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Engaging neuroscience to advance translational research in brain barrier biology

Nature Reviews Neuroscience volume 12, pages 169–182 (2011)Cite this article

Subjects

Key Points

  • Summary points that barrier scientists and neuroscientists need to collaborate on:

  • The neurovascular unit (NVU; comprising cellular and acellular elements of brain vessels, parenchymal cells and peripheral immune cells) incorporates three main functionalities — blood–brain barrier, neuroimmune axis and regulation of the cerebral blood flow — that are tightly integrated in brain physiology and play a part in the pathogenesis of numerous neurological diseases.

  • Exchange of information, nutrients and molecules between systemic and central compartments is controlled by the myriad of NVU transporters, which become dysfunctional in brain diseases such as epilepsy, brain tumours and Alzheimer's disease.

  • Targeting the intracellular signalling pathways that regulate selective blood–brain barrier transporters can potentially be used to enhance brain drug delivery, protect the brain from xenobiotics and prevent the pathogenesis and/or slow the progression of CNS diseases.

  • Neurogenesis and angiogenesis are co-regulated in embryonic and adult brains and are often controlled by the same classes of mediators. Novel methods for co-ordinated stimulation of both neuronal and vascular regeneration will be essential to develop successful brain repair strategies.

  • Progress in understanding and treating brain disease is contingent upon better understanding of the integral function of the NVU in disease, advancing the means to interrogate molecular and functional aspects of the NVU, and the development of strategies to deliver therapeutics across the blood–brain barrier.

  • New high resolution imaging techniques are providing stubstantial advances in the blood–brain barrier field and have a powerful potential for further progress. In particular, in vivo two-photon imaging studies of interactions of glial cells and blood cells with the blood–brain barrier are required to compose an integrated picture of blood–brain barrier regulation and function.

Abstract

The delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain is restricted by brain barriers, of which the most well known are the blood–brain barrier (BBB) and the blood–cerebrospinal fluid (CSF) barrier. Recent studies have shown numerous additional roles of these barriers, including an involvement in neurodevelopment, in the control of cerebral blood flow, and — when barrier integrity is impaired — in the pathology of many common CNS disorders such as Alzheimer's disease, Parkinson's disease and stroke.

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Figure 1: The extended neurovascular unit.
Figure 2: Primary transporters in the neurovascular unit.
Figure 3: Barrier interfaces.
Figure 4: MicroPET images of the head biodistribution of a calcium channel blocker.

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References

  1. Selkoe, D. J. Alzheimer disease: mechanistic understanding predicts novel therapies. Ann. Intern. Med. 140, 627–638 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Zlokovic, B. V. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 28, 202–208 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Iadecola, C. The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol. 120, 287–296 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kortekaas, R. et al. Blood–brain barrier dysfunction in parkinsonian midbrain in vivo. Ann. Neurol. 57, 176–179 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Gold, R., Linington, C. & Lassmann, H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129, 1953–1971 (2006).

    Article  PubMed  Google Scholar 

  6. Hemmer, B., Cepok, S., Zhou, D. & Sommer, N. Multiple sclerosis — a coordinated immune attack across the blood brain barrier. Curr. Neurovasc. Res. 1, 141–150 (2004).

    Article  PubMed  Google Scholar 

  7. Shlosberg, D., Benifla, M., Kaufer, D. & Friedman, A. Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury. Nature Rev. Neurol. 6, 393–403 (2010).

    Article  CAS  Google Scholar 

  8. Barzo, P., Marmarou, A., Fatouros, P., Hayasaki, K. & Corwin, F. Contribution of vasogenic and cellular edema to traumatic brain swelling measured by diffusion-weighted imaging. J. Neurosurg. 87, 900–907 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Jain, R. K. et al. Angiogenesis in brain tumours. Nature Rev. Neurosci. 8, 610–622 (2007).

    Article  CAS  Google Scholar 

  10. Papadopoulos, M. C. et al. Occludin expression in microvessels of neoplastic and non-neoplastic human brain. Neuropathol. Appl. Neurobiol. 27, 384–395 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Moskowitz, M. A., Lo, E. H. & Iadecola, C. The science of stroke: mechanisms in search of treatments. Neuron 67, 181–198 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Belayev, L., Busto, R., Zhao, W. & Ginsberg, M. D. Quantitative evaluation of blood–brain barrier permeability following middle cerebral artery occlusion in rats. Brain Res. 739, 88–96 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Benchenane, K., Lopez-Atalaya, J. P., Fernandez-Monreal, M., Touzani, O. & Vivien, D. Equivocal roles of tissue-type plasminogen activator in stroke-induced injury. Trends Neurosci. 27, 155–160 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Kuroiwa, T., Ting, P., Martinez, H. & Klatzo, I. The biphasic opening of the blood–brain barrier to proteins following temporary middle cerebral artery occlusion. Acta Neuropathol. 68, 122–129 (1985).

    Article  CAS  PubMed  Google Scholar 

  15. Navarro Mora, G. et al. Does pilocarpine-induced epilepsy in adult rats require status epilepticus? PLoS ONE 4, e5759 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Takano, T. et al. Astrocyte-mediated control of cerebral blood flow. Nature Neurosci. 9, 260–267 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Iadecola, C. & Nedergaard, M. Glial regulation of the cerebral microvasculature. Nature Neurosci. 10, 1369–1376 (2007). A comprehensive review of the role of astrocytes in the control of cerebral blood flow, highlighting some of the areas that require more research.

    Article  CAS  PubMed  Google Scholar 

  18. Stenman, J. M. et al. Canonical Wnt signalling regulates organ-specific assembly and differentiation of CNS vasculature. Science 322, 1247–1250 (2008). This study provides evidence of the brain-specific role of canonical Wnt signalling in differentiation of highly specialized CNS vasculature, including BBB phenotype.

    Article  CAS  PubMed  Google Scholar 

  19. Abbott, N. J., Ronnback, L. & Hansson, E. Astrocyte-endothelial interactions at the blood–brain barrier. Nature Rev. Neurosci. 7, 41–53 (2006). This review gives a detailed picture of astrocyte–endothelial interactions and signalling.

    Article  CAS  Google Scholar 

  20. Neuwelt, E. et al. Strategies to advance translational research into brain barriers. Lancet Neurol. 7, 84–96 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Perea, G., Navarrete, M. & Araque, A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci. 32, 421–431 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Araque, A., Parpura, V., Sanzgiri, R. P. & Haydon, P. G. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 22, 208–215 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Grotta, J. C., Jacobs, T. P., Koroshetz, W. J. & Moskowitz, M. A. Stroke program review group: an interim report. Stroke 39, 1364–1370 (2008).

    Article  PubMed  Google Scholar 

  24. Barres, B. A. The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60, 430–440 (2008). A concise and complete primer on the role of astrocytes in brain function, with emphasis on their role in BBB function.

