Blood-brain barrier function in intracerebral hemorrhage

  • R. F. Keep
  • J. Xiang
  • S. R. Ennis
  • A. Andjelkovic
  • Y. Hua
  • G. Xi
  • J. T. Hoff
Part of the Acta Neurochirurgica Supplementum book series (NEUROCHIRURGICA, volume 105)


In this paper, we review current knowledge on blood-brain barrier (BBB) dysfunction following intracerebral hemorrhage (ICH). BBB disruption is a hallmark of ICH-induced brain injury. Such disruption contributes to edema formation, the influx of leukocytes, and the entry of potentially neuroactive agents into the perihematomal brain, all of which may contribute to brain injury. A range of factors have been implicated in inducing BBB disruption, including inflammatory mediators (e.g., cytokines and chemokines), thrombin, hemoglobin breakdown products, oxidative stress, complement, and matrix metalloproteinases. While there is interaction between some of these mediators, it is probable that prevention of ICH-induced BBB disruption will involve blocking multiple pathways or blocking a common end pathway (e.g., by stabilizing tight junction structure). While the effects of ICH on BBB passive permeability have been extensively examined, effects on other ‘barrier’ properties (metabolic and transport functions) have been less well-studied. However, recent data suggests that ICH can affect transport and that this may help protect the BBB and the brain. Indeed, it is possible in small bleeds that BBB disruption may be beneficial, and it is only in the presence of larger bleeds that disruption has detrimental effects.


