Translational Stroke Research

, Volume 2, Issue 4, pp 492–516 | Cite as

Blood–Brain Barrier Pathophysiology in Traumatic Brain Injury

  • Adam Chodobski
  • Brian J. Zink
  • Joanna Szmydynger-Chodobska
Review Article


The blood–brain barrier (BBB) is formed by tightly connected cerebrovascular endothelial cells, but its normal function also depends on paracrine interactions between the brain endothelium and closely located glia. There is a growing consensus that brain injury, whether it is ischemic, hemorrhagic, or traumatic, leads to dysfunction of the BBB. Changes in BBB function observed after injury are thought to contribute to the loss of neural tissue and to affect the response to neuroprotective drugs. New discoveries suggest that considering the entire gliovascular unit, rather than the BBB alone, will expand our understanding of the cellular and molecular responses to traumatic brain injury (TBI). This review will address the BBB breakdown in TBI, the role of blood-borne factors in affecting the function of the gliovascular unit, changes in BBB permeability and post-traumatic edema formation, and the major pathophysiological factors associated with TBI that may contribute to post-traumatic dysfunction of the BBB. The key role of neuroinflammation and the possible effect of injury on transport mechanisms at the BBB will also be described. Finally, the potential role of the BBB as a target for therapeutic intervention through restoration of normal BBB function after injury and/or by harnessing the cerebrovascular endothelium to produce neurotrophic growth factors will be discussed.


Blood–brain barrier Gliovascular unit Traumatic brain injury 



We thank Ms. Julie Sarri for her secretarial help in preparing this manuscript. This work was supported by grant NS49479 from the NIH and by funds from the Department of Emergency Medicine at the Alpert Medical School of Brown University.

Financial and Competing Interests Disclosure

The authors have no financial and/or competing interests to disclose.


  1. 1.
    Saatman KE, Duhaime AC, Bullock R, Maas AI, Valadka A, Manley GT, et al. Classification of traumatic brain injury for targeted therapies. J Neurotrauma. 2008;25(7):719–38.PubMedGoogle Scholar
  2. 2.
    Abbott NJ, Rönnbäck L, Hansson E. Astrocyte–endothelial interactions at the blood–brain barrier. Nat Rev Neurosci. 2006;7(1):41–53.PubMedGoogle Scholar
  3. 3.
    Wolburg H, Noell S, Mack A, Wolburg-Buchholz K, Fallier-Becker P. Brain endothelial cells and the glio-vascular complex. Cell Tissue Res. 2009;335(1):75–96.PubMedGoogle Scholar
  4. 4.
    Lassmann H, Zimprich F, Vass K, Hickey WF. Microglial cells are a component of the perivascular glia limitans. J Neurosci Res. 1991;28(2):236–43.PubMedGoogle Scholar
  5. 5.
    Neuwelt E, Abbott NJ, Abrey L, Banks WA, Blakley B, Davis T, et al. Strategies to advance translational research into brain barriers. Lancet Neurol. 2008;7(1):84–96.PubMedGoogle Scholar
  6. 6.
    Gennarelli TA. Animate models of human head injury. J Neurotrauma. 1994;11(4):357–68.PubMedGoogle Scholar
  7. 7.
    Povlishock JT, Hayes RL, Michel ME, McIntosh TK. Workshop on animal models of traumatic brain injury. J Neurotrauma. 1994;11(6):723–32.PubMedGoogle Scholar
  8. 8.
    Dietrich WD, Alonso O, Halley M. Early microvascular and neuronal consequences of traumatic brain injury: a light and electron microscopic study in rats. J Neurotrauma. 1994;11(3):289–301.PubMedGoogle Scholar
  9. 9.
    Stein SC, Chen XH, Sinson GP, Smith DH. Intravascular coagulation: a major secondary insult in nonfatal traumatic brain injury. J Neurosurg. 2002;97(6):1373–7.PubMedGoogle Scholar
  10. 10.
    Schwarzmaier SM, Kim SW, Trabold R, Plesnila N. Temporal profile of thrombogenesis in the cerebral microcirculation after traumatic brain injury in mice. J Neurotrauma. 2010;27(1):121–30.PubMedGoogle Scholar
  11. 11.
    del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab. 2003;23(8):879–94.PubMedGoogle Scholar
  12. 12.
    Schröder ML, Muizelaar JP, Fatouros PP, Kuta AJ, Choi SC. Regional cerebral blood volume after severe head injury in patients with regional cerebral ischemia. Neurosurgery. 1998;42(6):1276–80. discussion 1280–1.PubMedGoogle Scholar
  13. 13.
    von Oettingen G, Bergholt B, Gyldensted C, Astrup J. Blood flow and ischemia within traumatic cerebral contusions. Neurosurgery. 2002;50(4):781–8. discussion 788–90.Google Scholar
  14. 14.
    Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308(5726):1314–8.PubMedGoogle Scholar
  15. 15.
    Adams RA, Bauer J, Flick MJ, Sikorski SL, Nuriel T, Lassmann H, et al. The fibrin-derived γ377–395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J Exp Med. 2007;204(3):571–82.PubMedGoogle Scholar
  16. 16.
    Lishko VK, Kudryk B, Yakubenko VP, Yee VC, Ugarova TP. Regulated unmasking of the cryptic binding site for integrin αMβ2 in the γC-domain of fibrinogen. Biochemistry. 2002;41(43):12942–51.PubMedGoogle Scholar
  17. 17.
    Altieri DC, Plescia J, Plow EF. The structural motif glycine 190-valine 202 of the fibrinogen γ chain interacts with CD11b/CD18 integrin (αMβ2, Mac-1) and promotes leukocyte adhesion. J Biol Chem. 1993;268(3):1847–53.PubMedGoogle Scholar
  18. 18.
    Smiley ST, King JA, Hancock WW. Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4. J Immunol. 2001;167(5):2887–94.PubMedGoogle Scholar
  19. 19.
    Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, Strassheim D, et al. High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol. 2006;290(3):C917–24.Google Scholar
  20. 20.
    Schachtrup C, Lu P, Jones LL, Lee JK, Lu J, Sachs BD, et al. Fibrinogen inhibits neurite outgrowth via β3 integrin-mediated phosphorylation of the EGF receptor. Proc Natl Acad Sci USA. 2007;104(28):11814–9.PubMedGoogle Scholar
  21. 21.
    Schachtrup C, Ryu JK, Helmrick MJ, Vagena E, Galanakis DK, Degen JL, et al. Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-β after vascular damage. J Neurosci. 2010;30(17):5843–54.PubMedGoogle Scholar
  22. 22.
    Dihanich M, Kaser M, Reinhard E, Cunningham D, Monard D. Prothrombin mRNA is expressed by cells of the nervous system. Neuron. 1991;6(4):575–81.PubMedGoogle Scholar
  23. 23.
    Shikamoto Y, Morita T. Expression of factor X in both the rat brain and cells of the central nervous system. FEBS Lett. 1999;463(3):387–9.PubMedGoogle Scholar
  24. 24.
    Citron BA, Smirnova IV, Arnold PM, Festoff BW. Upregulation of neurotoxic serine proteases, prothrombin, and protease-activated receptor 1 early after spinal cord injury. J Neurotrauma. 2000;17(12):1191–203.PubMedGoogle Scholar
  25. 25.
    Riek-Burchardt M, Striggow F, Henrich-Noack P, Reiser G, Reymann KG. Increase of prothrombin-mRNA after global cerebral ischemia in rats, with constant expression of protease nexin-1 and protease-activated receptors. Neurosci Lett. 2002;329(2):181–4.PubMedGoogle Scholar
  26. 26.
    Coughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000;407(6801):258–64.PubMedGoogle Scholar
  27. 27.
    Striggow F, Riek-Burchardt M, Kiesel A, Schmidt W, Henrich-Noack P, Breder J, et al. Four different types of protease-activated receptors are widely expressed in the brain and are up-regulated in hippocampus by severe ischemia. Eur J Neurosci. 2001;14(4):595–608.PubMedGoogle Scholar
  28. 28.
    Xi G, Reiser G, Keep RF. The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: deleterious or protective? J Neurochem. 2003;84(1):3–9.PubMedGoogle Scholar
  29. 29.