    Article  CAS  PubMed  Google Scholar 

  25. Leybaert, L. Neurobarrier coupling in the brain: a partner of neurovascular and neurometabolic coupling? J. Cereb. Blood Flow Metab. 25, 2–16 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Lok, J. et al. Cell–cell signalling in the neurovascular unit. Neurochem. Res. 32, 2032–2045 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Daneman, R. et al. Wnt/beta-catenin signalling is required for CNS, but not non-CNS, angiogenesis. Proc. Natl Acad. Sci. USA 106, 641–646 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  28. McCarty, J. H. Cell adhesion and signalling networks in brain neurovascular units. Curr. Opin. Hematol. 16, 209–214 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  29. MacAulay, N. & Zeuthen, T. Water transport between CNS compartments: contributions of aquaporins and cotransporters. Neuroscience 168, 941–956 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Miller, D. S. Regulation of P-glycoprotein and other ABC drug transporters at the blood–brain barrier. Trends Pharmacol. Sci. 31, 246–254 (2010). A comprehensive, up-to-date survey of efflux transporters at the BBB, with a review of current knowledge of Pgp (the best studied efflux transporter) mechanisms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kimelberg, H. K. & Nedergaard, M. Functions of astrocytes and their potential as therapeutic targets. Neurotherapeutics 7, 338–353 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zlokovic, B. V. The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008). A very detailed analysis of BBB alterations, including its various transporters, in neurodegenerative disease.

    Article  CAS  PubMed  Google Scholar 

  33. Pedersen, S. F., O'Donnell, M. E., Anderson, S. E. & Cala, P. M. Physiology and pathophysiology of Na+/H+ exchange and Na+-K+-2Cl− cotransport in the heart, brain, and blood. Am. J. Physiol. Regul. Integr Comp. Physiol. 291, R1–R25 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Persidsky, Y., Ramirez, S. H., Haorah, J. & Kanmogne, G. D. Blood–brain barrier: structural components and function under physiologic and pathologic conditions. J. Neuroimmune Pharmacol. 1, 223–236 (2006).

    Article  PubMed  Google Scholar 

  35. Jin, R., Yang, G. & Li, G. Molecular insights and therapeutic targets for blood–brain barrier disruption in ischemic stroke: critical role of matrix metalloproteinases and tissue-type plasminogen activator. Neurobiol. Dis. 38, 376–385 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bell, R. D. et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409–427 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Madri, J. A. Modeling the neurovascular niche: implications for recovery from CNS injury. J. Physiol. Pharmacol. 60 (Suppl. 4), 95–104 (2009).

    Google Scholar 

  38. Ohtsuki, S. & Terasaki, T. 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 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Enerson, B. E. & Drewes, L. R. The rat blood–brain barrier transcriptome. J. Cereb. Blood Flow Metab. 26, 959–973 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Pardridge, W. M. Molecular biology of the blood–brain barrier. Methods Mol. Med. 89, 385–399 (2003).

    CAS  PubMed  Google Scholar 

  41. Torres, G. E. & Amara, S. G. Glutamate and monoamine transporters: new visions of form and function. Curr. Opin. Neurobiol. 17, 304–312 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Locher, K. P. Review. Structure and mechanism of ATP-binding cassette transporters. Phil. Trans. R. Soc. Lond. B 364, 239–245 (2009).

    CAS  Google Scholar 

  43. Melzer, N., Torres-Salazar, D. & Fahlke, C. A dynamic switch between inhibitory and excitatory currents in a neuronal glutamate transporter. Proc. Natl Acad. Sci. USA 102, 19214–19218 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bunch, L., Erichsen, M. N. & Jensen, A. A. Excitatory amino acid transporters as potential drug targets. Expert Opin. Ther. Targets. 13, 719–731 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Bridges, R. J. & Esslinger, C. S. The excitatory amino acid transporters: pharmacological insights on substrate and inhibitor specificity of the EAAT subtypes. Pharmacol. Ther. 107, 271–285 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Gonzalez, M. I. & Robinson, M. B. Neurotransmitter transporters: why dance with so many partners? Curr. Opin. Pharmacol. 4, 30–35 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Chen, L. M., Haddad, G. G. & Boron, W. F. Effects of chronic continuous hypoxia on the expression of SLC4A8 (NDCBE) in neonatal versus adult mouse brain. Brain Res. 1238, 85–92 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bevensee, M. O. & Boron, W. F. Effects of acute hypoxia on intracellular-pH regulation in astrocytes cultured from rat hippocampus. Brain Res. 1193, 143–152 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Chen, L. M. et al. Expression and localization of Na-driven Cl–HCO3– exchanger (SLC4A8) in rodent CNS. Neuroscience 153, 162–174 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Amiry-Moghaddam, M. et al. An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. Proc. Natl Acad. Sci. USA 100, 2106–2111 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Benfenati, V. & Ferroni, S. Water transport between CNS compartments: functional and molecular interactions between aquaporins and ion channels. Neuroscience 168, 926–940 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Speake, T., Freeman, L. J. & Brown, P. D. Expression of aquaporin 1 and aquaporin 4 water channels in rat choroid plexus. Biochim. Biophys. Acta 1609, 80–86 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Gunnarson, E., Zelenina, M. & Aperia, A. Regulation of brain aquaporins. Neuroscience 129, 947–955 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. King, L. S., Kozono, D. & Agre, P. From structure to disease: the evolving tale of aquaporin biology. Nature Rev. Mol. Cell Biol. 5, 687–698 (2004).

    Article  CAS  Google Scholar 

  55. Badaut, J., Lasbennes, F., Magistretti, P. J. & Regli, L. Aquaporins in brain: distribution, physiology, and pathophysiology. J. Cereb Blood Flow Metab. 22, 367–378 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Francesca, B. & Rezzani, R. Aquaporin and blood brain barrier. Curr. Neuropharmacol. 8, 92–96 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Musa-Aziz, R., Chen, L. M., Pelletier, M. F. & Boron, W. F. Relative CO2/NH3 selectivities of AQP1, AQP4, AQP5, AmtB, and RhAG. Proc. Natl Acad. Sci. USA 106, 5406–5411 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Rigor, R. R., Hawkins, B. T. & Miller, D. S. Activation of PKC isoform beta(I) at the blood–brain barrier rapidly decreases P-glycoprotein activity and enhances drug delivery to the brain. J. Cereb Blood Flow Metab. 30, 1373–1383 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Raffa, R. B. & Tallarida, R. J. Effects on the visual system might contribute to some of the cognitive deficits of cancer chemotherapy-induced 'chemo-fog'. J. Clin. Pharm. Ther. 35, 249–255 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hartz, A. M., Miller, D. S. & Bauer, B. Restoring blood–brain barrier P-glycoprotein reduces brain amyloid-beta in a mouse model of Alzheimer's disease. Mol. Pharmacol. 77, 715–723 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Loscher, W. & Potschka, H. Drug resistance in brain diseases and the role of drug efflux transporters. Nature Rev. Neurosci. 6, 591–602 (2005).