Blood-brain barrier tight junctions transport intracerebral hemorrhage 


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  1. 1.
    Abbott NJ (2000) Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol Neurobiol 20: 131–147PubMedCrossRefGoogle Scholar
  2. 2.
    Abbott NJ, Rönnbäck L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7: 41–53PubMedCrossRefGoogle Scholar
  3. 3.
    Alvarez-Sabin J, Delgado P, Abilleira S, Molina CA, Arenillas J, Ribó M, Santamarina E, Quintana M, Monasterio J, Montaner J (2004) Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke 35: 1316–1322PubMedCrossRefGoogle Scholar
  4. 4.
    Belayev L, Saul I, Busto R, Danielyan K, Vigdorchik A, Khoutorova L, Ginsberg MD (2005) Albumin treatment reduces neurological deficit and protects blood-brain barrier integrity after acute intra-cortical hematoma in the rat. Stroke 36: 326–331PubMedCrossRefGoogle Scholar
  5. 5.
    Bhasin RR, Xi G, Hua Y, Keep RF, Hoff JT (2002) Experimental intracerebral hemorrhage: effect of lysed erythrocytes on brain edema and blood-brain barrier permeability. Acta Neurochir Suppl 81: 249–251PubMedGoogle Scholar
  6. 6.
    Cipolla MJ, Crete R, Vitullo L, Rix RD (2004) Transcellular transport as a mechanism of blood-brain barrier disruption during stroke. Front Biosci 9: 777–785PubMedCrossRefGoogle Scholar
  7. 7.
    Delgado P, Alvarez Sabin J, Santamarina E, Molina CA, Quintana M, Rosell A, Montaner J (2006) Plasma S100B level after acute spontaneous intracerebral hemorrhage. Stroke 37: 2837–2839PubMedCrossRefGoogle Scholar
  8. 8.
    Dimitrijevic OB, Stamatovic SM, Keep RF, Andjelkovic AV (2006) Effects of the chemokine CCL2 on blood-brain barrier permeability during ischemia-reperfusion injury. J Cereb Blood Flow Metab 26: 797–810PubMedCrossRefGoogle Scholar
  9. 9.
    Goldstein JN, Fazen LE, Snider R, Schwab K, Greenberg SM, Smith EE, Lev MH, Rosand J (2007) Contrast extravasation on CT angiography predicts hematoma expansion in intracerebral hemorrhage. Neurology 68: 889–894PubMedCrossRefGoogle Scholar
  10. 10.
    Guan JX, Sun SG, Cao XB, Chen ZB, Tong ET (2004) Effect of thrombin on blood-brain barrier permeability and its mechanism. Chin Med J (Engl) 117: 1677–1681Google Scholar
  11. 11.
    Hawkins BT, Davis TP (2005) The blood-brain barrier/neurovas-cular unit in health and disease. Pharmacol Rev 57: 173–185PubMedCrossRefGoogle Scholar
  12. 12.
    Hosoya K, Tomi M, Ohtsuki S, Takanaga H, Saeki S, Kanai Y, Endou H, Naito M, Tsuruo T, Terasaki T (2002) Enhancement of L-cystine transport activity and its relation to xCT gene induction at the blood-brain barrier by diethyl maleate treatment. J Pharmacol Exp Ther 302: 225–231PubMedCrossRefGoogle Scholar
  13. 13.
    Hua Y, Xi G, Keep RF, Hoff JT (2000) Complement activation in the brain after experimental intracerebral hemorrhage. J Neurosurg 92: 1016–1022PubMedGoogle Scholar
  14. 14.
    Iida S, Baumbach GL, Lavoie JL, Faraci FM, Sigmund CD, Heistad DD (2005) Spontaneous stroke in a genetic model of hypertension in mice. Stroke 36: 1253–1258PubMedCrossRefGoogle Scholar
  15. 15.
    Keep RF (2001) The blood-brain barrier. In: Walz W (ed) The neuronal microenvironment: brain homeostasis in health and disease. Humana Press, Totowa, pp 277–307Google Scholar
  16. 16.
    Keep RF, Kawai N, Stummer W, Fujisawa M, Patel T, Abdelkarim GE, Ennis SR, Betz AL (1999) Sodium-dependent transport at the blood-brain barrier and the effects of cerebral ischemia. In: Paulson OB, Knudsen GM, Moos T (eds) Review of brain barrier systems, Alfred Benzon Symposium 45. Munksgaard Press, Copenhagen, pp 387–395Google Scholar
  17. 17.
    Kidwell CS, Latour LL, Hsia AW, Merino JG, Burgess RE, Copenhaver BR, Castle A, Warach S (2007) Demonstration of blood-brain barrier disruption in humans with primary intracere-bral hemorrhage (Abstract #47). Stroke 38: 464CrossRefGoogle Scholar
  18. 18.
    Lee KR, Kawai N, Kim S, Sagher O, Hoff JT (1997) Mechanisms of edema formation after intracerebral hemorrhage: effects of throm-bin on cerebral blood flow, blood-brain barrier permeability, and cell survival in a rat model. J Neurosurg 86: 272–278PubMedGoogle Scholar
  19. 19.
    Lu A, Tang Y, Ran R, Ardizzone TL, Wagner KR, Sharp FR (2006) Brain genomics of intracerebral hemorrhage. J Cereb Blood Flow Metab 26: 230–252PubMedCrossRefGoogle Scholar
  20. 20.
    MacLellan CL, Davies LM, Fingas MS, Colbourne F (2006) The influence of hypothermia on outcome after intracerebral hemorrhage in rats. Stroke 37:1266–1270PubMedCrossRefGoogle Scholar
  21. 21.
    Marchi N, Rasmussen P, Kapural M, Fazio V, Kight K, Mayberg MR, Kanner A, Ayumar B, Albensi B, Cavaglia M, Janigro D (2003) Peripheral markers of brain damage and blood-brain barrier dysfunction. Restor Neurol Neuros 21: 109–121Google Scholar
