRefGoogle Scholar
  75. Martin I (2004) Prediction of blood–brain barrier penetration: are we missing the point? Drug Discov Today 9:161–162PubMedCrossRefGoogle Scholar
  76. Matthes F, Wölte P, Böckenhoff A et al (2011) Transport of arylsulfatase A across the blood-brain barrier in vitro. J Biol Chem 286:17487–17494Google Scholar
  77. Matzner U, Herbst E, Hedayati KK et al (2005) Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy. Hum Mol Genet 14:1139–1152PubMedCrossRefGoogle Scholar
  78. Matzner U, Lüllmann-Rauch R, Stroobants S et al (2009) Enzyme replacement improves ataxic gait and central nervous system histopathology in a mouse model of metachromatic leukodystrophy. Mol Ther 17:600–606PubMedCrossRefGoogle Scholar
  79. Mayor S, Pagano RE (2007) Pathways of clathrin-independent endocytosis. Nat Rev Mol Cell Biol 8:603–612PubMedCrossRefGoogle Scholar
  80. Miller DS (2010) Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier. Trends Pharmacol Sci 31:246–254PubMedCrossRefGoogle Scholar
  81. Muldoon LL, Alvarez JI, Begley DJ et al (2013) Immunologic privilege in the central nervous system and the blood–brain barrier. J Cereb Blood Flow Metab 33:13–21. doi:10.1038/jcbfm.2012.153 Google Scholar
  82. Naik P, Cucullo L (2012) In vitro blood–brain barrier models: current and perspective technologies. J Pharm Sci 101:1337–1354PubMedCrossRefGoogle Scholar
  83. Nakagawa S, Deli MA, Kawaguchi H et al (2009) A new blood–brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem Int 54:253–263PubMedCrossRefGoogle Scholar
  84. Neuwelt EA (2004) Mechanisms of disease: the blood–brain barrier. Neurosurgery 54:131–140, discussion 141–142PubMedCrossRefGoogle Scholar
  85. Neuwelt EA, Bauer B, Fahlke C et al (2011) Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci 12:169–182PubMedCrossRefGoogle Scholar
  86. Ni Z, Bikadi Z, Rosenberg MF, Mao Q (2010) Structure and function of the human breast cancer resistance protein (BCRP/ABCG2). Curr Drug Metab 11:603–617PubMedCrossRefGoogle Scholar
  87. Ni Z, Bikadi Z, Shuster DL, Zhao C, Rosenberg MF, Mao Q (2011) Identification of proline residues in or near the transmembrane helices of the human breast cancer resistance protein (BCRP/ABCG2) that are important for transport activity and substrate specificity. Biochemistry 50:8057–8066PubMedCrossRefGoogle Scholar
  88. Ogunshola OO (2011) In vitro modeling of the blood–brain barrier: simplicity versus complexity. Curr Pharm Des 17:2755–2761PubMedCrossRefGoogle Scholar
  89. Ohtsuki S, Terasaki T (2007) Contribution of carrier-mediated transport systems to the blood–brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development. Pharm Res 24:1745–1758PubMedCrossRefGoogle Scholar
  90. Pajouhesh H, Lenz GR (2005) Medicinal chemical properties of successful central nervous system drugs. NeuroRx 2:541–553PubMedCrossRefGoogle Scholar
  91. Pardridge WM, Eisenberg J, Cefalu WT (1985) Absence of albumin receptor on brain capillaries in vivo or in vitro. Am J Physiol 249:E264–E267PubMedGoogle Scholar
  92. Parenti G, Pignata C, Vajro P, Salerno M (2013) New strategies for the treatment of lysosomal storage diseases (review). Int J Mol Med 31:11–20Google Scholar
  93. Patabendige A, Skinner RA, Abbott NJ (2012) Establishment of a simplified in vitro porcine blood–brain barrier model with high transendothelial electrical resistance. Brain Res Jul 10. [Epub ahead of print] PubMed PMID: 22789905Google Scholar
  94. Platt FM, Jeyakumar M (2008) Substrate reduction therapy. Acta Paediatr Suppl 97:88–93PubMedCrossRefGoogle Scholar
  95. Prinz M, Priller J, Sisodia SS, Ransohoff RM (2011) Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci 14:1227–1235PubMedCrossRefGoogle Scholar
  96. 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
  97. 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 PubMedCrossRefGoogle Scholar