    Article  CAS  Google Scholar 

  62. Fletcher, J. I., Haber, M., Henderson, M. J. & Norris, M. D. ABC transporters in cancer: more than just drug efflux pumps. Nature Rev. Cancer 10, 147–156 (2010).

    Article  CAS  Google Scholar 

  63. Schinkel, A. H. P-Glycoprotein, a gatekeeper in the blood–brain barrier. Adv. Drug Deliv. Rev. 36, 179–194 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Bauer, B., Hartz, A. M. & Miller, D. S. Tumor necrosis factor alpha and endothelin-1 increase P-glycoprotein expression and transport activity at the blood–brain barrier. Mol. Pharmacol. 71, 667–675 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Hartz, A. M., Bauer, B., Fricker, G. & Miller, D. S. Rapid regulation of P-glycoprotein at the blood–brain barrier by endothelin-1. Mol. Pharmacol. 66, 387–394 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Hartz, A. M., Bauer, B., Fricker, G. & Miller, D. S. Rapid modulation of P-glycoprotein-mediated transport at the blood–brain barrier by tumor necrosis factor-alpha and lipopolysaccharide. Mol. Pharmacol. 69, 462–470 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Bankstahl, J. P., Hoffmann, K., Bethmann, K. & Loscher, W. Glutamate is critically involved in seizure-induced overexpression of P-glycoprotein in the brain. Neuropharmacology 54, 1006–1016 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Bauer, B. et al. Seizure-induced up-regulation of P-glycoprotein at the blood–brain barrier through glutamate and cyclooxygenase-2 signalling. Mol. Pharmacol. 73, 1444–1453 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Pekcec, A. et al. Targeting prostaglandin E2 EP1 receptors prevents seizure-associated P-glycoprotein up-regulation. J. Pharmacol. Exp. Ther. 330, 939–947 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Zibell, G. et al. Prevention of seizure-induced up-regulation of endothelial P-glycoprotein by COX-2 inhibition. Neuropharmacology 56, 849–855 (2009).

    Article  CAS  PubMed  Google Scholar 

  71. Schlichtiger, J. et al. Celecoxib treatment restores pharmacosensitivity in a rat model of pharmacoresistant epilepsy. Br. J. Pharmacol. 160, 1062–1071 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bauer, B. et al. In vivo activation of human pregnane X receptor tightens the blood–brain barrier to methadone through P-glycoprotein up-regulation. Mol. Pharmacol. 70, 1212–1219 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Wang, X., Sykes, D. B. & Miller, D. S. Constitutive androstane receptor-mediated up-regulation of ATP-driven xenobiotic efflux transporters at the blood–brain barrier. Mol. Pharmacol. 78, 376–383 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang, X., Hawkins, B. T. & Miller, D. S. Aryl hydrocarbon receptor-mediated up-regulation of ATP-driven xenobiotic efflux transporters at the blood–brain barrier. FASEB J. 25, 646–652 (2010).

    CAS  Google Scholar 

  75. Bauer, B., Hartz, A. M., Fricker, G. & Miller, D. S. Pregnane X receptor up-regulation of P-glycoprotein expression and transport function at the blood–brain barrier. Mol. Pharmacol. 66, 413–419 (2004).

    CAS  PubMed  Google Scholar 

  76. Dauchy, S. et al. ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood–brain barrier. J. Neurochem. 107, 1518–1528 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Narang, V. S. et al. Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood–brain barrier. Am. J. Physiol. Cell Physiol. 295, C440–450 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ott, M., Fricker, G. & Bauer, B. Pregnane X receptor (PXR) regulates P-glycoprotein at the blood–brain barrier: functional similarities between pig and human PXR. J. Pharmacol. Exp. Ther. 329, 141–149 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Miller, D. S., Bauer, B. & Hartz, A. M. Modulation of P-glycoprotein at the blood–brain barrier: opportunities to improve central nervous system pharmacotherapy. Pharmacol. Rev. 60, 196–209 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Hartz, A. M. & Bauer, B. Regulation of ABC transporters at the blood–brain barrier: new targets for CNS therapy. Mol. Interv. 10, 293–304 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Hawkins, B. T. & Davis, T. P. The blood–brain barrier/neurovascular unit in health and disease. Pharmacol. Rev. 57, 173–185 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Nitta, T. et al. Size-selective loosening of the blood–brain barrier in claudin-5-deficient mice. Journal of Cell Biology 161, 653–660 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Saitou, M. et al. Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol. Biol. Cell 11, 4131–4142 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Volterra, A. & Meldolesi, J. Astrocytes, from brain glue to communication elements: the revolution continues. Nature Rev. Neurosci. 6, 626–640 (2005).

    Article  CAS  Google Scholar 

  85. Wang, X. et al. Astrocytic Ca2+ signalling evoked by sensory stimulation in vivo. Nature Neurosci. 9, 816–823 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Ding, S. et al. Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus. J. Neurosci. 27, 10674–10684 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Takata, N. & Hirase, H. Cortical layer 1 and layer 2/3 astrocytes exhibit distinct calcium dynamics in vivo. PLoS ONE 3, e2525 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mulligan, S. J. & MacVicar, B. A. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431, 195–199 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Zonta, M. et al. Neuron-to-astrocyte signalling is central to the dynamic control of brain microcirculation. Nature Neurosci. 6, 43–50 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Koehler, R. C., Roman, R. J. & Harder, D. R. Astrocytes and the regulation of cerebral blood flow. Trends Neurosci. 30, 160–169 (2009).

    Article  CAS  Google Scholar 

  91. Haydon, P. G. & Carmignoto, G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiol. Rev. 86, 1009–1031 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Gordon, G. R., Choi, H. B., Rungta, R. L., Ellis-Davies, G. C. & MacVicar, B. A. Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature 456, 745–749 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Simard, M., Arcuino, G., Takano, T., Liu, Q. S. & Nedergaard, M. Signalling at the gliovascular interface. J. Neurosci. 23, 9254–9262 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Tam, S. J. & Watts, R. J. Connecting vascular and nervous system development: angiogenesis and the blood–brain barrier. Annu. Rev. Neurosci. 33, 379–408 (2010). A comprehensive, up-to-date review of parallels in angiogenesis and development of BBB properties.

    Article  CAS  PubMed  Google Scholar 

  95. Carmeliet, P. & Tessier-Lavigne, M. Common mechanisms of nerve and blood vessel wiring. Nature 436, 193–200 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Stubbs, D. et al. Neurovascular congruence during cerebral cortical development. Cereb Cortex 19, (Suppl. 1) I32–I41 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Javaherian, A. & Kriegstein, A. A stem cell niche for intermediate progenitor cells of the embryonic cortex. Cereb Cortex 19, (Suppl. 1) I70I77 (2009).

