Cellular and Molecular Neurobiology

, Volume 20, Issue 2, pp 131–147 | Cite as

Inflammatory Mediators and Modulation of Blood–Brain Barrier Permeability

  • N. Joan Abbott


1. Unlike some interfaces between the blood and the nervous system (e.g., nerve perineurium), the brain endothelium forming the blood–brain barrier can be modulated by a range of inflammatory mediators. The mechanisms underlying this modulation are reviewed, and the implications for therapy of the brain discussed.

2. Methods for measuring blood–brain barrier permeability in situ include the use of radiolabeled tracers in parenchymal vessels and measurements of transendothelial resistance and rate of loss of fluorescent dye in single pial microvessels. In vitro studies on culture models provide details of the signal transduction mechanisms involved.

3. Routes for penetration of polar solutes across the brain endothelium include the paracellular tight junctional pathway (usually very tight) and vesicular mechanisms. Inflammatory mediators have been reported to influence both pathways, but the clearest evidence is for modulation of tight junctions.

4. In addition to the brain endothelium, cell types involved in inflammatory reactions include several closely associated cells including pericytes, astrocytes, smooth muscle, microglia, mast cells, and neurons. In situ it is often difficult to identify the site of action of a vasoactive agent. In vitro models of brain endothelium are experimentally simpler but may also lack important features generated in situ by cell:cell interaction (e.g. induction, signaling).

5. Many inflammatory agents increase both endothelial permeability and vessel diameter, together contributing to significant leak across the blood–brain barrier and cerebral edema. This review concentrates on changes in endothelial permeability by focusing on studies in which changes in vessel diameter are minimized.

6. Bradykinin (Bk)2 increases blood–brain barrier permeability by acting on B2 receptors. The downstream events reported include elevation of [Ca2+]i, activation of phospholipase A2, release of arachidonic acid, and production of free radicals, with evidence that IL-1β potentiates the actions of Bk in ischemia.

7. Serotonin (5HT) has been reported to increase blood–brain barrier permeability in some but not all studies. Where barrier opening was seen, there was evidence for activation of 5-HT2 receptors and a calcium-dependent permeability increase.

8. Histamine is one of the few central nervous system neurotransmitters found to cause consistent blood–brain barrier opening. The earlier literature was unclear, but studies of pial vessels and cultured endothelium reveal increased permeability mediated by H2 receptors and elevation of [Ca2+]i and an H1 receptor-mediated reduction in permeability coupled to an elevation of cAMP.

9. Brain endothelial cells express nucleotide receptors for ATP, UTP, and ADP, with activation causing increased blood–brain barrier permeability. The effects are mediated predominantly via a P2U (P2Y2) G-protein-coupled receptor causing an elevation of [Ca2+]i; a P2Y1 receptor acting via inhibition of adenyl cyclase has been reported in some in vitro preparations.

10. Arachidonic acid is elevated in some neural pathologies and causes gross opening of the blood–brain barrier to large molecules including proteins. There is evidence that arachidonic acid acts via generation of free radicals in the course of its metabolism by cyclooxygenase and lipoxygenase pathways.

11. The mechanisms described reveal a range of interrelated pathways by which influences from the brain side or the blood side can modulate blood–brain barrier permeability. Knowledge of the mechanisms is already being exploited for deliberate opening of the blood–brain barrier for drug delivery to the brain, and the pathways capable of reducing permeability hold promise for therapeutic treatment of inflammation and cerebral edema.

