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Regulation of Permeability Across the Blood-Brain Barrier

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Biology and Regulation of Blood-Tissue Barriers

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 763))

Abstract

The blood-brain barrier refers to the very low permeability across microvessels in the Central Nervous System (CNS), created by the interaction between vascular endothelial cells and surrounding cells of the neurovascular unit. Permeability can be modulated (increased and decreased) by a variety of factors including inflammatory mediators, inflammatory cells such as neutrophils and through alterations in the phenotype of blood vessels during angiogenesis and apoptosis. In this chapter, some of these factors are discussed as well as the challenge of treating harmful increases in permeability that result in brain swelling (vasogenic cerebral edema).

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References

  1. Biedl A, Kraus R. Über einer bisher unbekannte toxische wirking der gallensaüren auf das zentralnervensustem. Zentralblatt inn Med 1898; 19:185–200.

    Google Scholar 

  2. Lewandowsky M. Zur lehre der cerebrospinal flüssigkeit. Z Klin Med 1900; 40:480–494.

    Google Scholar 

  3. Erlich P. Über die beziehungen von chemischer constitution, Vertheilung, und pharmakologischer wirkung. Republished and translated in: Collected Studies in Immunity. New York: John Wiley, 1902:567–595.

    Google Scholar 

  4. Goldmann EE. Vitalfarbung am zentralnervensystem. Abh Preuss Akad Wiss Phys-Math. 1913; 1:1–60.

    Google Scholar 

  5. Stern L, Gautier R. Rapports entre le liquide céphalo-rachidien et al circulation sanguine. Arch Int Physiol 1921; 17:138–192.

    CAS  Google Scholar 

  6. Krogh A. The active and passive exchanges of inorganic ions through the surfaces of living cells and through living membranes generally. Proc Roy Soc B 1946; 133:140–200.

    CAS  Google Scholar 

  7. Davson H. A comparative study of the aqueous humour and cerebrospinal fluid in the rabbit. J Physiol 1955; 129:111–133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Brodie BB, Kurz H, Schanker LS. The importance of dissociation constant and lipid solubility in influencing the passage of drugs into the cerebrospinal fluid. J Pharmacol 1960; 130:20–25.

    CAS  Google Scholar 

  9. Reese TS, Karnovsky MJ. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 1967; 34:207–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Brightman MW, Reese TS. Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 1969; 40:648–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nagy Z, Peters H, Hüttner I. Fracture faces of cell junctions in cerebral endothelium during normal and hyperosmotic conditions. Lab Invest 1984; 50:313–322.

    CAS  PubMed  Google Scholar 

  12. Petty MA, Lo EH. Junctional complexes of the blood-brain barrier: permeability changes in neuroinflammation. Prog Neurobiol 2002; 68:311–323.

    Article  CAS  PubMed  Google Scholar 

  13. Connell CJ, Mercer KL. Freeze-fracture appearance of the capillary endothelium in the cerebral cortex of mouse brain. Am J Anat 1974; 140:595–598.

    Article  CAS  PubMed  Google Scholar 

  14. Janzer RC, Raff MC. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 1987; 325:253–257.

    Article  CAS  PubMed  Google Scholar 

  15. Stewart PA, Wiley MJ. Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: a study using quail-chick transplantation chimeras. Dev Biol 1981; 84:183–192.

    Article  CAS  PubMed  Google Scholar 

  16. Cucullo L, Couraud PO, Weksler B et al. Immortalized human brain endothelial cells and flow-based vascular modeling: a marriage of convenience for rational neurovascular studies. J Cereb Blood Flow Metab 2008; 28, 312–328.

    Article  CAS  PubMed  Google Scholar 

  17. Hoheisel D, Nitz T, Franke H et al. Hydrocortisone reinforces the blood-brain barrier properties in a serum free cell culture system. Biochem Biophys Res Comm 1998; 247:312–315.

    Article  CAS  PubMed  Google Scholar 

  18. Renkin EM. Transport of potassium-42 from blood to tissue in isolated mammalian skeletal muscle. Am J Physiol 1959; 197:1205–1210.

    Article  CAS  PubMed  Google Scholar 

  19. Crone C. Permeability of capillaries in various organs as determined by the use of the indicator diffusion method. Acta Physiol Scand 1963; 58:292–305.