    Google Scholar 

  98. Risau, W. & Wolburg, H. Development of the blood–brain barrier. Trends Neurosci. 13, 174–178 (1990).

    Article  CAS  PubMed  Google Scholar 

  99. Harrigan, M. R. Angiogenic factors in the central nervous system. Neurosurgery 53, 639–660 (2003).

    Article  PubMed  Google Scholar 

  100. Risau, W. Mechanisms of angiogenesis. Nature 386, 671–674 (1997).

    Article  CAS  PubMed  Google Scholar 

  101. Stone, J. et al. Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. J. Neurosci. 15, 4738–4747 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Jain, R. K. Molecular regulation of vessel maturation. Nature Med. 9, 685–693 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Greenberg, D. A. & Jin, K. From angiogenesis to neuropathology. Nature 438, 954–959 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Dziegielewska, K. M. et al. Plasma proteins in fetal sheep brain: blood–brain barrier and intracerebral distribution. J. Physiol. 318, 239–250 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Dziegielewska, K. M. et al. Studies of the development of brain barrier systems to lipid insoluble molecules in fetal sheep. J. Physiol. 292, 207–231 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Evans, C. A., Reynolds, J. M., Reynolds, M. L., Saunders, N. R. & Segal, M. B. The development of a blood–brain barrier mechanism in foetal sheep. J. Physiol. 238, 371–386 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Mollgard, K. & Saunders, N. R. The development of the human blood–brain and blood–CSF barriers. Neuropathol. Appl. Neurobiol. 12, 337–358 (1986).

    Article  CAS  PubMed  Google Scholar 

  108. Johansson, P. A., Dziegielewska, K. M., Liddelow, S. A. & Saunders, N. R. The blood–CSF barrier explained: when development is not immaturity. Bioessays 30, 237–248 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Ek, C. J., Dziegielewska, K. M., Stolp, H. & Saunders, N. R. Functional effectiveness of the blood–brain barrier to small water-soluble molecules in developing and adult opossum (Monodelphis domestica). J. Comp. Neurol. 496, 13–26 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Gazzin, S. et al. Differential expression of the multidrug resistance-related proteins ABCb1 and ABCc1 between blood–brain interfaces. J. Comp. Neurol. 510, 497–507 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Kalabis, G. M., Petropoulos, S., Gibb, W. & Matthews, S. G. Breast cancer resistance protein (Bcrp1/Abcg2) in mouse placenta and yolk sac: ontogeny and its regulation by progesterone. Placenta 28, 1073–1081 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Ek, C. J. et al. Efflux mechanisms at the developing brain barriers: ABC-transporters in the fetal and postnatal rat. Toxicol. Lett. 197, 51–59 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Daneman, R., Zhou, L., Kebede, A. A. & Barres, B. A. Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468, 562–566 (2010). A comprehensive study of the involvement of pericytes in BBB development.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Daneman, R. et al. The mouse blood–brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS ONE 5, e13741 (2010). A large-scale screen of gene expression in adult and postnatal cerebral endothelial cells compared with liver and lung endothelial cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wosik, K. et al. Angiotensin II controls occludin function and is required for blood brain barrier maintenance: relevance to multiple sclerosis. J. Neurosci. 27, 9032–9042 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Liddelow, S. A. et al. Cellular transfer of macromolecules across the developing choroid plexus of Monodelphis domestica. Eur. J. Neurosci. 29, 253–266 (2009).

    Article  PubMed  Google Scholar 

  117. Liddelow, S. A. et al. Modification of protein transfer across blood/cerebrospinal fluid barrier in response to altered plasma protein composition during development. Eur. J. Neurosci. 33, 391–400 (2010).

    Article  PubMed  Google Scholar 

  118. Krasney, J. A. A neurogenic basis for acute altitude illness. Med. Sci. Sports Exerc. 26, 195–208 (1994).

    Article  CAS  PubMed  Google Scholar 

  119. Severinghaus, J. W. Hypothetical roles of angiogenesis, osmotic swelling, and ischemia in high-altitude cerebral edema. J. Appl. Physiol. 79, 375–379 (1995).

    Article  CAS  PubMed  Google Scholar 

  120. Wilson, M. H., Newman, S. & Imray, C. H. The cerebral effects of ascent to high altitudes. Lancet Neurol. 8, 175–191 (2009).

    Article  CAS  PubMed  Google Scholar 

  121. Laursen, H. Cerebral vessels and glial cells in liver disease. A morphometric and electron microscopic investigation. Acta Neurol. Scand. 65, 381–412 (1982).

    Article  CAS  PubMed  Google Scholar 

  122. Martinez, A. Electron microscopy in human hepatic encephalopathy. Acta Neuropathol. 11, 82–86 (1968).

    Article  CAS  PubMed  Google Scholar 

  123. Tripathi, A. K., Sha, W., Shulaev, V., Stins, M. F. & Sullivan, D. J. Jr. Plasmodium falciparum-infected erythrocytes induce NF-kappaB regulated inflammatory pathways in human cerebral endothelium. Blood 114, 4243–4252 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Tripathi, A. K., Sullivan, D. J. & Stins, M. F. Plasmodium falciparum-infected erythrocytes increase intercellular adhesion molecule 1 expression on brain endothelium through NF-kappaB. Infect. Immun. 74, 3262–3270 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Tripathi, A. K., Sullivan, D. J. & Stins, M. F. Plasmodium falciparum-infected erythrocytes decrease the integrity of human blood–brain barrier endothelial cell monolayers. J. Infect. Dis. 195, 942–950 (2007).

    Article  PubMed  Google Scholar 

  126. Engelhardt, B. & Kappos, L. Natalizumab: targeting alpha4-integrins in multiple sclerosis. Neurodegener. Dis. 5, 16–22 (2008).

    Article  CAS  PubMed  Google Scholar 

  127. Spencer, B. J. & Verma, I. M. Targeted delivery of proteins across the blood–brain barrier. Proc. Natl Acad. Sci. USA 104, 7594–7599 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Hoffman, A. S. The origins and evolution of 'controlled' drug delivery systems. J. Control Release 132, 153–163 (2008).

    Article  CAS  PubMed  Google Scholar 

  129. Pardridge, W. M. Biopharmaceutical drug targeting to the brain. J. Drug Target 18, 157–167 (2010). A review of methods for delivering large molecules to the brain.