blood–brain barrier inflammation permeability electrical resistance calcium tight junction signal transduction receptor 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abbott, N. J. (1998). Role of intracellular calcium in regulation of blood-brain barrier permeability. In Pardridge, W. M. (ed.), An Introduction to the Blood-Brain Barrier: Methodology and Biology, Cambridge University Press, Cambridge, pp. 345-353.Google Scholar
  2. Abbott, N. J., and Revest, P. A. (1991). Control of brain endothelial permeability. Cerebrovasc. Brain Metab. Rev. 3:39-72.Google Scholar
  3. Abbott, N. J., and Romero, I. A. (1996). Transporting therapeutics across the blood-brain barrier. Mol. Med. Today 2:106-113.Google Scholar
  4. Abbott, N. J., Bundgaard, N., and Cserr, H. F. (1986). Comparative physiology of the blood-brain barrier. In Suckling, J., Rumsby, M. G., and Bradbury, M. W. B. (eds.), The Blood-Brain Barrier in Health and Disease, Ellis Horwood, Chichester, pp. 52-72.Google Scholar
  5. Abbott, N. J., Revest, P. A., and Romero, I. A. (1992). Astrocyte-endothelial interaction: Physiology and pathology. Neuropathol. Appl. Neurobiol. 18:424-433.Google Scholar
  6. Abbott, N. J., Roux, F., Couraud, P.-O., and Begley, D. J. (1995). Studies on an immortalized brain endothelial cell line: Differentiation, permeability and transport. In Greenwood, J., Begley, D. J., and Segal, M. B. (eds.), New Concepts of a Blood-Brain Barrier, Plenum Press, New York, pp. 239-249.Google Scholar
  7. Allt, G., and Lawrenson, J. G. (1997). Is the pial microvessel a good model for blood-brain barrier studies? Brain Res. Rev. 24:67-76.Google Scholar
  8. Bauer, H.-C., and Bauer, H. (1999). Neural induction of the blood-brain barrier: Still an enigma. Cell. Mol. Neurobiol. 20:13-28.Google Scholar
  9. Boarder, M. R., and Hourani, S. M. O. (1998) The regulation of vascular function by P2 receptors: Multiple sites and multiple receptors. Trends Pharmacol. Sci. 19:99-107.Google Scholar
  10. Bradbury, M. W. B. (1979). The Concept of a Blood-Brain Barrier, J. Wiley, Chichester.Google Scholar
  11. Bradbury, M. W. B. (ed.) (1992). Physiology and Pharmacology of the Blood-Brain Barrier, Springer-Verlag, Berlin.Google Scholar
  12. Bradbury, M. W. B. (1997). Transport of iron in the blood-brain-cerebrospinal fluid system. J. Neurochem. 69:443-454.Google Scholar
  13. Bundgaard, M. (1982). Ultrastructure of frog cerebral and pial microvessels and their impermeability to lanthanum ions. Brain Res. 241:57-65.Google Scholar
  14. Butt, A. M. (1995). Effect of inflammatory agents on electrical resistance across the blood-brain barrier in pial microvessels of anaesthetized rats. Brain Res. 696:145-150.Google Scholar
  15. Butt, A. M., and Jones, H. C. (1992). Effect of histamine and antagonists on electrical resistance across the blood-brain barrier in rat brain-surface microvessels. Brain Res. 569:100-105.Google Scholar
  16. Butt, A. M., Jones, H. C., and Abbott, N. J. (1990). Electrical resistance across the blood-brain barrier in anaesthetized rats: A developmental study. J. Physiol. 429:47-62.Google Scholar
  17. Chan, P. H., and Fishman, R. A. (1984). The role of arachidonic acid in vasogenic brain edema. Fed. Proc. 43:210-213.Google Scholar
  18. Coomber, B. L., and Stewart, P. A. (1985). Morphometric analysis of CNS microvascular endothelium. Microvasc. Res. 30:99-115.Google Scholar
  19. Crone, C., and Olesen, S.-P. (1982). Electrical resistance of brain microvascular endothelium. Brain Res. 241:49-55.Google Scholar
