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

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  • Published:
Journal of Inherited Metabolic Disease

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.

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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

K p,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

LogD octanol :

log compound distribution coefficient octanol/buffer at given pH

LogP octanol :

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

P app :

apparent permeability

PBEC:

porcine brain endothelial cells (primary)

PBEC/As:

PBEC co-cultured with rat astrocytes

PDGF-B:

platelet-derived growth factor B

P e :

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

  • 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 371–396

    Google Scholar 

  • Abbott NJ (2004a) Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int 45:545–552

    Article  PubMed  CAS  Google Scholar 

  • 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 1:407–416

    Article  CAS  Google Scholar 

  • Abbott NJ, Friedman A (2012) Overview and introduction: the blood–brain barrier in health and disease. Epilepsia 53(Suppl 6:1–6)

    Google Scholar 

  • Abbott NJ, Rönnbäck L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7:41–53

    Article  PubMed  CAS  Google Scholar 

  • Abbott NJ, Dolman DE, Patabendige AK (2008) Assays to predict drug permeation across the blood–brain barrier, and distribution to brain. Curr Drug Metab 9:901–910

    Article  PubMed  CAS  Google Scholar 

  • Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood–brain barrier. Neurobiol Dis 37:13–25

    Article  PubMed  CAS  Google Scholar 

  • Anson DS, McIntyre C, Byers S (2011) Therapies for neurological disease in the mucopolysaccharidoses. Curr Gene Ther 11:132–143

    Article  PubMed  CAS  Google Scholar 

  • 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 103:18–25

    Article  PubMed  CAS  Google Scholar 

  • Armulik A, Genové G, Mäe M et al (2010) Pericytes regulate the blood–brain barrier. Nature 468:557–561

    Article  PubMed  CAS  Google Scholar 

  • Armulik A, Genové G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21:193–215

    Article  PubMed  CAS  Google Scholar 

  • 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 43:109–124

    Article  PubMed  CAS  Google Scholar 

  • Avdeef A (2012) Absorption and drug development: Solubility, permeability, and charge, 2nd edn. Wiley, Hoboken, p 698pp

    Book  Google Scholar 

  • Begley DJ, Brightman MW (2003) Structural and functional aspects of the blood–brain barrier. Progr Drug Res 61:39–78

    CAS  Google Scholar 

  • Begley DJ, Pontikis CC, Scarpa M (2008) Lysosomal storage diseases and the blood–brain barrier. Curr Pharm Des 14:1566–1580

    Article  PubMed  CAS  Google Scholar 

  • 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 68:409–427

    Article  PubMed  CAS  Google Scholar 

  • Bellettato CM, Scarpa M (2010) Pathophysiology of neuropathic lysosomal storage disorders. J Inherit Metab Dis 33:347–362

    Article  PubMed  CAS  Google Scholar 

  • Benarroch EE (2011) Circumventricular organs: receptive and homeostatic functions and clinical implications. Neurology 77:1198–1204

    Article  PubMed  Google Scholar 

  • 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:e25815

    Article  PubMed  CAS  Google Scholar 

  • 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:e43310

    Article  PubMed  CAS  Google Scholar 

  • 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:e30341

    Article  PubMed  CAS  Google Scholar 

  • 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 15:254–264

    Article  PubMed  CAS  Google Scholar 

  • 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 22:849–859

    PubMed  CAS  Google Scholar 

  • 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–E848

    Article  PubMed  CAS  Google Scholar 

  • 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 36:165–178

    Article  PubMed  CAS  Google Scholar 

  • Cecchelli R, Berezowski V, Lundquist S et al (2007) Modelling of the blood–brain barrier in drug discovery and development. Nat Rev Drug Discov 6:650–661

    Article  PubMed  CAS  Google Scholar 

  • 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 20:1393–1399

    Article  PubMed  CAS  Google Scholar 

  • Costantino L, Boraschi D (2012) Is there a clinical future for polymeric nanoparticles as brain-targeting drug delivery agents? Drug Discov Today 17:367–378

    Article  PubMed  CAS  Google Scholar 

  • 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 38:121–137

    Article  PubMed  CAS  Google Scholar 

  • 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 106:641–646

    Article  PubMed  CAS  Google Scholar 

  • Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468:562–566

    Article  PubMed  CAS  Google Scholar 

  • 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 107:1518–1528

    Article  PubMed  CAS  Google Scholar 

  • 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 25:59–127

    Article  PubMed  Google Scholar 

  • 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–H1158

    PubMed  CAS  Google Scholar 

  • Dickson PI, Chen AH (2011) Intrathecal enzyme replacement therapy for mucopolysaccharidosis I: translating success in animal models to patients. Curr Pharm Biotechnol 12:946–955