    Article  CAS  PubMed  Google Scholar 

  130. Vastag, B. Biotechnology: Crossing the barrier. Nature 466, 916–918 (2010).

    Article  CAS  PubMed  Google Scholar 

  131. Farkas, E., De Jong, G. I., de Vos, R. A., Jansen Steur, E. N. & Luiten, P. G. Pathological features of cerebral cortical capillaries are doubled in Alzheimer's disease and Parkinson's disease. Acta Neuropathol. 100, 395–402 (2000).

    Article  CAS  PubMed  Google Scholar 

  132. Levy, E. et al. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248, 1124–1126 (1990).

    Article  CAS  PubMed  Google Scholar 

  133. Herzig, M. C. et al. Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nature Neurosci. 7, 954–960 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Premkumar, D. R., Cohen, D. L., Hedera, P., Friedland, R. P. & Kalaria, R. N. Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer's disease. Am. J. Pathol. 148, 2083–2095 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Westerlund, M. et al. Association of a polymorphism in the ABCB1 gene with Parkinson's disease. Parkinsonism Relat Disord. 15, 422–424 (2009).

    Article  PubMed  Google Scholar 

  136. Weber, Y. G. et al. GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. J. Clin. Invest. 118, 2157–2168 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Suls, A. et al. Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain 131, 1831–1844 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Newmeyer, A., Cecil, K. M., Schapiro, M., Clark, J. F. & Degrauw, T. J. Incidence of brain creatine transporter deficiency in males with developmental delay referred for brain magnetic resonance imaging. J. Dev. Behav. Pediatr. 26, 276–282 (2005).

    Article  PubMed  Google Scholar 

  139. Klepper, J. Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic diet. Epilepsia 49 (Suppl. 8) 46–49 (2008).

    Article  PubMed  Google Scholar 

  140. Kim, W. S., Weickert, C. S. & Garner, B. Role of ATP-binding cassette transporters in brain lipid transport and neurological disease. J. Neurochem. 104, 1145–1166 (2008).

    Article  CAS  PubMed  Google Scholar 

  141. Drozdzik, M. et al. Polymorphism in the P-glycoprotein drug transporter MDR1 gene: a possible link between environmental and genetic factors in Parkinson's disease. Pharmacogenetics 13, 259–263 (2003).

    Article  CAS  PubMed  Google Scholar 

  142. Dean, M. The genetics of ATP-binding cassette transporters. Methods Enzymol. 400, 409–429 (2005).

    Article  CAS  PubMed  Google Scholar 

  143. Blanz, J. et al. Leukoencephalopathy upon disruption of the chloride channel ClC-2. J. Neurosci. 27, 6581–6589 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Fabene, P. F. et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nature Med. 14, 1377–1383 (2008).

    Article  CAS  PubMed  Google Scholar 

  145. Kreutzberg, G. W. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312–318 (1996).

    Article  CAS  PubMed  Google Scholar 

  146. Appel, S. H., Beers, D. R. & Henkel, J. S. T cell-microglial dialogue in Parkinson's disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol. 31, 7–17 (2010).

    Article  CAS  PubMed  Google Scholar 

  147. Raj, A., van den Bogaard, P., Rifkin, S. A., van Oudenaarden, A. & Tyagi, S. Imaging individual mRNA molecules using multiple singly labeled probes. Nature Methods 5, 877–879 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Freudiger, C. W. et al. Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy. Science 322, 1857–1861 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Seeley, E. H. & Caprioli, R. M. Molecular imaging of proteins in tissues by mass spectrometry. Proc. Natl Acad. Sci. USA 105, 18126–18131 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Todman, M. G., Han, S. K. & Herbison, A. E. Profiling neurotransmitter receptor expression in mouse gonadotropin-releasing hormone neurons using green fluorescent protein-promoter transgenics and microarrays. Neuroscience 132, 703–712 (2005).

    Article  CAS  PubMed  Google Scholar 

  151. Turney, S. G. & Lichtman, J. W. Imaging fluorescent mice in vivo using confocal microscopy. Methods Cell Biol. 89, 309–327 (2008).

    Article  PubMed  Google Scholar 

  152. Zhuo, L. et al. Live astrocytes visualized by green fluorescent protein in transgenic mice. Dev. Biol. 187, 36–42 (1997).

    Article  CAS  PubMed  Google Scholar 

  153. Priller, J. et al. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nature Med. 7, 1356–1361 (2001).

    Article  CAS  PubMed  Google Scholar 

  154. Miesenbock, G. The optogenetic catechism. Science 326, 395–399 (2009).

    Article  CAS  PubMed  Google Scholar 

  155. Iqbal, U. et al. Molecular imaging of glioblastoma multiforme using anti-insulin-like growth factor-binding protein-7 single-domain antibodies. Br. J. Cancer 103, 1606–1616 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Elsinga, P. H., Hendrikse, N. H., Bart, J., van Waarde, A. & Vaalburg, W. Positron emission tomography studies on binding of central nervous system drugs and P-glycoprotein function in the rodent brain. Mol. Imaging Biol. 7, 37–44 (2005).

    Article  PubMed  Google Scholar 

  157. Weinstein, J. S. et al. Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review. J. Cereb Blood Flow Metab. 30, 15–35 (2010). This shows the current status of research into iron oxide nanoparticles, which are becoming increasingly important in dynamic MRI of brain tumours and in assessing inflammation in a variety of neurologic diseases.

    Article  CAS  PubMed  Google Scholar 

  158. Muldoon, L. L. et al. Chemotherapy delivery issues in central nervous system malignancy: a reality check. J. Clin. Oncol. 25, 2295–2305 (2007). This paper demonstrated the important finding that most chemotherapy crosses the blood–tumour barrier to some degree but not nearly as well as systemic tissues, even in highly malignant tumours.

    Article  CAS  PubMed  Google Scholar 

  159. Angelov, L. et al. Blood-brain barrier disruption and intra-arterial methotrexate-based therapy for newly diagnosed primary CNS lymphoma: a multi-institutional experience. J. Clin. Oncol. 27, 3503–3509 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Eliceiri, B. P., Gonzalez, A. M. & Baird, A. Zebrafish model of the blood–brain barrier: morphological and permeability studies. Methods Mol. Biol. 686, 371–378 (2011). An important new model for in vivo BBB studies, especially in development.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Hartz, A. M. & Bauer, B. ABC Transporters in the CNS — an inventory. Curr. Pharm. Biotechnol. 12, 423–440 (2011).

    Article  Google Scholar 

  162. Saunders, N. R., Ek, C. J., Habgood, M. D. & Dziegielewska, K. M. Barriers in the brain: a renaissance? Trends Neurosci. 31, 279–286 (2008).

    Article  CAS  PubMed  Google Scholar 

  163. Bates, K. A. et al. Clearance mechanisms of Alzheimer's amyloid-beta peptide: implications for therapeutic design and diagnostic tests. Mol. Psychiatry 16, 16 (2008).

    Google Scholar 

  164. Vogelgesang, S. et al. Deposition of Alzheimer's beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics 12, 535–541 (2002).