    Article  CAS  PubMed  Google Scholar 

  20. Robinson PJ. Measurement of blood-brain barrier permeability. Clin Exp Pharmacol Physiol 1990; 17:829–840.

    Article  CAS  PubMed  Google Scholar 

  21. Gauden V, Hu DE, Kurokawa T et al. Novel technique for estimating cerebrovascular permeability demonstrates capsazepine protection following ischemia-reperfusion. Microcirculation 2007; 14:767–778.

    Article  CAS  PubMed  Google Scholar 

  22. Fraser PA, Dallas AD. Permeability of disrupted cerebral microvessels in the frog. J Physiol 1993; 461:619–632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Crone C, Olesen S-P. Electrical resistance of brain microvascular endothelium. Brain Research 1982; 241:49–55.

    Article  CAS  PubMed  Google Scholar 

  24. Inglis VI, Jones MP, Tse AD et al. Neutrophils both reduce and increase permeability in a cell culture model of the blood-brain barrier. Brain Research 2004; 998:218–229.

    Article  CAS  PubMed  Google Scholar 

  25. Rubin LL, Hall DE, Porter S et al. A cell culture model of the blood-brain barrier. J Cell Biol 1991; 115:1725–1735.

    Article  CAS  PubMed  Google Scholar 

  26. Easton AS, Sarker MH, Fraser PA. Two components of blood-brain barrier disruption in the rat. J Physiol 1997; 503:613–623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Easton AS, Fraser PA. Variable restriction of albumin diffusion across inflamed cerebral microvessels of the anaesthetized rat. J Physiol 1994; 475:147–157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Weller RO, Galea I, Carare RO et al. Pathophysiology of the lymphatic drainage of the central nervous system: implications for pathogenesis and therapy of multiple sclerosis. Pathophysiology Electronic publication ahead of print 2009.

    Google Scholar 

  29. Klatzo I. Pathophysiological aspects of brain edema. Acta Neuropathol 1987; 72:236–239.

    Article  CAS  PubMed  Google Scholar 

  30. Simard JM, Kent TA, Chen M et al. Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol 2007; 6:258–268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fraser PA, Dallas AD. Measurement of filtration coefficient in single cerebral microvessels of the frog. J Physiol 1990; 423:343–361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Manley GT, Binder DK, Papadopoulos MC et al. New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice. Neuroscience 2004; 129:983–991.

    Article  CAS  PubMed  Google Scholar 

  33. Manley GT, Fujimura M, Ma T et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nature Med 2000; 6:159–163.

    Article  CAS  PubMed  Google Scholar 

  34. Papadopoulos MC, Manley GT, Krishna S et al. Aquaporin-4 facilitates the reabsorption of excess fluid in vasogenic brain edema. FASEB J 2004; 18:1291–1293.

    Article  CAS  PubMed  Google Scholar 

  35. Fraser PA. Can a broken barrier be repaired? J Physiol 2006; 573:287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Heiss JD, Papavassiliou E, Merrill MJ et al. Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor. J Clin Invest 1996; 98:1400–1408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ron NP, Kazianis JA, Padbury JF et al. Ontogeny and the effects of corticosteroid pretreatment on aquaporin water channels in the ovine cerebral cortex. Reprod Fertility Dev 2005; 17:535–542.

    Article  CAS  Google Scholar 

  38. Putney LK, Brandt JD, O’Donnell ME. Effects of dexamethasone on sodium-potassium-chloride cotransport in trabecular meshwork cells. Invest Opthalmol Vis Sci 1997; 38:1229–1240.

    CAS  Google Scholar 

  39. Dimberg A. Chemokines in angiogenesis. Curr Top Microbiol Immunol. E-published ahead of print 2010.

    Google Scholar 

  40. Shakur H, Andrews P, Asser T et al. The BRAIN TRIAL: a randomized, placebo controlled trial of a bradykinin B2 receptor antagonist (Anatibant) in patients with traumatic brain injury. Trials 2009; 10:109.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Emerich DF, Dean RL, Osborn C et al. The development of the bradykinin agonist labradimil as a means to increase the permeability of the blood-brain barrier: from concept to clinical evaluation. Clin Pharmacokin 2001; 40:105–123.

    Article  CAS  Google Scholar 

  42. Sarker MH, Easton AS, Fraser PA. Regulation of cerebral microvascular permeability by histamine in the anaesthetized rat. J Physiol 1998; 507:909–918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Easton AS, Fraser PA. Arachidonic acid increases cerebral microvascular permeability by free radicals in single pial microvessels of the anaesthetized rat. J Physiol 1998; 507:541–547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sarker MH, Hu D-E, Fraser PA. Acute effects of bradykinin on cerebral microvascular permeability in the anaesthetized rat. J Physiol 2000; 528:177–187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sarker MH, Fraser PA. The role of guanylyl cyclases in the permeability response to inflammatory mediators in pial venular capillaries in the rat. J Physiol 2002; 540:209–218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hu D-E, Fraser PA. Evidence for interleukin-1b mediating enhanced permeability responses to bradykinin in single pial capillaries of anaesthetized rats. J Physiol 1997; 505:53P.