    Donovan FM, Pike CJ, Cotman CW, Cunningham DD. Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities. J Neurosci. 1997;17(14):5316–26.PubMedGoogle Scholar
  30. 30.
    Nicole O, Goldshmidt A, Hamill CE, Sorensen SD, Sastre A, Lyuboslavsky P, et al. Activation of protease-activated receptor-1 triggers astrogliosis after brain injury. J Neurosci. 2005;25(17):4319–29.PubMedGoogle Scholar
  31. 31.
    Möller T, Hanisch UK, Ransom BR. Thrombin-induced activation of cultured rodent microglia. J Neurochem. 2000;75(4):1539–47.PubMedGoogle Scholar
  32. 32.
    Ryu J, Pyo H, Jou I, Joe E. Thrombin induces NO release from cultured rat microglia via protein kinase C, mitogen-activated protein kinase, and NF-κB. J Biol Chem. 2000;275(39):29955–9.PubMedGoogle Scholar
  33. 33.
    Suo Z, Wu M, Ameenuddin S, Anderson HE, Zoloty JE, Citron BA, et al. Participation of protease-activated receptor-1 in thrombin-induced microglial activation. J Neurochem. 2002;80(4):655–66.PubMedGoogle Scholar
  34. 34.
    Nagy Z, Kolev K, Csonka E, Pék M, Machovich R. Contraction of human brain endothelial cells induced by thrombogenic and fibrinolytic factors. An in vitro cell culture model. Stroke. 1995;26(2):265–70.PubMedGoogle Scholar
  35. 35.
    Bartha K, Dömötör E, Lanza F, Adam-Vizi V, Machovich R. Identification of thrombin receptors in rat brain capillary endothelial cells. J Cereb Blood Flow Metab. 2000;20(1):175–82.PubMedGoogle Scholar
  36. 36.
    Choi BH, Suzuki M, Kim T, Wagner SL, Cunningham DD. Protease nexin-1. Localization in the human brain suggests a protective role against extravasated serine proteases. Am J Pathol. 1990;137(4):741–7.PubMedGoogle Scholar
  37. 37.
    Hooper C, Taylor DL, Pocock JM. Pure albumin is a potent trigger of calcium signalling and proliferation in microglia but not macrophages or astrocytes. J Neurochem. 2005;92(6):1363–76.PubMedGoogle Scholar
  38. 38.
    Ralay Ranaivo H, Wainwright MS. Albumin activates astrocytes and microglia through mitogen-activated protein kinase pathways. Brain Res. 2010;1313:222–31.PubMedGoogle Scholar
  39. 39.
    Cacheaux LP, Ivens S, David Y, Lakhter AJ, Bar-Klein G, Shapira M, et al. Transcriptome profiling reveals TGF-β signaling involvement in epileptogenesis. J Neurosci. 2009;29(28):8927–35.PubMedGoogle Scholar
  40. 40.
    Ralay Ranaivo H, Patel F, Wainwright MS. Albumin activates the canonical TGF receptor-smad signaling pathway but this is not required for activation of astrocytes. Exp Neurol. 2010;226(2):310–9.PubMedGoogle Scholar
  41. 41.
    Ivens S, Kaufer D, Flores LP, Bechmann I, Zumsteg D, Tomkins O, et al. TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain. 2007;130(2):535–47.PubMedGoogle Scholar
  42. 42.
    David Y, Cacheaux LP, Ivens S, Lapilover E, Heinemann U, Kaufer D, et al. Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis? J Neurosci. 2009;29(34):10588–99.PubMedGoogle Scholar
  43. 43.
    Zhao TZ, Xia YZ, Li L, Li J, Zhu G, Chen S, et al. Bovine serum albumin promotes IL-1β and TNF-α secretion by N9 microglial cells. Neurol Sci. 2009;30(5):379–83.PubMedGoogle Scholar
  44. 44.
    Hooper C, Pinteaux-Jones F, Fry VA, Sevastou IG, Baker D, Heales SJ, et al. Differential effects of albumin on microglia and macrophages; implications for neurodegeneration following blood–brain barrier damage. J Neurochem. 2009;109(3):694–705.PubMedGoogle Scholar
  45. 45.
    Nakamura Y, Si QS, Takaku T, Kataoka K. Identification of a peptide sequence in albumin that potentiates superoxide production by microglia. J Neurochem. 2000;75(6):2309–15.PubMedGoogle Scholar
  46. 46.
    Shapira Y, Setton D, Artru AA, Shohami E. Blood–brain barrier permeability, cerebral edema, and neurologic function after closed head injury in rats. Anesth Analg. 1993;77(1):141–8.PubMedGoogle Scholar
  47. 47.
    Baldwin SA, Fugaccia I, Brown DR, Brown LV, Scheff SW. Blood–brain barrier breach following cortical contusion in the rat. J Neurosurg. 1996;85(3):476–81.PubMedGoogle Scholar
  48. 48.
    Hicks RR, Baldwin SA, Scheff SW. Serum extravasation and cytoskeletal alterations following traumatic brain injury in rats. Comparison of lateral fluid percussion and cortical impact models. Mol Chem Neuropathol. 1997;32(1–3):1–16.PubMedGoogle Scholar
  49. 49.
    Bașkaya MK, Rao AM, Doğan A, Donaldson D, Dempsey RJ. The biphasic opening of the blood–brain barrier in the cortex and hippocampus after traumatic brain injury in rats. Neurosci Lett. 1997;226(1):33–6.PubMedGoogle Scholar
  50. 50.
    Castejón OJ. Formation of transendothelial channels in traumatic human brain edema. Pathol Res Pract. 1984;179(1):7–12.PubMedGoogle Scholar
  51. 51.
    Vaz R, Sarmento A, Borges N, Cruz C, Azevedo I. Ultrastructural study of brain microvessels in patients with traumatic cerebral contusions. Acta Neurochir (Wien). 1997;139(3):215–20.Google Scholar
  52. 52.
    Preston E, Webster J. Differential passage of [14C]sucrose and [3H]inulin across rat blood–brain barrier after cerebral ischemia. Acta Neuropathol. 2002;103(3):237–42.PubMedGoogle Scholar
  53. 53.
    Liu KF, Li F, Tatlisumak T, Garcia JH, Sotak CH, Fisher M, et al. Regional variations in the apparent diffusion coefficient and the intracellular distribution of water in rat brain during acute focal ischemia. Stroke. 2001;32(8):1897–905.PubMedGoogle Scholar
  54. 54.
    Kelley BJ, Lifshitz J, Povlishock JT. Neuroinflammatory responses after experimental diffuse traumatic brain injury. J Neuropathol Exp Neurol. 2007;66(11):989–1001.PubMedGoogle Scholar
  55. 55.
    Marmarou A, Signoretti S, Fatouros PP, Portella G, Aygok GA, Bullock MR. Predominance of cellular edema in traumatic brain swelling in patients with severe head injuries. J Neurosurg. 2006;104(5):720–30.PubMedGoogle Scholar
  56. 56.
    Tomkins O, Shelef I, Kaizerman I, Eliushin A, Afawi Z, Misk A, et al. Blood–brain barrier disruption in post-traumatic epilepsy. J Neurol Neurosurg Psychiatry. 2008;79(7):774–7.PubMedGoogle Scholar
  57. 57.
    Liu W, Tang Y, Feng J. Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system. Life Sci. 2011;89(5–6):141–6.PubMedGoogle Scholar
  58. 58.
    Koli K, Myllärniemi M, Keski-Oja J, Kinnula VL. Transforming growth factor-β activation in the lung: focus on fibrosis and reactive oxygen species. Antioxid Redox Signal. 2008;10(2):333–42.PubMedGoogle Scholar
  59. 59.
    Pircher R, Jullien P, Lawrence DA. β-transforming growth factor is stored in human blood platelets as a latent high molecular weight complex. Biochem Biophys Res Commun. 1986;136(1):30–7.PubMedGoogle Scholar
  60. 60.
    Constam DB, Philipp J, Malipiero UV, ten Dijke P, Schachner M, Fontana A. Differential expression of transforming growth factor-β1, -β2, and -β3 by glioblastoma cells, astrocytes, and microglia. J Immunol. 1992;148(5):1404–10.PubMedGoogle Scholar
  61. 61.