    Article  CAS  PubMed  Google Scholar 

  165. Cirrito, J. R. et al. P-glycoprotein deficiency at the blood–brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J. Clin. Invest. 115, 3285–3290 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Xiong, H. et al. ABCG2 is upregulated in Alzheimer's brain with cerebral amyloid angiopathy and may act as a gatekeeper at the blood–brain barrier for Abeta(1–40) peptides. J. Neurosci. 29, 5463–5475 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Lu, A. et al. Reperfusion activates metalloproteinases that contribute to neurovascular injury. Exp. Neurol. 210, 549–559 (2008).

    Article  CAS  PubMed  Google Scholar 

  168. Rosenberg, G. A. Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol. 8, 205–216 (2009).

    Article  CAS  PubMed  Google Scholar 

  169. Wang, X., Rosell, A. & Lo, E. H. Targeting extracellular matrix proteolysis for hemorrhagic complications of tPA stroke therapy. CNS Neurol. Disord. Drug Targets. 7, 235–242 (2008).

    Article  CAS  PubMed  Google Scholar 

  170. Xue, M. & Yong, V. W. Matrix metalloproteinases in intracerebral hemorrhage. Neurol. Res. 30, 775–782 (2008).

    Article  PubMed  Google Scholar 

  171. Argaw, A. T., Gurfein, B. T., Zhang, Y., Zameer, A. & John, G. R. VEGF-mediated disruption of endothelial CLN-5 promotes blood–brain barrier breakdown. Proc. Natl Acad. Sci. USA. 106(6):1977–1982 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Guzeloglu-Kayisli, O. et al. KRIT1/cerebral cavernous malformation 1 protein localizes to vascular endothelium, astrocytes, and pyramidal cells of the adult human cerebral cortex. Neurosurgery 54, 943–949; discussion 949 (2004).

    Article  PubMed  Google Scholar 

  173. Pagenstecher, A., Stahl, S., Sure, U. & Felbor, U. A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells. Hum. Mol. Genet. 18, 911–918 (2009).

    Article  CAS  PubMed  Google Scholar 

  174. Candelario-Jalil, E., Yang, Y. & Rosenberg, G. A. Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience 158, 983–994 (2009).

    Article  CAS  PubMed  Google Scholar 

  175. Gidday, J. M. et al. Leukocyte-derived matrix metalloproteinase-9 mediates blood–brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am. J. Physiol. Heart Circ. Physiol. 289, H558–H568 (2005).

    Article  CAS  PubMed  Google Scholar 

  176. Strbian, D. et al. The blood–brain barrier is continuously open for several weeks following transient focal cerebral ischemia. Neuroscience 153, 175–181 (2008).

    Article  CAS  PubMed  Google Scholar 

  177. Simard, J. M. et al. Newly expressed SUR1-regulated NCCa-ATP channel mediates cerebral edema after ischemic stroke. Nature Med. 12, 433–440 (2006).

    Article  CAS  PubMed  Google Scholar 

  178. Hughes, J. R. One of the hottest topics in epileptology: ABC proteins. Their inhibition may be the future for patients with intractable seizures. Neurol. Res. 30, 920–925 (2008).

    Article  CAS  PubMed  Google Scholar 

  179. Mignot, C. et al. Alexander disease: putative mechanisms of an astrocytic encephalopathy. Cell. Mol. Life Sci. 61, 369–385 (2004).

    Article  CAS  PubMed  Google Scholar 

  180. Chaudhuri, A., Yang, B., Gendelman, H. E., Persidsky, Y. & Kanmogne, G. D. STAT1 signalling modulates HIV-1-induced inflammatory responses and leukocyte transmigration across the blood–brain barrier. Blood 111, 2062–2072 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Huang, W., Eum, S. Y., Andras, I. E., Hennig, B. & Toborek, M. PPARalpha and PPARgamma attenuate HIV-induced dysregulation of tight junction proteins by modulations of matrix metalloproteinase and proteasome activities. FASEB J. 23, 1596–1606 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Yamamoto, M. et al. Phosphorylation of claudin-5 and occludin by rho kinase in brain endothelial cells. Am. J. Pathol. 172, 521–533 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. de Lagerie, S. B. et al. MDR1A (ABCB1)-deficient CF-1 mutant mice are susceptible to cerebral malaria induced by Plasmodium berghei ANKA. J. Parasitol. 94, 1139–1142 (2008).

    Article  PubMed  Google Scholar 

  184. Unkmeir, A. et al. Fibronectin mediates Opc-dependent internalization of Neisseria meningitidis in human brain microvascular endothelial cells. Mol. Microbiol 46, 933–946 (2002).

    Article  CAS  PubMed  Google Scholar 

  185. Wang, L. & Lin, M. A novel cell wall-anchored peptidoglycan hydrolase (autolysin), IspC, essential for Listeria monocytogenes virulence: genetic and proteomic analysis. Microbiology 154, 1900–1913 (2008).

    Article  CAS  PubMed  Google Scholar 

  186. Banks, W. A. Physiology and pathology of the blood–brain barrier: implications for microbial pathogenesis, drug delivery and neurodegenerative disorders. J. Neurovirol. 5, 538–555 (1999).

    Article  CAS  PubMed  Google Scholar 

  187. Haorah, J. et al. Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood–brain barrier dysfunction. J. Neurochem. 101, 566–576 (2007).

    Article  CAS  PubMed  Google Scholar 

  188. Man, S., Ubogu, E. E. & Ransohoff, R. M. Inflammatory cell migration into the central nervous system: a few new twists on an old tale. Brain Pathol. 17, 243–250 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Suidan, G. L., McDole, J. R., Chen, Y., Pirko, I. & Johnson, A. J. Induction of blood brain barrier tight junction protein alterations by CD8 T cells. PLoS ONE 3, e3037 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Verkman, A. S. Mammalian aquaporins: diverse physiological roles and potential clinical significance. Expert Rev. Mol. Med. 10, e13 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Yang, B., Zador, Z. & Verkman, A. S. Glial cell aquaporin-4 overexpression in transgenic mice accelerates cytotoxic brain swelling. J. Biol. Chem. 283, 15280–15286 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Blecharz, K. G., Drenckhahn, D. & Forster, C. Y. Glucocorticoids increase VE-cadherin expression and cause cytoskeletal rearrangements in murine brain endothelial cEND cells. J. Cereb Blood Flow Metab. 28, 1139–1149 (2008).

    Article  CAS  PubMed  Google Scholar 

  193. Felinski, E. A., Cox, A. E., Phillips, B. E. & Antonetti, D. A. Glucocorticoids induce transactivation of tight junction genes occludin and claudin-5 in retinal endothelial cells via a novel cis-element. Exp. Eye Res. 86, 867–878 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Harke, N., Leers, J., Kietz, S., Drenckhahn, D. & Forster, C. Glucocorticoids regulate the human occludin gene through a single imperfect palindromic glucocorticoid response element. Mol. Cell Endocrinol. 295, 39–47 (2008).

