Molecular Neurobiology

, Volume 28, Issue 3, pp 229–244 | Cite as

Triggers and mediators of hemorrhagic transformation in cerebral ischemia

  • Xiaoying Wang
  • Eng H. Lo


Intracerebral hemorrhagic transformation is a multifactorial phenomenon in which ischemic brain tissue converts into a hemorrhagic lesion with blood-vessel leakage, extravasation, and further brain injury. It has been estimated that up to 30–40% of all ischemic strokes undergo spontaneous hemorrhagic transformation, and this phenomenon may become even more prevalent with the increasing use of thrombolytic stroke therapy. An emerging conceptual model suggests that the loss of microvascular integrity and disruption of neurovascular homeostasis connects the experimental findings of blood-cell extravasation to brain injury after hemorrhage. In this short article, we examine mechanisms related to reperfusion injury and oxidative stress, leukocyte infiltration, vascular activation, and dysregulated extracellular proteolysis as potential triggers of hemorrhagic transformation. Perturbations in cell-cell and cell-matrix signaling within the hypothesized neurovascular unit may ultimately lead to neuroinflammation and apoptotic-like cell death in the parenchyma. Further investigations into the molecular mediators of hemorrhagic transformation may reveal new therapeutic targets for this clinically complex problem.

Index Entries

Stroke neuroprotection neuromuscular unit endothelial blood-brain barrier 


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  1. 1.
    Lyden P.D. and Zivin J.A. (1993) Hemorrhagic transformation after cerebral ischemia: mechanisms and incidence. Cerebrovasc. Brain Metab. Rev. 5, 1–16.PubMedGoogle Scholar
  2. 2.
    Lapchak P.A. (2002) Hemorrhagic transfromation following ischemic stroke: significance, causes, and relationship to therapy and treatment. Curr. Neurol. Neurosci. Rep. 2, 38–43.PubMedCrossRefGoogle Scholar
  3. 3.
    Passero S., Ciacci G., and Reale F. (2001) Potential triggering factors of intracerebral hemorrhage. Cerebrovasc. Dis. 12, 220–227.PubMedCrossRefGoogle Scholar
  4. 4.
    Gebel J.M. and Broderick J.P. (2000) Intracerebral hemorrhage. Neurol. Clin. 18, 419–438.PubMedCrossRefGoogle Scholar
  5. 5.
    Andaluz N., Zuccarello M., and Wagner K.R. (2002) Experimental animal models of intracerebral hemorrhage. Neurosurg. Clin. N. Am. 3, 385–393.CrossRefGoogle Scholar
  6. 6.
    Vahedi K. and Bousser M.G. (2002) Thrombolysis in stroke. Curr. Opin. Hematol. 9, 443–447.PubMedCrossRefGoogle Scholar
  7. 7.
    Report of the Stroke Progress Review Group, NINDS, Scholar
  8. 8.
    Lo E.H., Dalkara T., and Moskowitz M.A. (2003) Mechanisms, challenges and opportunities in stroke. Nat. Rev. Neurosci. 4, 399–415.PubMedCrossRefGoogle Scholar
  9. 9.
    del Zoppo G.J. and Hallenbeck J.M. (2000) Advances in the vascular pathophysiology of ischemic stroke. Thromb. Res. 98, 73–81.PubMedCrossRefGoogle Scholar
  10. 10.
    Petty M.A. and Wettstein J.G. (2001) Elements of cerebral microvascular ischemia. Brain Res. 36, 23–34.CrossRefGoogle Scholar
  11. 11.
    Petty M.A. and Lo E.H. (2002) Junctional complexes of the blood-brain barrier:permeability changes in neuroinflammation. Prog. Neurobiol. 68, 311–323.PubMedCrossRefGoogle Scholar
  12. 12.
    Wolburg H. and Lippoldt A. (2002) Tight junctions of the blood-brain barrier:development, composition and regulation. Vascul. Pharmacol. 38, 323–337.PubMedCrossRefGoogle Scholar
  13. 13.
    Huber J.D., Egleton R.D., and Davis T.P. (2001) Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci. 24, 719–725.PubMedCrossRefGoogle Scholar
  14. 14.
    Mark K.S. and Davis T.P. (2002) Cerebral microvascular changes in permeability and tight junction induced by hypoxia-reoxygenation. Am. J. Physiol. Heart. Circ. Physiol. 282, H1485-H1494.PubMedGoogle Scholar
  15. 15.
    Yurchenco P.D. and Schittny J.C. (1990) Molecular architecture of basement membranes. FASEB J. 4, 1577–1590.PubMedGoogle Scholar
  16. 16.