  98. Reichel A (2009) Addressing central nervous system (CNS) penetration in drug discovery: basics and implications of the evolving new concept. Chem Biodivers 6:2030–2049PubMedCrossRefGoogle Scholar
  99. Reichel A, Begley DJ, Abbott NJ (2003) An overview of in vitro techniques for blood–brain barrier studies. Meth Mol Med 89:307–324Google Scholar
  100. Reinhardt RR, Bondy CA (1994) Insulin-like growth factors cross the blood–brain barrier. Endocrinology 135:1753–1761PubMedCrossRefGoogle Scholar
  101. Roberts AL, Fletcher JM, Moore L, Byers S (2010) Trans-generational exposure to low levels of rhodamine B does not adversely affect litter size or liver function in murine mucopolysaccharidosis type IIIA. Mol Genet Metab 101:208–213PubMedCrossRefGoogle Scholar
  102. Saha A, Sarkar C, Singh SP et al (2012) The blood–brain barrier is disrupted in a mouse model of infantile neuronal ceroid lipofuscinosis: amelioration by resveratrol. Hum Mol Genet 21:2233–2244PubMedCrossRefGoogle Scholar
  103. Saunders NR, Liddelow SA, Dziegielewska KM (2012) Barrier mechanisms in the developing brain. Front Pharmacol 3:46. doi:10.3389/fphar.2012.00046 PubMedCrossRefGoogle Scholar
  104. Schiffmann R (2010) Therapeutic approaches for neuronopathic lysosomal storage disorders. J Inherit Metab Dis 33:373–379PubMedCrossRefGoogle Scholar
  105. Schultz ML, Tecedor L, Chang M, Davidson BL (2011) Clarifying lysosomal storage diseases. Trends Neurosci 34:401–410PubMedCrossRefGoogle Scholar
  106. Sengillo JD, Winkler EA, Walker CT, Sullivan JS, Johnson M, Zlokovic BV (2013) Deficiency in mural vascular cells coincides with blood–brain barrier disruption in Alzheimer’s disease. Brain Pathol 23:303–310Google Scholar
  107. Shah KK, Yang L, Abbruscato TJ (2012) In vitro models of the blood–brain barrier. Meth Mol Biol 814:431–449CrossRefGoogle Scholar
  108. Shawahna R, Uchida Y, Declèves X et al (2011) and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. Mol Pharm 8:1332–1341PubMedCrossRefGoogle Scholar
  109. Simionescu M, Popov D, Sima A (2009) Endothelial transcytosis in health and disease. Cell Tissue Res 335:27–40PubMedCrossRefGoogle Scholar
  110. Skinner RA, Gibson RM, Rothwell NJ, Pinteaux E, Penny JI (2009) Transport of interleukin-1 across cerebromicrovascular endothelial cells. Br J Pharmacol 156:1115–1123PubMedCrossRefGoogle Scholar
  111. Smith QR (2003) A review of blood–brain barrier transport techniques. Meth Mol Med 89:193–208Google Scholar
  112. Spencer BJ, Verma IM (2007) Targeted delivery of proteins across the blood–brain barrier. Proc Natl Acad Sci U S A 104:7594–7599PubMedCrossRefGoogle Scholar
  113. Stamatovic SM, Sladojevic N, Keep RF, Andjelkovic AV (2012) Relocalization of junctional adhesion molecule A during inflammatory stimulation of brain endothelial cells. Mol Cell Biol 32:3414–3427PubMedCrossRefGoogle Scholar
  114. Stanimirovic DB, Friedman A (2012) Pathophysiology of the neurovascular unit: disease cause or consequence? J Cereb Blood Flow Metab 32:1207–1221PubMedCrossRefGoogle Scholar
  115. Stroobants S, Gerlach D, Matthes F et al (2011) Intracerebroventricular enzyme infusion corrects central nervous system pathology and dysfunction in a mouse model of metachromatic leukodystrophy. Hum Mol Genet 20:2760–2769PubMedCrossRefGoogle Scholar
  116. Thanabalasundaram G, Schneidewind J, Pieper C, Galla HJ (2011) The impact of pericytes on the blood–brain barrier integrity depends critically on the pericyte differentiation stage. Int J Biochem Cell Biol 43:1284–1293PubMedCrossRefGoogle Scholar
  117. Tomanin R, Zanetti A, Zaccariotto E, D’Avanzo F, Bellettato CM, Scarpa M (2012) Gene therapy approaches for lysosomal storage disorders, a good model for the treatment of mendelian diseases. Acta Paediatr 101:692–701PubMedCrossRefGoogle Scholar
  118. Tosi G, Fano RA, Bondioli L et al (2011) Investigation on mechanisms of glycopeptide nanoparticles for drug delivery across the blood–brain barrier. Nanomedicine (Lond) 6:423–436CrossRefGoogle Scholar