    Article  Google Scholar 

  47. Hayashi T, Deguchi K, Nagotani S et al. Cerebral ischemia and angiogenesis. Curr Neurovasc Res 2006; 3:119–129.

    Article  CAS  PubMed  Google Scholar 

  48. Zhang ZG, Zhang L, Tsang W et al. Correlation of VEGF and angiopoeitin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia. J Cereb Blood Flow Metab 2002; 22:379–392.

    Article  CAS  PubMed  Google Scholar 

  49. Croll SD, Weigand SJ. Vascular growth factors in cerebral ischemia. Mol. Neurobiol 2001; 23:121–135.

    Article  CAS  PubMed  Google Scholar 

  50. Zhang ZG, Zhang L, Jiang Q et al. VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest 2000; 106:829–838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rigau V, Morin M, Rousset M-C et al. Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy. Brain 2007; 130:1942–1956.

    Article  PubMed  Google Scholar 

  52. Hayashi T, Noshita N, Sugawara T et al. Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab 2003; 23:166–180.

    Article  CAS  PubMed  Google Scholar 

  53. Krupinski J, Kaluza J, Kumar P et al. Role of angiogenesis in patients with cerebral ischemic stroke. Stroke 1994; 25:1794–1798.

    Article  CAS  PubMed  Google Scholar 

  54. Kaya D, Gürsoy-Özdemir Y, Yemisci M et al. VEGF protects brain against focal ischemia without increasing blood-brain barrier permeability when administered intracerebroventricularly. J Cereb Blood Flow Metab 2005; 25:1111–1118.

    Article  CAS  PubMed  Google Scholar 

  55. Hayashi T, Abe K, Itoyama Y. Reduction of ischemic damage by application of vascular endothelial growth factor in rat brain after transient ischemia. J Cereb Blood Flow Metab 1998; 18:887–895.

    Article  CAS  PubMed  Google Scholar 

  56. Udo H, Yoshida Y, Kino T et al. Enhanced adult neurogenesis and angiogenesis and altered affective behaviours in mice overexpressing vascular endothelial growth factor 120. J Neurosci 2008; 28:14522–14536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhang ZG, Zhang L, Croll SD et al. Angiopoietin-1 reduces cerebral blood vessel leakage and ischemic lesion volume after focal cerebral embolic ischemia in mice. Neuroscience 2002; 113:683–687.

    Article  CAS  PubMed  Google Scholar 

  58. Zhu Y, Lee C, Shen F et al. Angiopoietin-2 facilitates vascular endothelial growth factor-induced angiogenesis in the mature mouse brain. Stroke 2005; 36:1533–1537.

    Article  CAS  PubMed  Google Scholar 

  59. Bermpohl D, Halle A, Freyer D et al. Bacterial programmed cell death of cerebral endothelial cells involves dual death pathways. Clin Invest 2005; 115:1607–1615.

    Article  CAS  Google Scholar 

  60. Hsu M-J, Hsu CY, Chen BC et al. Apoptosis signal regulating-kinase 1 in amyloid β peptide-induced cerebral endothelial cell apoptosis. J Neurosci 2007; 27:5719–5729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhang Y, Park TS, Gidday JM. Hypoxic preconditioning protects human brain endothelium from ischemic apoptosis by Akt-dependent surviving activation. Am J Physiol Heart Circ Physiol 2007; 292:H2573–H2581.

    Article  CAS  PubMed  Google Scholar 

  62. Chen P-L, Easton AS. Evidence that tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits angiogenesis by inducing vascular endothelial apoptosis. Biochem Biophys Res Commun 2010; 391:936–941.

    Article  CAS  PubMed  Google Scholar 

  63. Beck H, Acker T, Wiessner C et al. Expression of angiopoietin-1, angiopoietin-2 and Tie receptors after middle cerebral artery occlusion in rats. Am J Pathol 2000; 157:1473–1483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Li Y-Q, Chen P, Haimovitz-Friedman A et al. Endothelial apoptosis initiates acute blood-brain barrier disruption after ionizing radiation. Cancer Res 2003; 63:5950–5956.