    Article  PubMed  CAS  Google Scholar 

  • 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 91:61–68

    Article  PubMed  CAS  Google Scholar 

  • 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:e39565

    Article  PubMed  CAS  Google Scholar 

  • 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 6:1161–1174

    Article  PubMed  CAS  Google Scholar 

  • Engelhardt B, Ransohoff RM (2012) Capture, crawl, cross: the T cell code to breach the blood–brain barriers. Trends Immunol 33:579–589

    Article  PubMed  CAS  Google Scholar 

  • 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 20:1375–1386

    Article  PubMed  CAS  Google Scholar 

  • Fillebeen C, Descamps L, Dehouck MP et al (1999) Receptor-mediated transcytosis of lactoferrin through the blood–brain barrier. J Biol Chem 274:7011–7017

    Article  PubMed  CAS  Google Scholar 

  • 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 818:65–71

    Article  PubMed  CAS  Google Scholar 

  • 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 19:1025–1033

    Article  PubMed  CAS  Google Scholar 

  • 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:e16601

    Article  PubMed  CAS  Google Scholar 

  • 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 80:491–503

    Article  PubMed  CAS  Google Scholar 

  • 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 12:742–749

    Article  PubMed  CAS  Google Scholar 

  • Gleeson MP (2008) Generation of a set of simple, interpretable ADMET rules of thumb. J Med Chem 51:817–834

    Article  PubMed  CAS  Google Scholar 

  • 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 105:2616–2621

    Article  PubMed  CAS  Google Scholar 

  • Grubb JH, Vogler C, Sly WS (2010) New strategies for enzyme replacement therapy for lysosomal storage diseases. Rejuvenation Res 13:229–236

    Article  PubMed  CAS  Google Scholar 

  • 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 159:838–844

    Article  PubMed  CAS  Google Scholar 

  • 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

  • Hammarlund-Udenaes M, Fridén M, Syvänen S, Gupta A (2008) On the rate and extent of drug delivery to the brain. Pharm Res 25:1737–1750

    Article  PubMed  CAS  Google Scholar 

  • 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 2011:175364

    PubMed  Google Scholar 

  • Hemsley KM, Hopwood JJ (2010) Lessons learnt from animal models: pathophysiology of neuropathic lysosomal storage disorders. J Inherit Metab Dis 33:363–371

    Article  PubMed  CAS  Google Scholar 

  • Hervé F, Ghinea N, Scherrmann JM (2008) CNS delivery via adsorptive transcytosis. AAPS J 10:455–472

    Article  PubMed  Google Scholar 

  • Iadecola C, Nedergaard M (2007) Glial regulation of the cerebral microvasculature. Nat Neurosci 10:1369–1376

    Article  PubMed  CAS  Google Scholar 

  • 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 910:267–278

    Article  CAS  Google Scholar 

  • 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 37:414–422

    Article  PubMed  CAS  Google Scholar 

  • Jones AR, Shusta EV (2007) Blood–brain barrier transport of therapeutics via receptor-mediation. Pharm Res 24:1759–1771

    Article  PubMed  CAS  Google Scholar 

  • Kandel ER, Schwartz J, Jessel T (2000) Principles of neural science, 4th edn. McGraw Hill, New York

    Google Scholar 

  • 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 65:3830–3838

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Koshiba S, An R, Saito H, Wakabayashi K, Tamura A, Ishikawa T (2008) Human ABC transporters ABCG2 (BCRP) and ABCG4. Xenobiotica 38:863–888

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • 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:e33554

    Article  PubMed  CAS  Google Scholar 

  • Lippmann ES, Azarin SM, Kay JE et al (2012) Derivation of blood–brain barrier endothelial cells from human pluripotent stem cells. Nat Biotechnol 30:783–791

    Article  PubMed  CAS  Google Scholar 

  • 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: 22888853

  • 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 16:5664–5678

    Article  PubMed  CAS  Google Scholar 

  • Lohmann C, Hüwel S, Galla HJ (2002) Predicting blood–brain barrier permeability of drugs: evaluation of different in vitro assays. J Drug Target 10:263–276

    Article  PubMed  CAS  Google Scholar 

  • 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 19:976–981

    Article  PubMed  CAS  Google Scholar 

  • 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:e14192

    Article  PubMed  CAS  Google Scholar 

  • 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 77:265–274

    Article  PubMed  CAS  Google Scholar 

  • 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 81:49–56

    Article  PubMed  CAS  Google Scholar 

  • Martin I (2004) Prediction of blood–brain barrier penetration: are we missing the point? Drug Discov Today 9:161–162