  20. Curry, F. E. (1992). Modulation of venular microvessel permeability by calcium influx into endothelial cells. FASEB J. 6:2456-2466.Google Scholar
  21. Davson, H., and Segal, M. B. (1995). Physiology of the CSF and Blood-Brain Barriers, CRC Press, Boca Raton, FL.Google Scholar
  22. De Vries, H. E., Kuiper, J., De Boer, A. G., Van Berkel, T. J. C., and Breimer, D. D. (1997). The blood-brain barrier in neuroinflammatory diseases. Pharmacol. Rev. 49:143-155.Google Scholar
  23. Dejana, E., and Del Maschio, A. (1995). Molecular organization and functional regulation of cell to cell junctions in the endothelium. Thromb. Haemostas. 74:309-312.Google Scholar
  24. Doctrow, S. R., Abelleira, S. M., Curry, L. A., Heller-Harrison, R., Kozarich, J. W., Malfroy, B., McCarroll, L. A., Morgan, K. G., Morrow, A. R., Musso, G. F., Smart, J. L., Straub, J. A., Turnbull, B., and Gloff, C. A. (1994). The bradykinin analog RMP-7 increases intracellular free calcium levels in rat brain microvascular endothelial cells. J. Pharmacol. Exp. Ther. 271:229-237.Google Scholar
  25. Dropp, J. J. (1976). Mast cells in mammalian brain. I. Distribution. Acta Anat. 94:1-21.Google Scholar
  26. Dux, E., Temesvari, P., Szerdahelyi, P., Nagy, A., Kovacs, J., and Joó, F. (1987). Protective effect of antihistamines on cerebral oedema induced by experimental pneumothorax in newborn piglets. Neuroscience 22:317-321.Google Scholar
  27. Easton, A. S., and Abbott, N. J. (1997). The effects of bradykinin on a cell culture model of the blood-brain barrier. J. Physiol. 505:49-50P.Google Scholar
  28. Easton, A. S., and Fraser, P. A. (1994). Variable restriction of albumin diffusion across inflamed cerebral microvessels. J. Physiol. 475:147-157.Google Scholar
  29. Easton, A. S., and Fraser, P. A. (1998). Arachidonic acid increases cerebral microvascular permeability by free radicals in single pial microvessels of the anaesthetized rat. J. Physiol. 507:541-547.Google Scholar
  30. Easton, A. S., Sarker, M. H., and Fraser, P. (1997). Two components of blood-brain barrier disruption in the rat. J. Physiol. 503:613-623.Google Scholar
  31. Elliott, P. J., Hayward, N. J., Huff, M. R., Nagle, T. L., Black, K. L., and Bartus, R. T. (1996). Unlocking the blood-brain barrier: A role for RMP-7 in brain tumor therapy. Exp. Neurol. 141:214-224.Google Scholar
  32. Feolde, E., Vigne, P., Breittmayer, J. P., and Frelin, C. (1995). ATP, a partial agonist of atypical P2Y purinoceptors in rat brain microvascular endothelial cells. Br. J. Pharmacol. 115:1199-1203.Google Scholar
  33. Frelin, C., Breittmayer, J. P., and Vigne, P. (1993). ADP induces inositol phosphate-independent intracellular Ca2+ mobilization in brain capillary endothelial cells. J. Biol. Chem. 268:8787-8792.Google Scholar
  34. Gehrmann, J., Matsumoto, Y., and Kreutzberg, G. W. (1995). Microglia: Intrinsic immuneffector cell of the brain. Brain Res. Rev. 20:269-287.Google Scholar
  35. Grant, G. A., Abbott, N. J., and Janigro, D. (1998). Understanding the physiology of the blood-brain barrier: In vitro models. News Physiol. Sci. 13:287-293.Google Scholar
  36. Greenwood, J. (1992). Experimental manipulation of the blood-brain barrier and blood-retinal barriers. In Bradbury, M. W. B. (ed.), Physiology and Pharmacology of the Blood-Brain Barrier, Springer Verlag, Berlin, pp. 459-479.Google Scholar
  37. Hardebo, J. E., Owman, Ch., and Wiklund, L. (1981). Influence of neurotransmitter monoamines and neurotoxic analogues on morphological blood-brain barrier function. In Cervos-Navarro, J., and Fristschka, E. (eds.), Cerebral Microcirculation and Metabolism, Raven Press, New York, pp. 177-180.Google Scholar