  22. 22.
    Mendelow AD, Gregson BA, Fernandes HM, Murray GD, Teasdale GM, Hope DT, Karimi A, Shaw MD, Barer DH, STICH investigators (2005) Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 365: 387–397PubMedGoogle Scholar
  23. 23.
    Mun-Bryce S, Rosenberg GA (1998) Metrix metalloproteinases in cerebrovascular disease. J Cereb Blood Flow Metab 18: 1163–1172PubMedCrossRefGoogle Scholar
  24. 24.
    Murai Y, Ikeda Y, Teramoto A, Tsuji Y (1998) Magnetic resonance imaging-documented extravasation as an indicator of acute hypertensive intracerebral hemorrhage. J Neurosurg 88: 650–655PubMedGoogle Scholar
  25. 25.
    Patel TR, Fujisawa M, Schielke GP, Hoff JT, Betz AL, Keep RF (1999) Effect of intracerebral and subdural hematomas on energy-dependent transport across the blood-brain barrier. J Neurotraum 16: 1049–1055CrossRefGoogle Scholar
  26. 26.
    Petito CK (1979) Early and late mechanisms of increased vascular permeability following experimental cerebral infarction. J Neuro-pathol Exp Neurol 38: 222–234Google Scholar
  27. 27.
    Preston E, Webster J (2002) Differential passage of [14C]sucrose and [3H]inulin across rat blood-brain barrier after cerebral ischemia. Acta Neuropathol 103: 237–242PubMedCrossRefGoogle Scholar
  28. 28.
    Qin Z, Song S, Xi G, Silbergleit R, Keep RF, Hoff JT, Hua Y (2007) Preconditioning with hyperbaric oxygen attenuates brain edema after experimental intracerebral hemorrhage. Neurosurg Focus 22: E13PubMedCrossRefGoogle Scholar
  29. 29.
    Rosenberg GA, Estrada E, Kelley RO, Kornfeld M (1993) Bacterial collagenase disrupts extracellular matrix and opens blood-brain barrier in rat. Neurosci Lett 160: 117–119PubMedCrossRefGoogle Scholar
  30. 30.
    Rosenberg GA, Kornfeld M, Estrada E, Kelley RO, Liotta LA, Stetler-Stevenson WG (1992) TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase. Brain Res 576: 203–207PubMedCrossRefGoogle Scholar
  31. 31.
    Rosenberg GA, Mun-Bryce S, Wesley M, Kornfeld M (1990) Collagenase-induced intracerebral hemorrhage in rats. Stroke 21: 801–807PubMedGoogle Scholar
  32. 32.
    Stamatovic SM, Shakui P, Keep RF, Moore BB, Kunkel SL, VanRooijen N, Andjelkovic AV (2005) Monocyte chemoattractant protein-1 regulation of blood-brain barrier permeability. J Cereb Blood Flow Metab 25: 593–606PubMedCrossRefGoogle Scholar
  33. 33.
    Stamatovic SM, Dimitrijevic OB, Keep RF, Andjelkovic AV (2006) Protein kinase C-alpha-RhoA cross-talk in CCL2-induced alterations in brain endothelial permeability. J Biol Chem 281: 8379–8388PubMedCrossRefGoogle Scholar
  34. 34.
    Wagner KR (2007) Modeling intracerebral hemorrhage: glutamate, nuclear factor-kappa B signaling and cytokines. Stroke 38: 753–758PubMedCrossRefGoogle Scholar
  35. 35.
    Wagner KR, Xi G, Hua Y, Kleinholz M, de Courten-Myers GM, Myers RE, Broderick JP, Brott TG (1996) Lobar intracerebral hemorrhage model in pigs: rapid edema development in perihema-tomal white matter. Stroke 27: 490–497PubMedGoogle Scholar
  36. 36.
    Wagner KR, Xi G, Hua Y, Zuccarello M, de Courten-Myers GM, Broderick JP, Brott TG (1999) Ultra-early clot aspiration after lysis with tissue plasminogen activator in a porcine model of intracerebral hemorrhage: edema reduction and blood brain barrier protection. J Neurosurg 90: 491–498PubMedGoogle Scholar
  37. 37.
    Wagner KR, Beiler S, Beiler C, Kirkman J, Casey K, Robinson T, Larnard D, de Courten-Myers GM, Linke MJ, Zuccarello M (2006) Delayed profound local brain hypothermia markedly reduces inter-leukin-1beta gene expression and vasogenic edema development in a porcine model of intracerebral hemorrhage. Acta Neurochir Suppl 96: 177–182PubMedCrossRefGoogle Scholar
  38. 38.
    Xi G, Hua Y, Bhasin RR, Ennis SR, Keep RF, Hoff JT (2001) Mechanisms of edema formation after intracerebral hemorrhage: effects of extravasated red blood cells on blood flow and blood-brain barrier integrity. Stroke 32: 2932–2938PubMedCrossRefGoogle Scholar
  39. 39.
    Xi G, Keep RF, Hoff JT (2006) Mechanisms of brain injury after intracerebral hemorrhage. Lancet Neurol 5: 53–63PubMedCrossRefGoogle Scholar
  40. 40.
    Yang GY, Betz AL, Chenevert TL, Brunberg JA, Hoff JT (1994) Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. J Neurosurg 81: 93–102PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • R. F. Keep
    • 1
    • 2
  • J. Xiang
    • 1
  • S. R. Ennis
    • 1
  • A. Andjelkovic
    • 1
    • 3
  • Y. Hua
    • 1
  • G. Xi
    • 1
  • J. T. Hoff
    • 1
  1. 1.Department of NeurosurgeryUniversity of Michigan Medical SchoolAnn ArborUSA
  2. 2.Department of Molecular and Integrative PhysiologyUniversity of Michigan Medical SchoolAnn ArborUSA
  3. 3.Department of PathologyUniversity of Michigan Medical SchoolAnn ArborUSA

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