    Article  PubMed  Google Scholar 

  • Matthes F, Wölte P, Böckenhoff A et al (2011) Transport of arylsulfatase A across the blood-brain barrier in vitro. J Biol Chem 286:17487–17494

    Google Scholar 

  • 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 14:1139–1152

    Article  PubMed  CAS  Google Scholar 

  • 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 17:600–606

    Article  PubMed  CAS  Google Scholar 

  • Mayor S, Pagano RE (2007) Pathways of clathrin-independent endocytosis. Nat Rev Mol Cell Biol 8:603–612

    Article  PubMed  CAS  Google Scholar 

  • Miller DS (2010) Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier. Trends Pharmacol Sci 31:246–254

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Naik P, Cucullo L (2012) In vitro blood–brain barrier models: current and perspective technologies. J Pharm Sci 101:1337–1354

    Article  PubMed  CAS  Google Scholar 

  • 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 54:253–263

    Article  PubMed  CAS  Google Scholar 

  • Neuwelt EA (2004) Mechanisms of disease: the blood–brain barrier. Neurosurgery 54:131–140, discussion 141–142

    Article  PubMed  Google Scholar 

  • Neuwelt EA, Bauer B, Fahlke C et al (2011) Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci 12:169–182

    Article  PubMed  CAS  Google Scholar 

  • Ni Z, Bikadi Z, Rosenberg MF, Mao Q (2010) Structure and function of the human breast cancer resistance protein (BCRP/ABCG2). Curr Drug Metab 11:603–617

    Article  PubMed  CAS  Google Scholar 

  • 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 50:8057–8066

    Article  PubMed  CAS  Google Scholar 

  • Ogunshola OO (2011) In vitro modeling of the blood–brain barrier: simplicity versus complexity. Curr Pharm Des 17:2755–2761

    Article  PubMed  CAS  Google Scholar 

  • 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 24:1745–1758

    Article  PubMed  CAS  Google Scholar 

  • Pajouhesh H, Lenz GR (2005) Medicinal chemical properties of successful central nervous system drugs. NeuroRx 2:541–553

    Article  PubMed  Google Scholar 

  • Pardridge WM, Eisenberg J, Cefalu WT (1985) Absence of albumin receptor on brain capillaries in vivo or in vitro. Am J Physiol 249:E264–E267

    PubMed  CAS  Google Scholar 

  • Parenti G, Pignata C, Vajro P, Salerno M (2013) New strategies for the treatment of lysosomal storage diseases (review). Int J Mol Med 31:11–20

    Google Scholar 

  • 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: 22789905

  • Platt FM, Jeyakumar M (2008) Substrate reduction therapy. Acta Paediatr Suppl 97:88–93

    Article  PubMed  Google Scholar 

  • Prinz M, Priller J, Sisodia SS, Ransohoff RM (2011) Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci 14:1227–1235

    Article  PubMed  CAS  Google Scholar 

  • Ransohoff RM, Engelhardt B (2012) The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol 12:623–635

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Reichel A (2009) Addressing central nervous system (CNS) penetration in drug discovery: basics and implications of the evolving new concept. Chem Biodivers 6:2030–2049

    Article  PubMed  CAS  Google Scholar 

  • Reichel A, Begley DJ, Abbott NJ (2003) An overview of in vitro techniques for blood–brain barrier studies. Meth Mol Med 89:307–324

    CAS  Google Scholar 

  • Reinhardt RR, Bondy CA (1994) Insulin-like growth factors cross the blood–brain barrier. Endocrinology 135:1753–1761

    Article  PubMed  CAS  Google Scholar 

  • 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 101:208–213

    Article  PubMed  CAS  Google Scholar 

  • 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 21:2233–2244

    Article  PubMed  CAS  Google Scholar 

  • Saunders NR, Liddelow SA, Dziegielewska KM (2012) Barrier mechanisms in the developing brain. Front Pharmacol 3:46. doi:10.3389/fphar.2012.00046

    Article  PubMed  Google Scholar 

  • Schiffmann R (2010) Therapeutic approaches for neuronopathic lysosomal storage disorders. J Inherit Metab Dis 33:373–379

    Article  PubMed  CAS  Google Scholar 

  • Schultz ML, Tecedor L, Chang M, Davidson BL (2011) Clarifying lysosomal storage diseases. Trends Neurosci 34:401–410

    Article  PubMed  CAS  Google Scholar 

  • 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 23:303–310

    Google Scholar 

  • Shah KK, Yang L, Abbruscato TJ (2012) In vitro models of the blood–brain barrier. Meth Mol Biol 814:431–449