    Article  CAS  PubMed  Google Scholar 

  195. Reijerkerk, A. et al. Tissue-type plasminogen activator is a regulator of monocyte diapedesis through the brain endothelial barrier. J. Immunol. 181, 3567–3574 (2008).

    Article  CAS  PubMed  Google Scholar 

  196. Kebir, H. et al. Human TH17 lymphocytes promote blood–brain barrier disruption and central nervous system inflammation. Nature Med. 13, 1173–1175 (2007).

    Article  CAS  PubMed  Google Scholar 

  197. Morgan, L. et al. Inflammation and dephosphorylation of the tight junction protein occludin in an experimental model of multiple sclerosis. Neuroscience 147, 664–673 (2007).

    Article  CAS  PubMed  Google Scholar 

  198. Goodin, D. S., Cohen, B. A., O'Connor, P., Kappos, L. & Stevens, J. C. Assessment: the use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 71, 766–773 (2008).

    Article  CAS  PubMed  Google Scholar 

  199. Lutterotti, A. & Martin, R. Getting specific: monoclonal antibodies in multiple sclerosis. Lancet Neurol. 7, 538–547 (2008).

    Article  CAS  PubMed  Google Scholar 

  200. Martin, C. et al. FGF2 plays a key role in embryonic cerebrospinal fluid trophic properties over chick embryo neuroepithelial stem cells. Dev. Biol. 297, 402–416 (2006).

    Article  CAS  PubMed  Google Scholar 

  201. Brooks, T. A. et al. Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain. Brain Res. 1120, 172–182 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Foroutan, S., Brillault, J., Forbush, B. & O'Donnell, M. E. Moderate-to-severe ischemic conditions increase activity and phosphorylation of the cerebral microvascular endothelial cell Na+-K+-Cl− cotransporter. Am. J. Physiol. Cell Physiol. 289, C1492–C1501 (2005).

    Article  CAS  PubMed  Google Scholar 

  203. Lam, T. I., Anderson, S. E., Glaser, N. & O'Donnell, M. E. Bumetanide reduces cerebral edema formation in rats with diabetic ketoacidosis. Diabetes 54, 510–516 (2005).

    Article  CAS  PubMed  Google Scholar 

  204. Lam, T. I. & O'Donnell, M. E. BBB Na/H exchange: plasma membrane distribution of NHE1 and NHE2 isoforms and stimulation by arginine vasopressin. FASEB J. 22, 734.3 (2008).

  205. O'Donnell, M. E., Duong, V., Suvatne, J., Foroutan, S. & Johnson, D. M. Arginine vasopressin stimulation of cerebral microvascular endothelial cell Na-K-Cl cotransporter activity is V1 receptor and [Ca] dependent. Am. J. Physiol. Cell Physiol. 289, C283–292 (2005).

    Article  CAS  PubMed  Google Scholar 

  206. O'Donnell, M. E., Lam, T. I., Tran, L. & Anderson, S. E. The role of the blood–brain barrier Na-K-2Cl cotransporter in stroke. Adv. Exp. Med. Biol. 559, 67–75 (2004).

    Article  CAS  PubMed  Google Scholar 

  207. Yuen, N., Anderson, S. E., Glaser, N., Tancredi, D. J. & O'Donnell, M. E. Cerebral blood flow and cerebral edema in rats with diabetic ketoacidosis. Diabetes 57, 2588–2594 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Banks, W. A. The blood–brain barrier as a cause of obesity. Curr. Pharm. Des. 14, 1606–1614 (2008).

    Article  CAS  PubMed  Google Scholar 

  209. Jequier, E. Leptin signalling, adiposity, and energy balance. Ann. NY Acad. Sci. 967, 379–388 (2002).

    Article  CAS  PubMed  Google Scholar 

  210. Pan, W. et al. Astrocyte leptin receptor (ObR) and leptin transport in adult-onset obese mice. Endocrinology 149, 2798–2806 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Luder, A. S., Tanner, S. M., de la Chapelle, A. & Walter, J. H. Amnionless (AMN) mutations in Imerslund-Grasbeck syndrome may be associated with disturbed vitamin B(12) transport into the CNS. J. Inherit Metab. Dis. 7, 7 (2008).

    Google Scholar 

  212. Gordon, N. Canavan disease: a review of recent developments. Eur. J. Paediatr. Neurol. 5, 65–69 (2001).

    Article  CAS  PubMed  Google Scholar 

  213. Urayama, A., Grubb, J. H., Sly, W. S. & Banks, W. A. Developmentally regulated mannose 6-phosphate receptor-mediated transport of a lysosomal enzyme across the blood–brain barrier. Proc. Natl Acad. Sci. USA 101, 12658–12663 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Uhr, M. et al. Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron 57, 203–209 (2008).

    Article  CAS  PubMed  Google Scholar 

  215. Tanigami, H. et al. Effect of glutamine synthetase inhibition on astrocyte swelling and altered astroglial protein expression during hyperammonemia in rats. Neuroscience 131, 437–449 (2005).

    Article  CAS  PubMed  Google Scholar 

  216. Sugimoto, H., Koehler, R. C., Wilson, D. A., Brusilow, S. W. & Traystman, R. J. Methionine sulfoximine, a glutamine synthetase inhibitor, attenuates increased extracellular potassium activity during acute hyperammonemia. J. Cereb Blood Flow Metab. 17, 44–49 (1997).

    Article  CAS  PubMed  Google Scholar 

  217. Strauss, G. I., Knudsen, G. M., Kondrup, J., Moller, K. & Larsen, F. S. Cerebral metabolism of ammonia and amino acids in patients with fulminant hepatic failure. Gastroenterology 121, 1109–1119 (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The meeting on which this report was based was partially funded by an R13 grant from the US National Institutes of Health (Grant 5 R13 CA086959-10). We would like to thank all of the people who attended the Engaging Neuroscience to Advance Brain Barriers Translational Research meeting (March 19–21, 2009), Gleneden Beach, Oregon, USA. Special thanks to Lester Drewes, Martha O'Donnell, Leslie Muldoon and Aliana Kim who were instrumental in the development of this report.