    CAS  PubMed  Google Scholar 

  65. Easton AS, Dorovini-Zis K. The kinetics, function and regulation of P-selectin expressed by human brain microvessel endothelial cells in primary culture. Microvasc Res 2001; 62:335–345.

    Article  CAS  PubMed  Google Scholar 

  66. Wong D, Prameya R, Dorovini-Zis K. Adhesion and migration of polymorphonuclear leukocytes across human brain microvessel endothelial cells are differentially regulated by endothelial cell adhesion molecules and modulate monolayer permeability. J Neuroimmunol 2007; 184:136–148.

    Article  CAS  PubMed  Google Scholar 

  67. Woodfin A, Voisin MB, Nourshargh S. Recent developments and complexities in neutrophil transmigration. Curr Opin Hematol 2010; 17:9–17.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Bell MD, Perry VH. Adhesion molecule expression on murine cerebral endothelium following the injection of a proinflammogen or during acute neuronal degeneration. J Neurocytol 1995; 24:695–710.

    Article  CAS  PubMed  Google Scholar 

  69. Bell MD, Taub DD, Perry VH. Overriding the brain’s intrinsic resistance to leukocyte recruitment with intraparenchymal injections of recombinant chemokines. Neuroscience 1996; 74:283–292.

    Article  CAS  PubMed  Google Scholar 

  70. Anthony DC, Bolton SJ, Fearn S et al. Age-related effects of interleukin-1 beta on polymorphonuclear neutrophil-dependent increases in blood-brain barrier permeability in rats. Brain 1997; 120:435–444.

    Article  PubMed  Google Scholar 

  71. Anthony D, Dempster R, Fearn S et al. CXC chemokines generate age-related increases in neutrophil-mediated brain inflammation and blood-brain barrier breakdown. Curr Biol 1998; 8:923–926.

    Article  CAS  PubMed  Google Scholar 

  72. Bolton SJ, Anthony DC, Perry VH. Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood-brain barrier breakdown in vivo. Neuroscience 1998; 86:1245–1257.

    Article  CAS  PubMed  Google Scholar 

  73. Inglis VI, Jones MPJ, Tse ADY et al. Neutrophils both reduce and increase permeability in a cell culture model of the blood-brain barrier. Brain Res 2004; 998:218–229.

    Article  CAS  PubMed  Google Scholar 

  74. Joice SL. Mydeen F, Couraud PO et al. Modulation of blood-brain barrier permeability by neutrophils: in vitro and in vivo studies. Brain Res 2009; 1298:13–23.

    Article  CAS  PubMed  Google Scholar 

  75. Cowan KM, Easton AS. Neutrophils block permeability increases induced by oxygen glucose deprivation in a culture model of the human blood-brain barrier. Brain Res 2010; 1332:20–31.

    Article  CAS  PubMed  Google Scholar 

  76. MacMillan CJ, Easton AS. In vivo effects of neutrophils on the blood-brain barrier. Poster abstract P-10, 8th Cerebrovascular Biology International conference 2009, Sendai, Japan.

    Google Scholar 

  77. Keep RF, Xi G, Hua Y et al. The deleterious or beneficial effects of different agents in intracerebral hemorrhage: think big, think small, or is hematoma size important? Stroke 2005; 36:1594–1596.

    Article  PubMed  Google Scholar 

  78. Kalia LV, Kalia SK, Salter MW. NMDA receptors in clinical neurology: excitatory times ahead. Lancet Neurol 2008; 7:742–755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Becker KJ. Anti-leukocyte antibodies: LeukArrest (Hu23F2G) and enlimomab (R6.5) in acute stroke. Curr Med Res Opin 2002; 18 (S2):S18–S22.

    Article  PubMed  Google Scholar 

  80. Engelhardt B, Pfeiffer F, Schafer J et al. TET-induced expression of claudin-1 in brain endothelium reduces edema formation and clinical disease in an animal model of multiple sclerosis. Symposium abstract, 8th Cerebrovascular Biology International conference 2009, Sendai, Japan.

    Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada

    Alexander S. Easton

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  1. Alexander S. Easton
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Editors and Affiliations

  1. Center for Biomedical Research, Population Council, New York, New York, USA

    C. Yan Cheng PhD

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Easton, A.S. (2013). Regulation of Permeability Across the Blood-Brain Barrier. In: Cheng, C.Y. (eds) Biology and Regulation of Blood-Tissue Barriers. Advances in Experimental Medicine and Biology, vol 763. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4711-5_1

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