    Cook JL, Marcheselli V, Alam J, Deininger PL, Bazan NG. Temporal changes in gene expression following cryogenic rat brain injury. Mol Brain Res. 1998;55(1):9–19.PubMedGoogle Scholar
  62. 62.
    Fee DB, Sewell DL, Andresen K, Jacques TJ, Piaskowski S, Barger BA, et al. Traumatic brain injury increases TGFβRII expression on endothelial cells. Brain Res. 2004;1012(1–2):52–9.PubMedGoogle Scholar
  63. 63.
    Shen W, Li S, Chung SH, Zhu L, Stayt J, Su T, et al. Tyrosine phosphorylation of VE-cadherin and claudin-5 is associated with TGF-β1-induced permeability of centrally derived vascular endothelium. Eur J Cell Biol. 2011;90(4):323–32.PubMedGoogle Scholar
  64. 64.
    Garcia CM, Darland DC, Massingham LJ, D'Amore PA. Endothelial cell-astrocyte interactions and TGFβ are required for induction of blood-neural barrier properties. Dev Brain Res. 2004;152(1):25–38.Google Scholar
  65. 65.
    Dohgu S, Takata F, Yamauchi A, Nakagawa S, Egawa T, Naito M, et al. Brain pericytes contribute to the induction and up-regulation of blood–brain barrier functions through transforming growth factor-β production. Brain Res. 2005;1038(2):208–15.PubMedGoogle Scholar
  66. 66.
    Li F, Lan Y, Wang Y, Wang J, Yang G, Meng F, et al. Endothelial Smad4 maintains cerebrovascular integrity by activating N-cadherin through cooperation with Notch. Dev Cell. 2011;20(3):291–302.PubMedGoogle Scholar
  67. 67.
    Tolias CM, Bullock MR. Critical appraisal of neuroprotection trials in head injury: what have we learned? NeuroRx. 2004;1(1):71–9.PubMedGoogle Scholar
  68. 68.
    Marklund N, Bakshi A, Castelbuono DJ, Conte V, McIntosh TK. Evaluation of pharmacological treatment strategies in traumatic brain injury. Curr Pharm Des. 2006;12(13):1645–80.PubMedGoogle Scholar
  69. 69.
    Katayama Y, Becker DP, Tamura T, Hovda DA. Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg. 1990;73(6):889–900.PubMedGoogle Scholar
  70. 70.
    Nilsson P, Hillered L, Pontén U, Ungerstedt U. Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats. J Cereb Blood Flow Metab. 1990;10(5):631–7.PubMedGoogle Scholar
  71. 71.
    Palmer AM, Marion DW, Botscheller ML, Swedlow PE, Styren SD, DeKosky ST. Traumatic brain injury-induced excitotoxicity assessed in a controlled cortical impact model. J Neurochem. 1993;61(6):2015–24.PubMedGoogle Scholar
  72. 72.
    Koizumi H, Fujisawa H, Ito H, Maekawa T, Di X, Bullock R. Effects of mild hypothermia on cerebral blood flow-independent changes in cortical extracellular levels of amino acids following contusion trauma in the rat. Brain Res. 1997;747(2):304–12.PubMedGoogle Scholar
  73. 73.
    Ikonomidou C, Turski L. Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol. 2002;1(6):383–6.PubMedGoogle Scholar
  74. 74.
    Anderson CM, Swanson RA. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia. 2000;32(1):1–14.PubMedGoogle Scholar
  75. 75.
    Maxwell WL, Bullock R, Landholt H, Fujisawa H. Massive astrocytic swelling in response to extracellular glutamate—a possible mechanism for post-traumatic brain swelling? Acta Neurochir Suppl (Wien). 1994;60:465–7.Google Scholar
  76. 76.
    Collard CD, Park KA, Montalto MC, Alapati S, Buras JA, Stahl GL, et al. Neutrophil-derived glutamate regulates vascular endothelial barrier function. J Biol Chem. 2002;277(17):14801–11.PubMedGoogle Scholar
  77. 77.
    Chodobski A, Chung I, Koźniewska E, Ivanenko T, Chang W, Harrington JF, et al. Early neutrophilic expression of vascular endothelial growth factor after traumatic brain injury. Neuroscience. 2003;122(4):853–67.PubMedGoogle Scholar
  78. 78.
    Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflügers Arch. 2010;460(2):525–42.PubMedGoogle Scholar
  79. 79.
    Krizbai IA, Deli MA, Pestenácz A, Siklós L, Szabó CA, András I, et al. Expression of glutamate receptors on cultured cerebral endothelial cells. J Neurosci Res. 1998;54(6):814–9.PubMedGoogle Scholar
  80. 80.
    Gillard SE, Tzaferis J, Tsui HC, Kingston AE. Expression of metabotropic glutamate receptors in rat meningeal and brain microvasculature and choroid plexus. J Comp Neurol. 2003;461(3):317–32.PubMedGoogle Scholar
  81. 81.
    Sharp CD, Hines I, Houghton J, Warren A, Jackson THt, Jawahar A, et al. Glutamate causes a loss in human cerebral endothelial barrier integrity through activation of NMDA receptor. Am J Physiol. 2003;285(6):H2592–8.Google Scholar
  82. 82.
    Morley P, Small DL, Murray CL, Mealing GA, Poulter MO, Durkin JP, et al. Evidence that functional glutamate receptors are not expressed on rat or human cerebromicrovascular endothelial cells. J Cereb Blood Flow Metab. 1998;18(4):396–406.PubMedGoogle Scholar
  83. 83.
    Sharp CD, Houghton J, Elrod JW, Warren A, Jackson THt, Jawahar A, et al. N-methyl-d-aspartate receptor activation in human cerebral endothelium promotes intracellular oxidant stress. Am J Physiol. 2005;288(4):H1893–9.Google Scholar
  84. 84.
    Dempsey RJ, Bașkaya MK, Doğan A. Attenuation of brain edema, blood–brain barrier breakdown, and injury volume by ifenprodil, a polyamine-site N-methyl-d-aspartate receptor antagonist, after experimental traumatic brain injury in rats. Neurosurgery. 2000;47(2):399–404. discussion 404–6.PubMedGoogle Scholar
  85. 85.
    Parfenova H, Basuroy S, Bhattacharya S, Tcheranova D, Qu Y, Regan RF, et al. Glutamate induces oxidative stress and apoptosis in cerebral vascular endothelial cells: contributions of HO-1 and HO-2 to cytoprotection. Am J Physiol. 2006;290(5):C1399–410.Google Scholar
  86. 86.
    Parfenova H, Fedinec A, Leffler CW. Ionotropic glutamate receptors in cerebral microvascular endothelium are functionally linked to heme oxygenase. J Cereb Blood Flow Metab. 2003;23(2):190–7.PubMedGoogle Scholar
  87. 87.
    Domoki F, Kis B, Gáspár T, Bari F, Busija DW. Cerebromicrovascular endothelial cells are resistant to l-glutamate. Am J Physiol. 2008;295(4):R1099–108.Google Scholar
  88. 88.
    Hall ED, Vaishnav RA, Mustafa AG. Antioxidant therapies for traumatic brain injury. Neurotherapeutics. 2010;7(1):51–61.PubMedGoogle Scholar
  89. 89.
    Smith SL, Andrus PK, Zhang JR, Hall ED. Direct measurement of hydroxyl radicals, lipid peroxidation, and blood–brain barrier disruption following unilateral cortical impact head injury in the rat. J Neurotrauma. 1994;11(4):393–404.PubMedGoogle Scholar
  90. 90.
    Mertsch K, Blasig I, Grune T. 4-Hydroxynonenal impairs the permeability of an in vitro rat blood–brain barrier. Neurosci Lett. 2001;314(3):135–8.PubMedGoogle Scholar
  91. 91.
    Agarwal R, Shukla GS. Potential role of cerebral glutathione in the maintenance of blood–brain barrier integrity in rat. Neurochem Res. 1999;24(12):1507–14.PubMedGoogle Scholar
  92. 92.