    Abrahamason D.R. (1986) Recent studies on the structure and pathology of basement membranes. J. Pathol. 149, 247–278.Google Scholar
  17. 17.
    Mohan P.S. and Spiro R.G. (1986) Macromolecular organization of basement membranes. J. Biol. Chem. 261, 4328–4336.PubMedGoogle Scholar
  18. 18.
    Siflinger-Birnboim A., Delvecchio P.J., Cooper J.A., Blumenstock F.A., Shepard J.M., and Malik A.B. (1987) Molecular sieving characteristics of cultured endothelial monolayer. J. Cell. Physiol. 132, 111–117.PubMedCrossRefGoogle Scholar
  19. 19.
    Cserr F.H. and Bungaard M. (1986) The neuronal microenvironment: a comparative view. Ann. NY. Acad. Sci. 481, 1–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Fishman R.A. (1975) Brain edema. N. Engl. J. Med. 293, 706–711.PubMedCrossRefGoogle Scholar
  21. 21.
    Carr F.J., McBride M.W., Carswell H.V.O., Graham D., Strahorn P., Clark J.S., et al. (2002) Genetic aspects of stroke: human and experimental studies. J. Cereb. Blood Flow Metab. 22, 767–773.PubMedCrossRefGoogle Scholar
  22. 22.
    Wagner K.R. and Broderick J.P. (2001) Hemorrhagic stroke: pathophysiological mechanisms and neuroprotective treatments, Lo E.H. and Marwah J. Neuroprotection. Prominent Press, Scottsdale A2, pp. 471–508.Google Scholar
  23. 23.
    Mayer S.A. (2002) Intracerebral hemorrhage:natural history and rationale of ultra-early hemostatic therapy. Intensive Care Med. 28, S235-S240.PubMedCrossRefGoogle Scholar
  24. 24.
    Castillo J., Davalos A., Alvarez-Sabin J., Pumar J.M., Leira R., Silva Y., et al. (2002) Molecular signatures of brain injury after intracerebral hemorrhage. Neurology 58, 624–629.PubMedGoogle Scholar
  25. 25.
    Golding E.M. (2002) Sequelae following traumatic brain injury. The cerebrovascular perspective. Brain Res. Brain Res. Rev. 38, 377–388.PubMedCrossRefGoogle Scholar
  26. 26.
    Qiu J., Whalen M.J., Lowenstein P., Fiskum G., Fahy B., Darwish R., et al. (2002) Upregulation of the Fas receptor death-inducing signaling complex after traumatic brain injury in mice and humans. J. Neurosci. 22, 3504–3511.PubMedGoogle Scholar
  27. 27.
    Zhang X., Chen J., Graham S.H., Du L., Kochanek P.M., Draviam R., et al. (2002) Intranuclear localization of apoptosis-inducing factor (AIF) and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite. J. Neurochem. 82, 181–191.PubMedCrossRefGoogle Scholar
  28. 28.
    Yang G.Y., Betz A.L., Chenevert T.L., Brunberg J.A., and Hoff J.T. (1994) Experimental intracerebral hemorrhage:relationship between brain edema, blood flow, and blood-brain barrier permeability in rats. J. Neurosurg. 81, 93–102.PubMedGoogle Scholar
  29. 29.
    Rosand J., Eskey C., Chang Y., Gonzalez R.G., Greenberg S.M., and Koroshetz W.J. (2002) Dynamic single-section CT demonstrates reduced cerebral blood flow in acute intracerebral hemorrhage. Cerebrovasc. Dis. 14, 214–220.PubMedCrossRefGoogle Scholar
  30. 30.
    Zazulia A.R., Diringer M.N., Videen T.O., Adams R.E., Yundt K., Aiyagari V., et al. (2001) Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage. J. Cereb. Blood Flow Metab. 21, 804–810.PubMedCrossRefGoogle Scholar
  31. 31.
    Zhang J., Sima B., Johns L.M., and Macdonald R.L. (1996) Time course of changes in arterial relaxation following subarachnoid hemorrhage in dogs. Neurol. Res. 18, 227–232.PubMedGoogle Scholar
  32. 32.
    Matsumoto K., Lo E.H., Pierce A.R., Halpern E.F., and Newcomb R. (1996) Secondary elevations in extracellular neurotransmitter amino acids in reperfusion phase following focal cerebral ischemia. J. Cereb. Blood Flow Metab. 16, 114–124.PubMedCrossRefGoogle Scholar
  33. 33.
    Chen Y. and Swanson R.A. (2003) Astrocytes and brain injury. J. Cereb. Blood Flow Metab. 23, 137–149.PubMedCrossRefGoogle Scholar
  34. 34.
    Striggow F., Riek M., Breder J., Henrich-Noack P., Reymann K.G., and Reiser G. (2000) The protease thrombin is an endogenous mediator of hippocampal neuroprotection against ischemia at low concentrations but causes degeneration at high concentrations. Proc. Natl. Acad. Sci. USA 97, 2264–2269.PubMedCrossRefGoogle Scholar