  38. He, P., and Curry, F. E. (1993). Differential actions of cAMP on endothelial [Ca2+]i and permeability in microvessels exposed to ATP. Am. J. Physiol. 265:H1019-1023.Google Scholar
  39. He, P., and Curry, F. E. (1994). Endothelial hyperpolarization increases [Ca2+]i and venular microvessel permeability. J. Appl. Physiol. 76:2288-2297.Google Scholar
  40. Hu, D.-E., and Fraser, P. A. (1997). Evidence for interleukin-1β mediating enhanced permeability responses to bradykinin in single pial venular capillaries of anaesthetized rats. J. Physiol. 505:53P.Google Scholar
  41. Inamura, T., Nomura, T., Bartus, R. T., and Black, K. L. (1994). Intracarotid infusion of RMP-7, a bradykinin analog-Amethod for selective drug-delivery to brain-tumors. J. Neurosurg. 81:752-758.Google Scholar
  42. Joó, F. (1992). The cerebral microvessels in culture, an update. J. Neurochem. 58:1-17.Google Scholar
  43. Joó, F. (1993). The role of second messenger molecules in the regulation of permeability in the cerebral endothelial cells. Adv. Exp. Med. Biol. 331:155-164.Google Scholar
  44. Joó, F. (1995). Isolated brain microvessels and cultured cerebral endothelial cells in blood-brain barrier research: 20 years on. In Greenwood, J., Begley, D. J., and Segal, M. B. (eds.), New Concepts of a Blood-Brain Barrier, Plenum Press, New York, pp. 229-237.Google Scholar
  45. Kniesel, U., and Wolburg, H. (1999). Tight junctions of the blood-brain barrier. Cell. Mol. Neurobiol. 20:57-77.Google Scholar
  46. Kurokawa, T., and Fraser, P. A. (1995). A bradykinin antagonist prevents cerebral microvascular permeability increase following reperfusion in rats. Physiol. 483:140P.Google Scholar
  47. Maier-Hauff, K., Baethmann, A. J., Lange, M., Schurer, L., and Unterberg, A. (1984). The kallikreinkinin system as mediator in vasogenic brain edema. Part 2: Studies on kinin formation in focal and perifocal brain tissue. J. Neurosurg. 61:97-106.Google Scholar
  48. Nagy, Z., Peters, H., and Huttner, I. (1984). Fracture faces of cell junctions in cerebral endothelium during normal and hyperosmotic conditions. Lab. Invest. 50:313-322.Google Scholar
  49. Neal, C. R., and Michel, C. C. (1992). Transcellular openings through microvascular walls in acutely inflammed frog mesentery. Exp. Physiol. 77:917-920.Google Scholar
  50. Nobles, M., and Abbott, N. J. (1996). Effects of cyclic nucleotides on the increase in [Ca2+]i caused by external ATP in the brain endothelial cell line, RBE4. J. Physiol. 491:38P.Google Scholar
  51. Nobles, M., Revest, P. A., Couraud, P.-O., and Abbott, N. J. (1995). Characteristics of nucleotide receptors that cause elevation of cytoplasmic calcium in immortalized rat brain endothelial cells (RBE4) and in primary cultures. Br. J. Pharmacol. 115:1245-1252.Google Scholar
  52. Ohnishi, T., Posner, J., and Shapiro, W. R. (1992). Vasogenic brain edema induced by arachidonic acid: Role of extracellular arachidonic acid in blood-brain barrier dysfunction. Neurosurgery 30:545-551.Google Scholar
  53. Olsen, S.-P. (1985). A calcium-dependent reversible permeability increase in microvessels in frog brain induced by serotonin. J. Physiol. 361:103-113.Google Scholar
  54. Olesen, S.-P. (1989). An electrophysiological study of microvascular permeability and its modulation by chemical mediators. Acta Physiol. Scand. 136 (Suppl 579):1-28.Google Scholar
  55. Olesen, S.-P., and Crone, C. (1986). Substances that rapidly augment ionic conductance of endothelium in cerebral venules. Acta Physiol. Scand. 127:233-241.Google Scholar
  56. Pardridge, W. M. (1994) New approaches to drug delivery through the blood-rain barrier. Trends Biotech. 12: 239-245.Google Scholar