    Schreibelt G, Kooij G, Reijerkerk A, van Doorn R, Gringhuis SI, van der Pol S, et al. Reactive oxygen species alter brain endothelial tight junction dynamics via RhoA, PI3 kinase, and PKB signaling. FASEB J. 2007;21(13):3666–76.PubMedGoogle Scholar
  93. 93.
    Fischer S, Wiesnet M, Renz D, Schaper W. H2O2 induces paracellular permeability of porcine brain-derived microvascular endothelial cells by activation of the p44/42 MAP kinase pathway. Eur J Cell Biol. 2005;84(7):687–97.PubMedGoogle Scholar
  94. 94.
    Haorah J, Ramirez SH, Schall K, Smith D, Pandya R, Persidsky Y. Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood–brain barrier dysfunction. J Neurochem. 2007;101(2):566–76.PubMedGoogle Scholar
  95. 95.
    Utepbergenov DI, Mertsch K, Sporbert A, Tenz K, Paul M, Haseloff RF, et al. Nitric oxide protects blood–brain barrier in vitro from hypoxia/reoxygenation-mediated injury. FEBS Lett. 1998;424(3):197–201.PubMedGoogle Scholar
  96. 96.
    Schreibelt G, van Horssen J, Haseloff RF, Reijerkerk A, van der Pol SM, Nieuwenhuizen O, et al. Protective effects of peroxiredoxin-1 at the injured blood–brain barrier. Free Radic Biol Med. 2008;45(3):256–64.PubMedGoogle Scholar
  97. 97.
    Bradley JR, Johnson DR, Pober JS. Endothelial activation by hydrogen peroxide. Selective increases of intercellular adhesion molecule-1 and major histocompatibility complex class I. Am J Pathol. 1993;142(5):1598–609.PubMedGoogle Scholar
  98. 98.
    Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69(3):562–73.PubMedGoogle Scholar
  99. 99.
    Cunningham LA, Wetzel M, Rosenberg GA. Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia. 2005;50(4):329–39.PubMedGoogle Scholar
  100. 100.
    Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab. 2007;27(4):697–709.PubMedGoogle Scholar
  101. 101.
    Rosenberg GA, Yang Y. Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus. 2007;22(5):E4.PubMedGoogle Scholar
  102. 102.
    Rosenberg GA, Cunningham LA, Wallace J, Alexander S, Estrada EY, Grossetete M, et al. Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res. 2001;893(1–2):104–12.PubMedGoogle Scholar
  103. 103.
    Borregaard N, Sørensen OE, Theilgaard-Mönch K. Neutrophil granules: a library of innate immunity proteins. Trends Immunol. 2007;28(8):340–5.PubMedGoogle Scholar
  104. 104.
    Newby AC. Metalloproteinase expression in monocytes and macrophages and its relationship to atherosclerotic plaque instability. Arterioscler Thromb Vasc Biol. 2008;28(12):2108–14.PubMedGoogle Scholar
  105. 105.
    Truettner JS, Alonso OF, Dalton Dietrich W. Influence of therapeutic hypothermia on matrix metalloproteinase activity after traumatic brain injury in rats. J Cereb Blood Flow Metab. 2005;25(11):1505–16.PubMedGoogle Scholar
  106. 106.
    Vilalta A, Sahuquillo J, Poca MA, De Los Rios J, Cuadrado E, Ortega-Aznar A, et al. Brain contusions induce a strong local overexpression of MMP-9. Results of a pilot study. Acta Neurochir Suppl. 2008;102:415–9.PubMedGoogle Scholar
  107. 107.
    Vilalta A, Sahuquillo J, Rosell A, Poca MA, Riveiro M, Montaner J. Moderate and severe traumatic brain injury induce early overexpression of systemic and brain gelatinases. Intensive Care Med. 2008;34(8):1384–92.PubMedGoogle Scholar
  108. 108.
    Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH. Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab. 2000;20(12):1681–9.PubMedGoogle Scholar
  109. 109.
    Wang X, Jung J, Asahi M, Chwang W, Russo L, Moskowitz MA, et al. Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci. 2000;20(18):7037–42.PubMedGoogle Scholar
  110. 110.
    Fujimoto M, Takagi Y, Aoki T, Hayase M, Marumo T, Gomi M, et al. Tissue inhibitor of metalloproteinases protect blood–brain barrier disruption in focal cerebral ischemia. J Cereb Blood Flow Metab. 2008;28(10):1674–85.PubMedGoogle Scholar
  111. 111.
    Tejima E, Guo S, Murata Y, Arai K, Lok J, van Leyen K, et al. Neuroprotective effects of overexpressing tissue inhibitor of metalloproteinase TIMP-1. J Neurotrauma. 2009;26(11):1935–41.PubMedGoogle Scholar
  112. 112.
    Zhao BQ, Wang S, Kim HY, Storrie H, Rosen BR, Mooney DJ, et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med. 2006;12(4):441–5.PubMedGoogle Scholar
  113. 113.
    Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76.PubMedGoogle Scholar
  114. 114.
    Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol. 1991;5(12):1806–14.PubMedGoogle Scholar
  115. 115.
    Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem. 1992;267(36):26031–7.PubMedGoogle Scholar
  116. 116.
    Park JE, Keller GA, Ferrara N. The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol Biol Cell. 1993;4(12):1317–26.PubMedGoogle Scholar
  117. 117.
    Plouët J, Moro F, Bertagnolli S, Coldeboeuf N, Mazarguil H, Clamens S, et al. Extracellular cleavage of the vascular endothelial growth factor 189-amino acid form by urokinase is required for its mitogenic effect. J Biol Chem. 1997;272(20):13390–6.PubMedGoogle Scholar
  118. 118.
    Lee S, Jilani SM, Nikolova GV, Carpizo D, Iruela-Arispe ML. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol. 2005;169(4):681–91.PubMedGoogle Scholar
  119. 119.
    Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling—in control of vascular function. Nat Rev Mol Cell Biol. 2006;7(5):359–71.PubMedGoogle Scholar
  120. 120.
    Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci USA. 1993;90(22):10705–9.PubMedGoogle Scholar
  121. 121.
    Ebos JM, Bocci G, Man S, Thorpe PE, Hicklin DJ, Zhou D, et al. A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma. Mol Cancer Res. 2004;2(6):315–26.PubMedGoogle Scholar
  122. 122.
    Kumai Y, Ooboshi H, Ibayashi S, Ishikawa E, Sugimori H, Kamouchi M, et al. Postischemic gene transfer of soluble Flt-1 protects against brain ischemia with marked attenuation of blood–brain barrier permeability. J Cereb Blood Flow Metab. 2007;27(6):1152–60.PubMedGoogle Scholar
  123. 123.
    Maharaj AS, Walshe TE, Saint-Geniez M, Venkatesha S, Maldonado AE, Himes NC, et al. VEGF and TGF-β are required for the maintenance of the choroid plexus and ependyma. J Exp Med. 2008;205(2):491–501.PubMedGoogle Scholar
  124. 124.
    Suzuki R, Fukai N, Nagashijma G, Asai JI, Itokawa H, Nagai M, et al. Very early expression of vascular endothelial growth factor in brain oedema tissue associated with brain contusion. Acta Neurochir Suppl. 2003;86:277–9.PubMedGoogle Scholar
  125. 125.
    Wang W, Dentler WL, Borchardt RT. VEGF increases BMEC monolayer permeability by affecting occludin expression and tight junction assembly. Am J Physiol. 2001;280(1):H434–40.Google Scholar
  126. 126.
    Murakami T, Felinski EA, Antonetti DA. Occludin phosphorylation and ubiquitination regulate tight junction trafficking and vascular endothelial growth factor-induced permeability. J Biol Chem. 2009;284(31):21036–46.PubMedGoogle Scholar
  127. 127.
    Argaw AT, Gurfein BT, Zhang Y, Zameer A, John GR. VEGF-mediated disruption of endothelial CLN-5 promotes blood–brain barrier breakdown. Proc Natl Acad Sci USA. 2009;106(6):1977–82.PubMedGoogle Scholar
  128. 128.
    Vogel C, Bauer A, Wiesnet M, Preissner KT, Schaper W, Marti HH, et al. Flt-1, but not Flk-1 mediates hyperpermeability through activation of the PI3-K/Akt pathway. J Cell Physiol. 2007;212(1):236–43.PubMedGoogle Scholar
  129. 129.