  35. 35.
    Xi G., Reiser G., and Keep R.F. (2003) The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: deleterious or protective? J. Neurochem. 84, 3–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Mayne M., Ni W., Yan H.J., Xue M., Johnston J.B., Del Bigio M.R., et al. (2001) Antisense oligodeoxynucleotide inhibition of tumor necrosis factor-alpha expression is neuroprotective after intracerebral hemorrhage. Stroke 32, 240–248.PubMedGoogle Scholar
  37. 37.
    Lenzlinger P.M., Marx A., Trentz O., Kossmann T., and Morganti-Kossmann M.C. (2002) Prolonged intrathecal release of soluble Fas following severe traumatic brain injury in humans. J. Neuroimmunol. 122, 167–174.PubMedCrossRefGoogle Scholar
  38. 38.
    Regan R.F. and Panter S.S. (1993) Neurotoxicity of hemoglobin in cortical cell culture. Neurosci. Lett. 153, 219–222.PubMedCrossRefGoogle Scholar
  39. 39.
    Meguro T., Chen B., Lancon J., and Zhang J.H. (2001) Oxyhemoglobin induces caspase-mediated cell death in cerebral endothelial cells. J. Neurochem. 77, 1128–1135.PubMedCrossRefGoogle Scholar
  40. 40.
    Glazner G.W., Boland A., Dresse A.E., Brenneman D.E., Gozes I., and Mattson M.P. (1999) Activity-dependent neurotrophic factor peptide (ADNF9) protects neurons against oxidative stress-induced death. J. Neurochem. 73, 2341–2347.PubMedCrossRefGoogle Scholar
  41. 41.
    Willmore L.J., and Rubin J.J. (1984) Effects of antiperoxidants on FeCl2-induced lipid peroxidation and focal edema in rat brain. Exp. Neurol. 83, 62–70.PubMedCrossRefGoogle Scholar
  42. 42.
    Chan P.H. (1994) Oxygen radicals in focal cerebral ischemia. Brain Pathol. 4, 59–65.PubMedCrossRefGoogle Scholar
  43. 43.
    Abe K., Yoshidomi M., and Kogure K. (1989) Arachidonic acid metabolism in ischemic neuronal damage. Ann. NY Acad. Sci. 559, 259–268.PubMedCrossRefGoogle Scholar
  44. 44.
    Glaser K.B., Mobillo D., Channg J.Y., and Senko N. (1993) Phospholipase A2 enzymes: regulation and inhibition. Trends Pharmacol. Sci. 14, 92–98.PubMedCrossRefGoogle Scholar
  45. 45.
    Asahi M., Ramahonan R., Sumii T., Wang X., Pauw R.J., Weissig V., et al. (2003) Targeted immunoliposomes reseal vascular damage and reduce hemorrhage after thrombolysis in embolic cerebral ischemia. J. Cereb. Blood Flow Metab. (in press).Google Scholar
  46. 46.
    Bolton S.J., Anthony D.C., and Perry V.H. (1998) Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil induced blood-brain barrier breakdown in vivo. Neuroscience. 86, 1245–1257.PubMedCrossRefGoogle Scholar
  47. 47.
    Kondo T., Kinouchi H., Kawase M., and Yoshimoto T. (1996) Astroglial cells inhibit the increasing permeability of brain endothelial cell monolayer following hypoxia/reoxygenation. Neurosci. Lett. 19, 101–104.CrossRefGoogle Scholar
  48. 48.
    Fischer S., Wobben M., Kleinstuck J., Renz D., and Schaper W. (2000) Effect of astroglial cells on hypoxia-induced permeability in PBMEC cells. Am. J. Physiol. Cell Physiol. 279, C935-C944.PubMedGoogle Scholar
  49. 49.
    Wei E.P., Christman C.W., Kontos H.A., and Povlishock J.T. (1985) effects of oxygen radicals on cerebral arterioles. Am. J. Physiol. 248, H157-H162.PubMedGoogle Scholar
  50. 50.
    Zweier J.L., Kuppusamy P., and Lutty G.A. (1988) Measurement of endothelial cell free radical generation: evidence for a central mechanism of free radical injury in postischemic tissue. Proc. Natl. Acad. Sci. USA 85, 4046–4050.PubMedCrossRefGoogle Scholar
  51. 51.
    Franko J., Pomfy M., Novakova B., and Bens L. (1999) Stobadine protects against ischemia-reperfusion induced morphological alterations of cerebral microcirculation in dogs. Life Sci. 65, 1963–1967.PubMedCrossRefGoogle Scholar
  52. 52.
    Kim G.W., Lewen A., Copin J., Watson B.D., and Chan P.H. (2001) The cytosolic antioxidant, copper/zinc superoxide dismutase, attenuates blood-brain barrier disruption and oxidative cellular injury after photothrombotic cortical ischemia in mice. Neuroscience 105, 1007–1018.PubMedCrossRefGoogle Scholar