  57. Purkiss, J. R., West, D., Wilkes, L. C., Scott, C., Yarrow, P., Wilkinson, G. F., and Boader, M. R. (1994). Stimulation of phospholipase C in cultured microvascular endothelial cells from human frontal lobe by histamine, endothelin and purinoceptor agonists. Br. J. Pharmacol. 111: 1041-1046.Google Scholar
  58. Revest, P. A., Abbott, N. J., and Gillespie, J. I. (1991). Receptor-mediated changes in intracellular [Ca2+] in cultured rat brain capillary endothelial cells. Brain Res. 549: 159-161.Google Scholar
  59. Rozniecki, J. J., Hauser, S. L., Stein, M., Lincoln, R., and Theoharides, T. C. (1995). Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients. Ann. Neurol. 37:63-66.Google Scholar
  60. Sardesai, V. M. (1992). Biochemical and nutritional aspects of lipoproteins and leukotriene biosynthesis as potential therapeutic targets. Progr. Drug Res. 37:9-90.Google Scholar
  61. Sarker, M. H., and Fraser, P. A. (1994). Evidence that bradykinin increases permeability of single cerebral microvessels via free-radicals in the rat. J. Physiol. 479:36P.Google Scholar
  62. Sarker, M. H., and Fraser, P. A. (1995). Bradykinin and des-Arg9-bradykinin increase permeability of single cerebral microvessels by different mechanisms in the rat. J. Physiol. 483:141P.Google Scholar
  63. Sarker, M. H., and Fraser, P. A. (1996). Effect of 5-HT in the regulation of cerebral microvascular permeability in the anaesthetized rat. J. Physiol. 491:29-30P.Google Scholar
  64. Sarker, M. H., and Fraser, P. A. (1998). Evidence that bradykinin increases cerebral microvascular permeability via cGMP generated independently from soluble guanylate cyclase in the anaesthetized rat. J. Physiol. 506:22P.Google Scholar
  65. Sarker, M. H., Easton, A. S., and Fraser, P. A. (1998). Regulation of cerebral microvascular permeability by histamine in the anaesthetized rat. J. Physiol. 507:909-918.Google Scholar
  66. Saunders, N. R., Knott, G. W., and Dziegielewska, K. M. (1999). Barriers in the immature brain. Cell. Mol. Neurobiol. 20:29-40.Google Scholar
  67. Schilling, L., and Wahl, M. (1994) Opening of the blood-brain barrier during cortical superfusion with histamine. Brain Res. 653:289-296.Google Scholar
  68. Schulze, C., and Firth, J. A. (1992) Interendothelial junctions during blood-brain barrier development in the rat: Morphological changes at the level of individual tight junctional contacts. Dev. Brain Res. 69:85-95.Google Scholar
  69. Schulze, C., and Firth, J. A. (1993). Junctions between pericytes and the endothelium in rat myocardial capillaries: A morphometric and immunogold study. Cell Tissue Res. 271:145-154.Google Scholar
  70. Sharma, H. S., and Dey, P. K. (1986a). Probable involvement of 5-hydroxytryptamine in increased permeability of blood-brain barrier under heat stress in young rats. Neuropharmacology 25:161-167.Google Scholar
  71. Sharma, H. S., and Dey, P. K. (1986b). Influence of long-term immobilization on regional blood-brain barrier permeability, cerebral blood flow and 5-HT level in conscious normotensive young rats. J. Neurol. Sci. 72:61-76.Google Scholar
  72. Sharma, H. S., Olsson, Y., and Dey, P. K. (1990). Changes in blood-brain barrier and cerebral blood flow following elevation of circulating serotonin level in anaesthetized rats. Brain Res. 517:215-223.Google Scholar
  73. Sharma, H. S., Olsson, Y., and Westman, J. (1995) A serotonin inhibitor, p-chlorophenylalanine reduces the heat-shock protein response following trauma to the spinal cord–An immunohistochemical and ultrastructural study in the rat. Neurosci. Res. 21:241-249.Google Scholar