    Esser S, Lampugnani MG, Corada M, Dejana E, Risau W. Vascular endothelial growth factor induces VE-cadherin tyrosine phosphorylation in endothelial cells. J Cell Sci. 1998;111(13):1853–65.PubMedGoogle Scholar
  130. 130.
    Monaghan-Benson E, Burridge K. The regulation of vascular endothelial growth factor-induced microvascular permeability requires Rac and reactive oxygen species. J Biol Chem. 2009;284(38):25602–11.PubMedGoogle Scholar
  131. 131.
    Soares HD, Hicks RR, Smith D, McIntosh TK. Inflammatory leukocytic recruitment and diffuse neuronal degeneration are separate pathological processes resulting from traumatic brain injury. J Neurosci. 1995;15(12):8223–33.PubMedGoogle Scholar
  132. 132.
    Royo NC, Wahl F, Stutzmann JM. Kinetics of polymorphonuclear neutrophil infiltration after a traumatic brain injury in rat. NeuroReport. 1999;10(6):1363–7.PubMedGoogle Scholar
  133. 133.
    Holmin S, Söderlund J, Biberfeld P, Mathiesen T. Intracerebral inflammation after human brain contusion. Neurosurgery. 1998;42(2):291–8. discussion 298–9.PubMedGoogle Scholar
  134. 134.
    Worthylake RA, Burridge K. Leukocyte transendothelial migration: orchestrating the underlying molecular machinery. Curr Opin Cell Biol. 2001;13(5):569–77.PubMedGoogle Scholar
  135. 135.
    Clark RS, Carlos TM, Schiding JK, Bree M, Fireman LA, DeKosky ST, et al. Antibodies against Mac-1 attenuate neutrophil accumulation after traumatic brain injury in rats. J Neurotrauma. 1996;13(6):333–41.PubMedGoogle Scholar
  136. 136.
    Weaver KD, Branch CA, Hernandez L, Miller CH, Quattrocchi KB. Effect of leukocyte-endothelial adhesion antagonism on neutrophil migration and neurologic outcome after cortical trauma. J Trauma. 2000;48(6):1081–90.PubMedGoogle Scholar
  137. 137.
    Knoblach SM, Faden AI. Administration of either anti-intercellular adhesion molecule-1 or a nonspecific control antibody improves recovery after traumatic brain injury in the rat. J Neurotrauma. 2002;19(9):1039–50.PubMedGoogle Scholar
  138. 138.
    Utagawa A, Bramlett HM, Daniels L, Lotocki G, Dekaban GA, Weaver LC, et al. Transient blockage of the CD11d/CD18 integrin reduces contusion volume and macrophage infiltration after traumatic brain injury in rats. Brain Res. 2008;1207:155–63.PubMedGoogle Scholar
  139. 139.
    Whalen MJ, Carlos TM, Dixon CE, Schiding JK, Clark RS, Baum E, et al. Effect of traumatic brain injury in mice deficient in intercellular adhesion molecule-1: assessment of histopathologic and functional outcome. J Neurotrauma. 1999;16(4):299–309.PubMedGoogle Scholar
  140. 140.
    Whalen MJ, Carlos TM, Dixon CE, Robichaud P, Clark RS, Marion DW, et al. Reduced brain edema after traumatic brain injury in mice deficient in P-selectin and intercellular adhesion molecule-1. J Leukoc Biol. 2000;67(2):160–8.PubMedGoogle Scholar
  141. 141.
    Mackay CR. Moving targets: cell migration inhibitors as new anti-inflammatory therapies. Nat Immunol. 2008;9(9):988–98.PubMedGoogle Scholar
  142. 142.
    Pineau I, Lacroix S. Endogenous signals initiating inflammation in the injured nervous system. Glia. 2009;57(4):351–61.PubMedGoogle Scholar
  143. 143.
    Nagyőszi P, Wilhelm I, Farkas AE, Fazakas C, Dung NT, Haskó J, et al. Expression and regulation of toll-like receptors in cerebral endothelial cells. Neurochem Int. 2010;57(5):556–64.PubMedGoogle Scholar
  144. 144.
    Farina C, Aloisi F, Meinl E. Astrocytes are active players in cerebral innate immunity. Trends Immunol. 2007;28(3):138–45.PubMedGoogle Scholar
  145. 145.
    Barnard EA, Simon J, Webb TE. Nucleotide receptors in the nervous system. An abundant component using diverse transduction mechanisms. Mol Neurobiol. 1997;15(2):103–29.PubMedGoogle Scholar
  146. 146.
    Albert JL, Boyle JP, Roberts JA, Challiss RA, Gubby SE, Boarder MR. Regulation of brain capillary endothelial cells by P2Y receptors coupled to Ca2+, phospholipase C and mitogen-activated protein kinase. Br J Pharmacol. 1997;122(5):935–41.PubMedGoogle Scholar
  147. 147.
    Abbracchio MP, Verderio C. Pathophysiological roles of P2 receptors in glial cells. Novartis Found Symp. 2006;276:91–103. discussion 103–12, 275–81.PubMedGoogle Scholar
  148. 148.
    Simard M, Arcuino G, Takano T, Liu QS, Nedergaard M. Signaling at the gliovascular interface. J Neurosci. 2003;23(27):9254–62.PubMedGoogle Scholar
  149. 149.
    Ostrow LW, Langan TJ, Sachs F. Stretch-induced endothelin-1 production by astrocytes. J Cardiovasc Pharmacol. 2000;36 Suppl 1:S274–7.PubMedGoogle Scholar
  150. 150.
    Ralay Ranaivo H, Zunich S, Choi N, Hodge J, Wainwright M. Mild stretch-induced injury increases susceptibility to interleukin-1β–induced release of matrix metalloproteinase-9 from astrocytes. J Neurotrauma. 2011;28(9):1757–66.Google Scholar
  151. 151.
    Fan L, Young PR, Barone FC, Feuerstein GZ, Smith DH, McIntosh TK. Experimental brain injury induces differential expression of tumor necrosis factor-α mRNA in the CNS. Mol Brain Res. 1996;36(2):287–91.PubMedGoogle Scholar
  152. 152.
    Szmydynger-Chodobska J, Strazielle N, Zink BJ, Ghersi-Egea JF, Chodobski A. The role of the choroid plexus in neutrophil invasion after traumatic brain injury. J Cereb Blood Flow Metab. 2009;29(9):1503–16.PubMedGoogle Scholar
  153. 153.
    Kinoshita K, Chatzipanteli K, Vitarbo E, Truettner JS, Alonso OF, Dietrich WD. Interleukin-1β messenger ribonucleic acid and protein levels after fluid-percussion brain injury in rats: importance of injury severity and brain temperature. Neurosurgery. 2002;51(1):195–203. discussion 203.PubMedGoogle Scholar
  154. 154.
    Taupin V, Toulmond S, Serrano A, Benavides J, Zavala F. Increase in IL-6, IL-1 and TNF levels in rat brain following traumatic lesion. Influence of pre- and post-traumatic treatment with Ro5 4864, a peripheral-type (p site) benzodiazepine ligand. J Neuroimmunol. 1993;42(2):177–85.PubMedGoogle Scholar
  155. 155.
    de Vries HE, Blom-Roosemalen MC, van Oosten M, de Boer AG, van Berkel TJ, Breimer DD, et al. The influence of cytokines on the integrity of the blood–brain barrier in vitro. J Neuroimmunol. 1996;64(1):37–43.PubMedGoogle Scholar
  156. 156.
    Mark KS, Miller DW. Increased permeability of primary cultured brain microvessel endothelial cell monolayers following TNF-α exposure. Life Sci. 1999;64(21):1941–53.PubMedGoogle Scholar
  157. 157.
    Shaftel SS, Carlson TJ, Olschowka JA, Kyrkanides S, Matousek SB, O'Banion MK. Chronic interleukin-1β expression in mouse brain leads to leukocyte infiltration and neutrophil-independent blood brain barrier permeability without overt neurodegeneration. J Neurosci. 2007;27(35):9301–9.PubMedGoogle Scholar
  158. 158.