    Article  CAS  Google Scholar 

  • 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 8:1332–1341

    Article  PubMed  CAS  Google Scholar 

  • Simionescu M, Popov D, Sima A (2009) Endothelial transcytosis in health and disease. Cell Tissue Res 335:27–40

    Article  PubMed  Google Scholar 

  • Skinner RA, Gibson RM, Rothwell NJ, Pinteaux E, Penny JI (2009) Transport of interleukin-1 across cerebromicrovascular endothelial cells. Br J Pharmacol 156:1115–1123

    Article  PubMed  CAS  Google Scholar 

  • Smith QR (2003) A review of blood–brain barrier transport techniques. Meth Mol Med 89:193–208

    CAS  Google Scholar 

  • Spencer BJ, Verma IM (2007) Targeted delivery of proteins across the blood–brain barrier. Proc Natl Acad Sci U S A 104:7594–7599

    Article  PubMed  CAS  Google Scholar 

  • 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 32:3414–3427

    Article  PubMed  CAS  Google Scholar 

  • Stanimirovic DB, Friedman A (2012) Pathophysiology of the neurovascular unit: disease cause or consequence? J Cereb Blood Flow Metab 32:1207–1221

    Article  PubMed  CAS  Google Scholar 

  • 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 20:2760–2769

    Article  PubMed  CAS  Google Scholar 

  • 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 43:1284–1293

    Article  PubMed  CAS  Google Scholar 

  • 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 101:692–701

    Article  PubMed  CAS  Google Scholar 

  • 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) 6:423–436

    Article  CAS  Google Scholar 

  • 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 28:337–363

    Article  PubMed  CAS  Google Scholar 

  • Tucker IG, Yang L, Mujoo H (2012) Delivery of drugs to the brain via the blood brain barrier using colloidal carriers. J Microencapsul 29:475–486

    Article  PubMed  CAS  Google Scholar 

  • 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 101:12658–12663

    Article  PubMed  CAS  Google Scholar 

  • 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 8:258–269

    Article  PubMed  CAS  Google Scholar 

  • 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 18:561–569

    Article  PubMed  CAS  Google Scholar 

  • Vezzani A, French J, Bartfai T, Baram TZ (2011) The role of inflammation in epilepsy. Nat Rev Neurol 7:31–40

    Article  PubMed  CAS  Google Scholar 

  • 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 116:5130–5139

    Article  PubMed  CAS  Google Scholar 

  • Vitner EB, Platt FM, Futerman AH (2010) Common and uncommon pathogenic cascades in lysosomal storage diseases. J Biol Chem 285:20423–20427

    Article  PubMed  CAS  Google Scholar 

  • 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 135:1724–1735

    Article  PubMed  Google Scholar 

  • 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 102:14777–14782

    Article  PubMed  CAS  Google Scholar 

  • Wang P, Xue Y, Shang X, Liu Y (2010) Diphtheria toxin mutant CRM197-mediated transcytosis across blood–brain barrier in vitro. Cell Mol Neurobiol 30:717–725

    Article  PubMed  CAS  Google Scholar 

  • 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 7:1599–1611

    PubMed  CAS  Google Scholar 

  • Wilhelm I, Fazakas C, Krizbai IA (2011) In vitro models of the blood–brain barrier. Acta Neurobiol Exp (Wars) 71:113–128

    Google Scholar 

  • Winkler EA, Bell RD, Zlokovic BV (2011) Central nervous system pericytes in health and disease. Nat Neurosci 14:1398–1405

    Article  PubMed  CAS  Google Scholar 

  • 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 32:1841–1852

    Article  PubMed  CAS  Google Scholar 

  • 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 125:111–120

    Article  PubMed  CAS  Google Scholar 

  • Wittkowski W (1998) Tanycytes and pituicytes: morphological and functional aspects of neuroglial interaction. Microsc Res Tech 41:29–42

    Article  PubMed  CAS  Google Scholar 

  • 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

  • Zlokovic BV (2005) Neurovascular mechanisms of Alzheimer’s neurodegeneration. Trends Neurosci 28:202–208

    Article  PubMed  CAS  Google Scholar 

  • Zlokovic BV (2010) Neurodegeneration and the neurovascular unit. Nat Med 16:1370–1371

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The author is grateful to Dr DJ Begley for discussion, and Dr SR Yusof for artwork on Fig. 3.

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  1. BBB Group, Institute of Pharmaceutical Science, King’s College London, 150 Stamford St, London, SE1 9NH, UK

    N. Joan Abbott

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Communicated by: Maurizio Scarpa

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Abbott, N.J. Blood–brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis 36, 437–449 (2013). https://doi.org/10.1007/s10545-013-9608-0

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