  74. Shepro, D., and Morel, N. M. L. (1993). Pericyte physiology. FASEB J. 7:1031-1038.Google Scholar
  75. Shi, F., Cavitt, J., and Audus, K. L. (1995). 21-Aminosteroid and 2-(aminomethyl)chromans inhibition of arachidonic acid-induced lipid peroxidation and permeability enhancement in bovine brain microvessel endothelial cell monolayers. Free Radical Biol. Med. 19:349-357.Google Scholar
  76. Smith, Q. (1992). Methods of study. In Bradbury, M. W. B. (ed.), Physiology and Pharmacology of the Blood-Brain Barrier, Springer Verlag, Berlin, pp. 23-52.Google Scholar
  77. Stewart, P. A. (2000). Endothelial vesicles in the blood-brain barrier: Are they related to permeability? Cell. Mol. Neurobiol. 20:149-163.Google Scholar
  78. Takagi, H., Morishima, Y., Matsuyama, T., Hayashi, H, Watanabe, T., and Wada H. (1986) Histaminergic axons in the neostriatum and cerebral cortex of the rat: A correlated light and electron microscopic immunocytochemical study using histidine decarboxylase as a marker. Brain Res. 364:114-123.Google Scholar
  79. Todd, B. A., Sedgwick, E. M., and Abbott, N. J. (1997) Effects of the bile salt sodium deoxycholate, protamine, and inflammatory mediators on the potassium permeability of the frog nerve perineurium. Brain Res. 776:214-221.Google Scholar
  80. Unterberg, A., Wahl, M., and Baethmann, A. (1984). Effects of bradykinin on permeability and diameter of pial vessels in vivo. J. Cereb. Blood Flow Metab. 4:574-585.Google Scholar
  81. Vigne, P., Lund, L., and Frelin, C. (1994). Cross talk among cyclic AMP, cyclic GMP, and Ca2+-dependent intracellular signalling mechanisms in brain capillary endothelial cells.J. Neurochem. 62:2269-2274.Google Scholar
  82. Vigne, P., Feolde, E., Breittmayer J. P., and Frelin, C. (1994). Characterization of the effects of 2-methylthio-ATP and 2-chloro-ATP on brain capillary endothelial cells: similarities to ADP and differences from ATP. Br. J. Pharmacol. 112:775-780.Google Scholar
  83. Wada, H., Inagaki, N., Yamatodani, A., and Watanabe, T. (1991) Is the histaminergic neuron system a regulatory center for whole brain activity? Trends Neurosci. 14:415-418.Google Scholar
  84. Wahl, M., Unterberg, A., Baethmann, A., and Schilling, L. (1988). Mediators of blood-brain barrier dysfunction and formation of vasogenic brain edema. J. Cereb. Blood Flow Metab. 8:621-634.Google Scholar
  85. Webb, T. E., Feolde, E., Vigne, P., Neary, J. T., Runberg, A., Frelin, C., and Barnard, E. A. (1996) The P2Y purinoceptor in rat brain microvascular endothelial cells couple to inhibition of adenylate cyclase. Br. J. Pharmacol. 119:1385-1392.Google Scholar
  86. Wei, E. P., Ellison, M. D., Kontos, H. A., and Povlishock, J. T. (1986). O2 radicals in arachidonate-induced increased blood-brain barrier permeability to proteins. Am J. Physiol. 251:H693-H699.Google Scholar
  87. Winkler, T., Sharma, H. S., Stalberg, E., Olsson, Y., and Dey, P. K. (1995). Impairment of bloodbrain barrier function by serotonin induces desynchronization of spontaneous cerebral cortical activity-Experimental observations in the anesthetized rat. Neuroscience 68:1097-1104.Google Scholar
  88. Wolburg H., and Risau, W. (1995). Formation of the blood-brain barrier. In Kettenmann, H., and Ransom, B. R. (eds.), Neuroglia, Oxford University Press, Oxford, pp. 763-776.Google Scholar

Copyright information

© Plenum Publishing Corporation 2000

Authors and Affiliations

  • N. Joan Abbott
    • 1
  1. 1.Division of Physiology, GKT School of Biomedical SciencesKing's College LondonLondonUK

Personalised recommendations