    Wójciak-Stothard B, Entwistle A, Garg R, Ridley AJ. Regulation of TNF-α-induced reorganization of the actin cytoskeleton and cell-cell junctions by Rho, Rac, and Cdc42 in human endothelial cells. J Cell Physiol. 1998;176(1):150–65.PubMedGoogle Scholar
  159. 159.
    Sakon S, Xue X, Takekawa M, Sasazuki T, Okazaki T, Kojima Y, et al. NF-κB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. EMBO J. 2003;22(15):3898–909.PubMedGoogle Scholar
  160. 160.
    Mankertz J, Tavalali S, Schmitz H, Mankertz A, Riecken EO, Fromm M, et al. Expression from the human occludin promoter is affected by tumor necrosis factor α and interferon γ. J Cell Sci. 2000;113(11):2085–90.PubMedGoogle Scholar
  161. 161.
    Hess DC, Bhutwala T, Sheppard JC, Zhao W, Smith J. ICAM-1 expression on human brain microvascular endothelial cells. Neurosci Lett. 1994;168(1–2):201–4.PubMedGoogle Scholar
  162. 162.
    Wong D, Dorovini-Zis K. Expression of vascular cell adhesion molecule-1 (VCAM-1) by human brain microvessel endothelial cells in primary culture. Microvasc Res. 1995;49(3):325–39.PubMedGoogle Scholar
  163. 163.
    Wong D, Dorovini-Zis K. Regualtion by cytokines and lipopolysaccharide of E-selectin expression by human brain microvessel endothelial cells in primary culture. J Neuropathol Exp Neurol. 1996;55(2):225–35.PubMedGoogle Scholar
  164. 164.
    Stanimirovic DB, Wong J, Shapiro A, Durkin JP. Increase in surface expression of ICAM-1, VCAM-1 and E-selectin in human cerebromicrovascular endothelial cells subjected to ischemia-like insults. Acta Neurochir Suppl. 1997;70:12–6.PubMedGoogle Scholar
  165. 165.
    Roebuck KA, Finnegan A. Regulation of intercellular adhesion molecule-1 (CD54) gene expression. J Leukoc Biol. 1999;66(6):876–88.PubMedGoogle Scholar
  166. 166.
    Carlos TM, Clark RS, Franicola-Higgins D, Schiding JK, Kochanek PM. Expression of endothelial adhesion molecules and recruitment of neutrophils after traumatic brain injury in rats. J Leukoc Biol. 1997;61(3):279–85.PubMedGoogle Scholar
  167. 167.
    Balabanov R, Goldman H, Murphy S, Pellizon G, Owen C, Rafols J, et al. Endothelial cell activation following moderate traumatic brain injury. Neurol Res. 2001;23(2–3):175–82.PubMedGoogle Scholar
  168. 168.
    McKeating EG, Andrews PJ, Mascia L. The relationship of soluble adhesion molecule concentrations in systemic and jugular venous serum to injury severity and outcome after traumatic brain injury. Anesth Analg. 1998;86(4):759–65.PubMedGoogle Scholar
  169. 169.
    Pleines UE, Stover JF, Kossmann T, Trentz O, Morganti-Kossmann MC. Soluble ICAM-1 in CSF coincides with the extent of cerebral damage in patients with severe traumatic brain injury. J Neurotrauma. 1998;15(6):399–409.PubMedGoogle Scholar
  170. 170.
    Yamasaki Y, Matsuo Y, Zagorski J, Matsuura N, Onodera H, Itoyama Y, et al. New therapeutic possibility of blocking cytokine-induced neutrophil chemoattractant on transient ischemic brain damage in rats. Brain Res. 1997;759(1):103–11.PubMedGoogle Scholar
  171. 171.
    Beech JS, Reckless J, Mosedale DE, Grainger DJ, Williams SC, Menon DK. Neuroprotection in ischemia-reperfusion injury: an antiinflammatory approach using a novel broad-spectrum chemokine inhibitor. J Cereb Blood Flow Metab. 2001;21(6):683–9.PubMedGoogle Scholar
  172. 172.
    Dimitrijevic OB, Stamatovic SM, Keep RF, Andjelkovic AV. Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice. Stroke. 2007;38(4):1345–53.PubMedGoogle Scholar
  173. 173.
    Semple BD, Bye N, Ziebell JM, Morganti-Kossmann MC. Deficiency of the chemokine receptor CXCR2 attenuates neutrophil infiltration and cortical damage following closed head injury. Neurobiol Dis. 2010;40(2):394–403.PubMedGoogle Scholar
  174. 174.
    Semple BD, Bye N, Rancan M, Ziebell JM, Morganti-Kossmann MC. Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2−/− mice. J Cereb Blood Flow Metab. 2010;30(4):769–82.PubMedGoogle Scholar
  175. 175.
    Bell MD, Taub DD, Kunkel SJ, Strieter RM, Foley R, Gauldie J, et al. Recombinant human adenovirus with rat MIP-2 gene insertion causes prolonged PMN recruitment to the murine brain. Eur J Neurosci. 1996;8(9):1803–11.PubMedGoogle Scholar
  176. 176.
    Fuentes ME, Durham SK, Swerdel MR, Lewin AC, Barton DS, Megill JR, et al. Controlled recruitment of monocytes and macrophages to specific organs through transgenic expression of monocyte chemoattractant protein-1. J Immunol. 1995;155(12):5769–76.PubMedGoogle Scholar
  177. 177.
    Chen Y, Hallenbeck JM, Ruetzler C, Bol D, Thomas K, Berman NE, et al. Overexpression of monocyte chemoattractant protein 1 in the brain exacerbates ischemic brain injury and is associated with recruitment of inflammatory cells. J Cereb Blood Flow Metab. 2003;23(6):748–55.PubMedGoogle Scholar
  178. 178.
    Szmydynger-Chodobska J, Fox LM, Lynch KM, Zink BJ, Chodobski A. Vasopressin amplifies the production of proinflammatory mediators in traumatic brain injury. J Neurotrauma. 2010;27(8):1449–61.PubMedGoogle Scholar
  179. 179.
    Scapini P, Lapinet-Vera JA, Gasperini S, Calzetti F, Bazzoni F, Cassatella MA. The neutrophil as a cellular source of chemokines. Immunol Rev. 2000;177:195–203.PubMedGoogle Scholar
  180. 180.
    Colotta F, Borré A, Wang JM, Tattanelli M, Maddalena F, Polentarutti N, et al. Expression of a monocyte chemotactic cytokine by human mononuclear phagocytes. J Immunol. 1992;148(3):760–5.PubMedGoogle Scholar
  181. 181.
    Zhang W, Smith C, Shapiro A, Monette R, Hutchison J, Stanimirovic D. Increased expression of bioactive chemokines in human cerebromicrovascular endothelial cells and astrocytes subjected to simulated ischemia in vitro. J Neuroimmunol. 1999;101(2):148–60.PubMedGoogle Scholar
  182. 182.
    Middleton J, Patterson AM, Gardner L, Schmutz C, Ashton BA. Leukocyte extravasation: chemokine transport and presentation by the endothelium. Blood. 2002;100(12):3853–60.PubMedGoogle Scholar
  183. 183.
    Ge S, Song L, Serwanski DR, Kuziel WA, Pachter JS. Transcellular transport of CCL2 across brain microvascular endothelial cells. J Neurochem. 2008;104(5):1219–32.PubMedGoogle Scholar
  184. 184.
    Szmydynger-Chodobska J, Zink BJ, Chodobski A. Multiple sites of vasopressin synthesis in the injured brain. J Cereb Blood Flow Metab. 2011;31(1):47–51.PubMedGoogle Scholar
  185. 185.
    Stamatovic SM, Shakui P, Keep RF, Moore BB, Kunkel SL, Van Rooijen N, et al. Monocyte chemoattractant protein-1 regulation of blood–brain barrier permeability. J Cereb Blood Flow Metab. 2005;25(5):593–606.PubMedGoogle Scholar
  186. 186.
    Stamatovic SM, Keep RF, Kunkel SL, Andjelkovic AV. Potential role of MCP-1 in endothelial cell tight junction ‘opening’: signaling via Rho and Rho kinase. J Cell Sci. 2003;116(22):4615–28.PubMedGoogle Scholar
  187. 187.