  119. Tsinman O, Tsinman K, Sun N, Avdeef A (2011) Physicochemical selectivity of the BBB microenvironment governing passive diffusion-matching with a porcine brain lipid extract artificial membrane permeability model. Pharm Res 28:337–363PubMedCrossRefGoogle Scholar
  120. Tucker IG, Yang L, Mujoo H (2012) Delivery of drugs to the brain via the blood brain barrier using colloidal carriers. J Microencapsul 29:475–486PubMedCrossRefGoogle Scholar
  121. Urayama A, Grubb JH, Sly WS, Banks WA (2004) Developmentally regulated mannose 6-phosphate receptor-mediated transport of a lysosomal enzyme across the blood–brain barrier. Proc Natl Acad Sci U S A 101:12658–12663PubMedCrossRefGoogle Scholar
  122. Vandenhaute E, Dehouck L, Boucau MC et al (2011) Modelling the neurovascular unit and the blood–brain barrier with the unique function of pericytes. Curr Neurovasc Res 8:258–269PubMedCrossRefGoogle Scholar
  123. Vercauteren D, Vandenbroucke RE, Jones AT et al (2010) The use of inhibitors to study endocytic pathways of gene carriers: optimization and pitfalls. Mol Ther 18:561–569PubMedCrossRefGoogle Scholar
  124. Vezzani A, French J, Bartfai T, Baram TZ (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7:31–40PubMedCrossRefGoogle Scholar
  125. Visigalli I, Delai S, Politi LS et al (2010) Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model. Blood 116:5130–5139PubMedCrossRefGoogle Scholar
  126. Vitner EB, Platt FM, Futerman AH (2010) Common and uncommon pathogenic cascades in lysosomal storage diseases. J Biol Chem 285:20423–20427PubMedCrossRefGoogle Scholar
  127. Vitner EB, Farfel-Becker T, Eilam R, Biton I, Futerman AH (2012) Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher’s disease. Brain 135:1724–1735PubMedCrossRefGoogle Scholar
  128. Vogler C, Levy B, Grubb JH et al (2005) Overcoming the blood–brain barrier with high-dose enzyme replacement therapy in murine mucopolysaccharidosis VII. Proc Natl Acad Sci U S A 102:14777–14782PubMedCrossRefGoogle Scholar
  129. Wang P, Xue Y, Shang X, Liu Y (2010) Diphtheria toxin mutant CRM197-mediated transcytosis across blood–brain barrier in vitro. Cell Mol Neurobiol 30:717–725PubMedCrossRefGoogle Scholar
  130. Wen CJ, Zhang LW, Al-Suwayeh SA, Yen TC, Fang JY (2012) Theranostic liposomes loaded with quantum dots and apomorphine for brain targeting and bioimaging. Int J Nanomedicine 7:1599–1611PubMedGoogle Scholar
  131. Wilhelm I, Fazakas C, Krizbai IA (2011) In vitro models of the blood–brain barrier. Acta Neurobiol Exp (Wars) 71:113–128Google Scholar
  132. Winkler EA, Bell RD, Zlokovic BV (2011) Central nervous system pericytes in health and disease. Nat Neurosci 14:1398–1405PubMedCrossRefGoogle Scholar
  133. Winkler EA, Sengillo JD, Bell RD, Wang J, Zlokovic BV (2012) Blood-spinal cord barrier pericyte reductions contribute to increased capillary permeability. J Cereb Blood Flow Metab 32:1841–1852PubMedCrossRefGoogle Scholar
  134. Winkler EA, Sengillo JD, Sullivan JS, Henkel JS, Appel SH, Zlokovic BV (2013) Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol 125:111–120PubMedCrossRefGoogle Scholar
  135. Wittkowski W (1998) Tanycytes and pituicytes: morphological and functional aspects of neuroglial interaction. Microsc Res Tech 41:29–42PubMedCrossRefGoogle Scholar
  136. Ylikangas H, Peura L, Malmioja K et al (2012) Structure-activity relationship study of compounds binding to large amino acid transporter 1 (LAT1) based on pharmacophore modeling and in situ rat brain perfusion. Eur J Pharm Sci 84:523–531. doi:10.1016/j.ejps.2012.11.014
  137. Zlokovic BV (2005) Neurovascular mechanisms of Alzheimer’s neurodegeneration. Trends Neurosci 28:202–208PubMedCrossRefGoogle Scholar
  138. Zlokovic BV (2010) Neurodegeneration and the neurovascular unit. Nat Med 16:1370–1371PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.BBB Group, Institute of Pharmaceutical ScienceKing’s College LondonLondonUK

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