Author information

Authors and Affiliations

  1. Edward A. Neuwelt is at the Oregon Health & Science University, 3181 SW Sam Jackson Park Road L603, Portland, Oregon 97239-2941, USA, and at the Portland Veterans Affairs Medical Center, 3710 SW U.S. Veterans Hospital Road, Portland, Oregon 97239, USA.,

    Edward A. Neuwelt

  2. Björn Bauer is at the University of Minnesota, College of Pharmacy, 1110 Kirby Drive, 232 Life Science, Duluth, Minnesota 55812-3003, USA.,

    Björn Bauer

  3. Christoph Fahlke is at the Institut für Neurophysiologie, OE 4230, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.,

    Christoph Fahlke

  4. Gert Fricker is at the Abteilung Pharmazeutische Technologie und Pharmakologie Im Neuenheimer, University of Heidelberg, Feld 366 D, 69120 Heidelberg, Germany.,

    Gert Fricker

  5. Constantino Iadecola is at the Division of Neurobiology, Weill Cornell Medical College, 407 East 61st Street, RR-303, New York, New York 10065, USA.,

    Constantino Iadecola

  6. Damir Janigro is at the Cleveland Clinic Foundation, 9500 Euclid Avenue, Mail Code NB20, Cleveland, Ohio 44195-0001, USA.,

    Damir Janigro

  7. Luc Leybaert is at the Department of Basic Medical Sciences, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium.,

    Luc Leybaert

  8. Zoltán Molnár is at the Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, South Parks Road, Oxford, OX1 3QX, United Kingdom.,

    Zoltán Molnár

  9. Martha E. O'Donnell is at the Department of Physiology and Membrane Biology, School of Medicine, University of California, One Shields Avenue, Davis, California 95616, USA.,

    Martha E. O'Donnell

  10. John T. Povlishock is at the Department of Anatomy and Neurobiology, Virginia Commonwealth University, P.O. Box 980709, Richmond, Virginia 23298-0709, USA.,

    John T. Povlishock

  11. Norman R. Saunders is at the Department of Pharmacology Parkville, University of Melbourne, Victoria 3010, Australia.,

    Norman R. Saunders

  12. Frank Sharp is at the UC Davis MIND Institute, University of California at Davis, 2825 50th Street, Sacramento, California 95817-2310, USA.,

    Frank Sharp

  13. Danica Stanimirovic is at the Institute for Biological Sciences, National Research Council of Canada, 1200 Montreal Road, Ottawa, ON K1A 0R7, Canada.,

    Danica Stanimirovic

  14. Ryan J. Watts is at the Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, California, 94080-4990, USA.,

    Ryan J. Watts

  15. Lester R. Drewes is at the University of Minnesota Medical School, Duluth, 1035 University Drive, Duluth, Minnesota 55812, USA.,

    Lester R. Drewes

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  1. Edward A. Neuwelt
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Corresponding author

Correspondence to Edward A. Neuwelt.

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Supplementary information

Supplementary information S1 (box)

Co-Chairs and Members of the Five Committees (PDF 164 kb)

Supplementary information S2 (box)

“Engaging Neuroscience to Advance Brain Barriers Translational Research” (PDF 171 kb)

Supplementary information S3 (box)

Molecular Physiology of the Brain and Brain Barriers Working Group Report (PDF 6070 kb)

Related links

Related links

FURTHER INFORMATION

The International Brain Barriers Society

Edward A. Neuwelt's homepage

Björn Bauer's homepage

Zoltán Molnár's homepage

Danica Stanimirovic's homepage

Glossary

Abluminal

Facing the neural cells or brain.

Basal lamina

A thin, continuous layer of extracellular matrix surrounding the brain endothelial cells and pericytes.

Blood–cerebrospinal fluid (CSF) barrier

The blood–CSF barrier is at the choroid plexus epithelial cells, which are joined together by tight junctions. The capillaries in the choroid plexus differ from those of the blood–brain barrier in that there is free movement of molecules between endothelial cells via fenestrations and intercellular gaps.

Blood–labyrinth barrier

The cochlea is a structure of the inner ear involved in sound transduction and is vascularized by a dense set of capillaries that are essential for delivering the nutrients and ions necessary for producing the fluids (endolymph and perilymph) present in the cochlea. These capillaries are lined with endothelial cells that are joined by tight junctions and physiologically form the blood–labyrinth barrier that is essential for sensitive auditory function.

Blood–nerve barrier

The endothelial lining of blood vessels in peripheral nerves is formed by continuous, non-fenestrated endothelia in which individual cells are linked by tight junctions, rendering them impermeable to intravascular macromolecules. This blood–nerve barrier, and a similar mechanism in the innermost perineurial sheath, isolate the endoneurial interstitium, in much the same way as the blood–brain barrier. Other factors, such as the absence of lymphatics, are also analogous to the central nervous system.

Blood–retinal barrier

The blood–retinal barrier has two components: the retinal vascular endothelium and the retinal pigment epithelium. The retinal vascular endothelium is non-fenestrated and has anatomical properties similar to those of cerebral vascular endothelium. The retinal pigment epithelium consists of a layer of epithelial cells, joined by tight junctions, that forms a barrier between the neuroretina and the choroid.

Ependyma

A thin cellular layer lining the ventricular system of the brain. The cells of the ependyma are called ependymal cells and are a type of glia. They are linked by gap junctions, which do not provide an impediment to diffusion of molecules, even against large proteins between cerebrospinal fluid and brain interstitial fluid.

Luminal

Facing the capillary lumen.

Neuro–angiogenic coupling

The coupling of the development of neurons (neurogenesis) with new blood vessel formation (angiogenesis and vasculogenesis).

Neuroependyma

(Also known as neuroepithelium or ventricular zone.) A deep pseudostratified layer of cells lining the embryonic ventricular system that proliferate into radial glial cells and neurons in the embryo, and into glial cells later in development. The cells of the neuroependyma are linked by strap junctions, which limit intercellular movement of molecules — particularly proteins — from cerebrospinal fluid to brain interstitial space in the embryo. By adulthood these cells have transformed to the layer of thin generally non-dividing ependymal cells lining the ventricular system of the mature brain.

Neuro–haemodynamic coupling

The coupling of neuronal firing and synaptic activity with haemodynamic changes (for example, blood volume and blood flow).

Neuro–metabolic coupling

The coupling of neural activity, an energy consuming process, with the energy producing metabolic processes to maintain cellular homeostasis.

Neuro–trophic coupling

The coupling of neuronal production of activity-dependent signals such as growth factors (for example, brain-derived neurotrophic factor (BDNF)) with control of neurogenesis.

Paracellular

Paracellular is used here to refer to the transfer of substances between cells of an endothelium or epithelium. It is in contrast to 'transcellular transport', in which the substances are transported through the cell.

Tripartite synapse

A tripartite (three-part) synapse consists of a presynapse, a postsynapse and a glial cell functioning as a single unit.

Xenobiotic-sensing nuclear receptor

A xenobiotic-activated transcription factor that controls the expression of proteins involved in xenobiotic metabolism and efflux transport.

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Neuwelt, E., Bauer, B., Fahlke, C. et al. Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci 12, 169–182 (2011). https://doi.org/10.1038/nrn2995

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