    Schoettle RJ, Kochanek PM, Magargee MJ, Uhl MW, Nemoto EM. Early polymorphonuclear leukocyte accumulation correlates with the development of posttraumatic cerebral edema in rats. J Neurotrauma. 1990;7(4):207–17.PubMedGoogle Scholar
  188. 188.
    Uhl MW, Biagas KV, Grundl PD, Barmada MA, Schiding JK, Nemoto EM, et al. Effects of neutropenia on edema, histology, and cerebral blood flow after traumatic brain injury in rats. J Neurotrauma. 1994;11(3):303–15.PubMedGoogle Scholar
  189. 189.
    Whalen MJ, Carlos TM, Kochanek PM, Clark RS, Heineman S, Schiding JK, et al. Neutrophils do not mediate blood–brain barrier permeability early after controlled cortical impact in rats. J Neurotrauma. 1999;16(7):583–94.PubMedGoogle Scholar
  190. 190.
    Osborn MT, Chambers TC. Role of the stress-activated/c-Jun NH2-terminal protein kinase pathway in the cellular response to adriamycin and other chemotherapeutic drugs. J Biol Chem. 1996;271(48):30950–5.PubMedGoogle Scholar
  191. 191.
    Dinkel K, Dhabhar FS, Sapolsky RM. Neurotoxic effects of polymorphonuclear granulocytes on hippocampal primary cultures. Proc Natl Acad Sci USA. 2004;101(1):331–6.PubMedGoogle Scholar
  192. 192.
    Neumann J, Sauerzweig S, Rönicke R, Gunzer F, Dinkel K, Ullrich O, et al. Microglia cells protect neurons by direct engulfment of invading neutrophil granulocytes: a new mechanism of CNS immune privilege. J Neurosci. 2008;28(23):5965–75.PubMedGoogle Scholar
  193. 193.
    DiStasi MR, Ley K. Opening the flood-gates: how neutrophil-endothelial interactions regulate permeability. Trends Immunol. 2009;30(11):547–56.PubMedGoogle Scholar
  194. 194.
    Armao D, Kornfeld M, Estrada EY, Grossetete M, Rosenberg GA. Neutral proteases and disruption of the blood–brain barrier in rat. Brain Res. 1997;767(2):259–64.PubMedGoogle Scholar
  195. 195.
    Stowe AM, Adair-Kirk TL, Gonzales ER, Perez RS, Shah AR, Park TS, et al. Neutrophil elastase and neurovascular injury following focal stroke and reperfusion. Neurobiol Dis. 2009;35(1):82–90.PubMedGoogle Scholar
  196. 196.
    Gidday JM, Gasche YG, Copin JC, Shah AR, Perez RS, Shapiro SD, et al. Leukocyte-derived matrix metalloproteinase-9 mediates blood–brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol. 2005;289(2):H558–68.Google Scholar
  197. 197.
    Gotsch U, Jäger U, Dominis M, Vestweber D. Expression of P-selectin on endothelial cells is upregulated by LPS and TNF-α in vivo. Cell Adhes Commun. 1994;2(1):7–14.PubMedGoogle Scholar
  198. 198.
    Andersson PB, Perry VH, Gordon S. Intracerebral injection of proinflammatory cytokines or leukocyte chemotaxins induces minimal myelomonocytic cell recruitment to the parenchyma of the central nervous system. J Exp Med. 1992;176(1):255–9.PubMedGoogle Scholar
  199. 199.
    Allt G, Lawrenson JG. Is the pial microvessel a good model for blood–brain barrier studies? Brain Res Rev. 1997;24(1):67–76.PubMedGoogle Scholar
  200. 200.
    Bartholomäus I, Kawakami N, Odoardi F, Schläger C, Miljkovic D, Ellwart JW, et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature. 2009;462(7269):94–8.PubMedGoogle Scholar
  201. 201.
    Kivisäkk P, Imitola J, Rasmussen S, Elyaman W, Zhu B, Ransohoff RM, et al. Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann Neurol. 2009;65(4):457–69.PubMedGoogle Scholar
  202. 202.
    Szmydynger-Chodobska J, Strazielle N, Gandy JR, Keefe TH, Zink BJ, Ghersi-Egea JF, et al. Posttraumatic invasion of monocytes across the blood-cerebrospinal fluid barrier. J Cereb Blood Flow Metab. 2011 (in press).Google Scholar
  203. 203.
    Strazielle N, Ghersi-Egea JF. Choroid plexus in the central nervous system: biology and physiopathology. J Neuropathol Exp Neurol. 2000;59(7):561–74.PubMedGoogle Scholar
  204. 204.
    O'Donnell ME, Tran L, Lam TI, Liu XB, Anderson SE. Bumetanide inhibition of the blood–brain barrier Na-K-Cl cotransporter reduces edema formation in the rat middle cerebral artery occlusion model of stroke. J Cereb Blood Flow Metab. 2004;24(9):1046–56.PubMedGoogle Scholar
  205. 205.
    Lam TI, Wise PM, O'Donnell ME. Cerebral microvascular endothelial cell Na/H exchange: evidence for the presence of NHE1 and NHE2 isoforms and regulation by arginine vasopressin. Am J Physiol. 2009;297(2):C278–89.Google Scholar
  206. 206.
    Pedersen SF, O'Donnell ME, Anderson SE, Cala PM. Physiology and pathophysiology of Na+/H+ exchange and Na+-K+-2Cl cotransport in the heart, brain, and blood. Am J Physiol. 2006;291(1):R1–R25.Google Scholar
  207. 207.
    Lu KT, Cheng NC, Wu CY, Yang YL. NKCC1-mediated traumatic brain injury-induced brain edema and neuron death via Raf/MEK/MAPK cascade. Crit Care Med. 2008;36(3):917–22.PubMedGoogle Scholar
  208. 208.
    Suzuki Y, Matsumoto Y, Ikeda Y, Kondo K, Ohashi N, Umemura K. SM-20220, a Na+/H+ exchanger inhibitor: effects on ischemic brain damage through edema and neutrophil accumulation in a rat middle cerebral artery occlusion model. Brain Res. 2002;945(2):242–8.PubMedGoogle Scholar
  209. 209.
    O'Donnell ME, Duong V, Suvatne J, Foroutan S, Johnson DM. Arginine vasopressin stimulation of cerebral microvascular endothelial cell Na-K-Cl cotransporter activity is V1 receptor and [Ca] dependent. Am J Physiol. 2005;289(2):C283–92.Google Scholar
  210. 210.
    Foroutan S, Brillault J, Forbush B, O'Donnell ME. Moderate-to-severe ischemic conditions increase activity and phosphorylation of the cerebral microvascular endothelial cell Na+-K+-Cl cotransporter. Am J Physiol. 2005;289(6):C1492–501.Google Scholar
  211. 211.
    Szmydynger-Chodobska J, Chung I, Koźniewska E, Tran B, Harrington FJ, Duncan JA, et al. Increased expression of vasopressin V1a receptors after traumatic brain injury. J Neurotrauma. 2004;21(8):1090–102.PubMedGoogle Scholar
  212. 212.
    Burke MA, Mutharasan RK, Ardehali H. The sulfonylurea receptor, an atypical ATP-binding cassette protein, and its regulation of the KATP channel. Circ Res. 2008;102(2):164–76.PubMedGoogle Scholar
  213. 213.
    Bryan J, Muñoz A, Zhang X, Düfer M, Drews G, Krippeit-Drews P, et al. ABCC8 and ABCC9: ABC transporters that regulate K+ channels. Pflügers Arch. 2007;453(5):703–18.PubMedGoogle Scholar
  214. 214.
    Chen M, Dong Y, Simard JM. Functional coupling between sulfonylurea receptor type 1 and a nonselective cation channel in reactive astrocytes from adult rat brain. J Neurosci. 2003;23(24):8568–77.PubMedGoogle Scholar
  215. 215.
    Simard JM, Tarasov KV, Gerzanich V. Non-selective cation channels, transient receptor potential channels and ischemic stroke. Biochim Biophys Acta. 2007;1772(8):947–57.PubMedGoogle Scholar
  216. 216.
    Gerzanich V, Woo SK, Vennekens R, Tsymbalyuk O, Ivanova S, Ivanov A, et al. De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury. Nat Med. 2009;15(2):185–91.PubMedGoogle Scholar
  217. 217.
    Simard JM, Tsymbalyuk O, Ivanov A, Ivanova S, Bhatta S, Geng Z, et al. Endothelial sulfonylurea receptor 1-regulated NCCa-ATP channels mediate progressive hemorrhagic necrosis following spinal cord injury. J Clin Invest. 2007;117(8):2105–13.PubMedGoogle Scholar
  218. 218.
    Simard JM, Chen M, Tarasov KV, Bhatta S, Ivanova S, Melnitchenko L, et al. Newly expressed SUR1-regulated NCCa-ATP channel mediates cerebral edema after ischemic stroke. Nat Med. 2006;12(4):433–40.PubMedGoogle Scholar
  219. 219.
    Simard JM, Geng Z, Woo SK, Ivanova S, Tosun C, Melnichenko L, et al. Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2009;29(2):317–30.PubMedGoogle Scholar
  220. 220.
    Simard JM, Kahle KT, Gerzanich V. Molecular mechanisms of microvascular failure in central nervous system injury—synergistic roles of NKCC1 and SUR1/TRPM4. J Neurosurg. 2010;113(3):622–9.PubMedGoogle Scholar
  221. 221.
    Simard JM, Yurovsky V, Tsymbalyuk N, Melnichenko L, Ivanova S, Gerzanich V. Protective effect of delayed treatment with low-dose glibenclamide in three models of ischemic stroke. Stroke. 2009;40(2):604–9.PubMedGoogle Scholar
  222. 222.
    Patel AD, Gerzanich V, Geng Z, Simard JM. Glibenclamide reduces hippocampal injury and preserves rapid spatial learning in a model of traumatic brain injury. J Neuropathol Exp Neurol. 2010;69(12):1177–90.PubMedGoogle Scholar
  223. 223.
    Bazarian JJ, Cernak I, Noble-Haeusslein L, Potolicchio S, Temkin N. Long-term neurologic outcomes after traumatic brain injury. J Head Trauma Rehabil. 2009;24(6):439–51.PubMedGoogle Scholar
  224. 224.
    Roberts GW, Gentleman SM, Lynch A, Murray L, Landon M, Graham DI. β amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 1994;57(4):419–25.PubMedGoogle Scholar
  225. 225.
    Ikonomovic MD, Uryu K, Abrahamson EE, Ciallella JR, Trojanowski JQ, Lee VM, et al. Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury. Exp Neurol. 2004;190(1):192–203.PubMedGoogle Scholar
  226. 226.
    Loane DJ, Pocivavsek A, Moussa CE, Thompson R, Matsuoka Y, Faden AI, et al. Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury. Nat Med. 2009;15(4):377–9.PubMedGoogle Scholar
  227. 227.
    Loane DJ, Washington PM, Vardanian L, Pocivavsek A, Hoe HS, Duff KE, et al. Modulation of ABCA1 by an LXR agonist reduces beta-amyloid levels and improves outcome after traumatic brain injury. J Neurotrauma. 2011;28(2):225–36.PubMedGoogle Scholar
  228. 228.
    Kim WS, Guillemin GJ, Glaros EN, Lim CK, Garner B. Quantitation of ATP-binding cassette subfamily-A transporter gene expression in primary human brain cells. NeuroReport. 2006;17(9):891–6.PubMedGoogle Scholar
  229. 229.
    Panzenboeck U, Kratzer I, Sovic A, Wintersperger A, Bernhart E, Hammer A, et al. Regulatory effects of synthetic liver X receptor- and peroxisome-proliferator activated receptor agonists on sterol transport pathways in polarized cerebrovascular endothelial cells. Int J Biochem Cell Biol. 2006;38(8):1314–29.PubMedGoogle Scholar
  230. 230.
    Do TM, Ouellet M, Calon F, Chimini G, Chacun H, Farinotti R, et al. Direct evidence of abca1-mediated efflux of cholesterol at the mouse blood–brain barrier. Mol Cell Biochem. 2011;357(1–2):397–404.PubMedGoogle Scholar
  231. 231.
    Deane R, Wu Z, Sagare A, Davis J, Du Yan S, Hamm K, et al. LRP/amyloid β-peptide interaction mediates differential brain efflux of Aβ isoforms. Neuron. 2004;43(3):333–44.PubMedGoogle Scholar
  232. 232.
    Akanuma S, Ohtsuki S, Doi Y, Tachikawa M, Ito S, Hori S, et al. ATP-binding cassette transporter A1 (ABCA1) deficiency does not attenuate the brain-to-blood efflux transport of human amyloid-β peptide (1–40) at the blood–brain barrier. Neurochem Int. 2008;52(6):956–61.PubMedGoogle Scholar
  233. 233.
    Löscher W, Potschka H. Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol. 2005;76(1):22–76.PubMedGoogle Scholar
  234. 234.
    Miller DS, Bauer B, Hartz AM. Modulation of P-glycoprotein at the blood–brain barrier: opportunities to improve central nervous system pharmacotherapy. Pharmacol Rev. 2008;60(2):196–209.PubMedGoogle Scholar
  235. 235.
    Potschka H. Targeting regulation of ABC efflux transporters in brain diseases: a novel therapeutic approach. Pharmacol Ther. 2010;125(1):118–27.PubMedGoogle Scholar
  236. 236.
    Spudich A, Kilic E, Xing H, Kilic U, Rentsch KM, Wunderli-Allenspach H, et al. Inhibition of multidrug resistance transporter-1 facilitates neuroprotective therapies after focal cerebral ischemia. Nat Neurosci. 2006;9(4):487–8.PubMedGoogle Scholar
  237. 237.
    Scheff SW, Sullivan PG. Cyclosporin A significantly ameliorates cortical damage following experimental traumatic brain injury in rodents. J Neurotrauma. 1999;16(9):783–92.PubMedGoogle Scholar
  238. 238.
    Sullivan PG, Thompson M, Scheff SW. Continuous infusion of cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury. Exp Neurol. 2000;161(2):631–7.PubMedGoogle Scholar
  239. 239.
    Sullivan PG, Rabchevsky AG, Hicks RR, Gibson TR, Fletcher-Turner A, Scheff SW. Dose-response curve and optimal dosing regimen of cyclosporin A after traumatic brain injury in rats. Neuroscience. 2000;101(2):289–95.PubMedGoogle Scholar
  240. 240.
    Hansson MJ, Persson T, Friberg H, Keep MF, Rees A, Wieloch T, et al. Powerful cyclosporin inhibition of calcium-induced permeability transition in brain mitochondria. Brain Res. 2003;960(1–2):99–111.PubMedGoogle Scholar
  241. 241.
    Merenda A, Bullock R. Clinical treatments for mitochondrial dysfunctions after brain injury. Curr Opin Crit Care. 2006;12(2):90–6.PubMedGoogle Scholar
  242. 242.
    Margulies S, Hicks R, The Combination Therapies for Traumatic Brain Injury Workshop Leaders. Combination therapies for traumatic brain injury: prospective considerations. J Neurotrauma. 2009;26(6):925–39.PubMedGoogle Scholar
  243. 243.
    Work LM, Büning H, Hunt E, Nicklin SA, Denby L, Britton N, et al. Vascular bed-targeted in vivo gene delivery using tropism-modified adeno-associated viruses. Mol Ther. 2006;13(4):683–93.PubMedGoogle Scholar
  244. 244.
    Guo S, Kim WJ, Lok J, Lee SR, Besancon E, Luo BH, et al. Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons. Proc Natl Acad Sci USA. 2008;105(21):7582–7.PubMedGoogle Scholar
  245. 245.
    Sawada N, Kim HH, Moskowitz MA, Liao JK. Rac1 is a critical mediator of endothelium-derived neurotrophic activity. Sci Signal. 2009;2(61):10.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Adam Chodobski
    • 1
  • Brian J. Zink
    • 1
  • Joanna Szmydynger-Chodobska
    • 1
  1. 1.Neurotrauma and Brain Barriers Research Laboratory, Department of Emergency MedicineAlpert Medical School of Brown UniversityProvidenceUSA

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