  53. 53.
    Schmid-Elsaesser R., Zausinger S., Hungerhuber E., Plesnila N., Baethmann A., Reulen H.J., et al. (1997) Superior neuroprotective efficacy of a novel antioxidant (U-101033E) with improved blood-brain barrier permeability in focal cerebral ischemia. Stroke 28, 2018–2024.PubMedGoogle Scholar
  54. 54.
    Kondo T, Reaume A.G., Huang T-T., Carlson E., Murakami K., Chen S.F., et al. (1997) Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia. J. Neurosci. 17, 4180–4189.PubMedGoogle Scholar
  55. 55.
    Lapchak P.A., Chapman D.F., and Zivin J.A. (2001) Pharmacological effects of the spin trap agents N-t-butyl-phenylnitrone (PBN) and 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) in a rabbit thromboembolic stroke model: combination studies with the thrombolytic tissue plasminogen activator. Stroke 32, 147–153.PubMedGoogle Scholar
  56. 56.
    Asahi M., Asahi K., Wang X., and Lo E.H. (2000) Reduction of tissue plasminogen activator-induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats. J. Cereb. Blood Flow Metab. 20, 452–457.PubMedCrossRefGoogle Scholar
  57. 57.
    Haddad J.J. (2002) Redox regulation of pro-inflammatory cytokines and IkappaB-alpha/NF kappaB nuclear translocation and activation. Biochem. Biophys. Res. Commun. 296, 847–856.PubMedCrossRefGoogle Scholar
  58. 58.
    Inoue N., Takeshita S., Gao D., Ishida T., Kawashima S., Akita H., et al. (2001) Lysophosphatidylcholine increases the secretion of matrix metalloproteinase 2 through the activation of NADH/NADPH oxidase in cultured aortic endothelial cells. Atherosclerosis 155, 45–52.PubMedCrossRefGoogle Scholar
  59. 59.
    Giulian D., Woodward J., Young D.G., Krebs J.F., and Lachman L.B. (1988) Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization. J. Neurosci. 8, 2485–2490.PubMedGoogle Scholar
  60. 60.
    Holmin S. and Matheisen T. (2000) Intracerebral adminstration of interleukin-1 and induction of inflammation, apoptosis and edema. J. Neurosurg. 92, 108–120.PubMedCrossRefGoogle Scholar
  61. 61.
    Shafer R.A. and Murphy S. (1997) Activated astrocytes induce nitric oxide synthase-2 in cerebral endothelium via tumor necrosis factor alpha. Glia 370–379.Google Scholar
  62. 62.
    Fischer S., Clauss M., Wiesnet M., Renz D., Schaper W., and Karliczek G.F. (1999) Hypoxia induces permeability in brain microvessel endothelial cells via VEGF and NO. Am. J. Physiol. 276, C812-C820.PubMedGoogle Scholar
  63. 63.
    Barone F.C. and Feuerstein G.Z. (1999) Inflammatory mediators and stroke: new opportunities for novel therapeutics. J. Cereb. Blood Flow Metab. 19, 819–834.PubMedCrossRefGoogle Scholar
  64. 64.
    Stanimirovic D. and Satoh K. (2000) Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol. 10, 113–126.PubMedCrossRefGoogle Scholar
  65. 65.
    Zhang W. and Stanimirovic D. (2002) Current and future therapeutic strategies to target inflammation in stroke. Current Drug Target—Inflammation & Allergy 1, 151–166.CrossRefGoogle Scholar
  66. 66.
    Janoff A. and Zeligs J.D. (1968) Vascular injury and lysis of basement membrane in vitro by neutral protease of human leukocyte. Science 161, 702–704.PubMedCrossRefGoogle Scholar
  67. 67.
    Weiss S.J., Peppin G., Ortiz X., Ragsdale C., and Test S.T. (1985) Oxidative autoactivation of latent collagenase by human neutrophils. Science 227, 747–749.PubMedCrossRefGoogle Scholar
  68. 68.
    Zhang R., Chopp M., Zhang Z., Jiang N., and Power C. (1998) The expression of P-and E-selectins in three models of middle cerebral artery occlusion. Brain Res. 785, 207–214.PubMedCrossRefGoogle Scholar
  69. 69.
    Haraldsen G., Kvale D., Lien B., Farstad I.N., and Brandtzaeg P. Cytokine-regulated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human microvascular endothelial cells. J. Immunol. 156, 2558–2565.Google Scholar
  70. 70.
    Gen J.G., Bevilacque M.P., Moore K.L., McIntyre T.M., and Prestcott S.M. (1990) Rapid neurophil adhesion to activated endothelium mediated by GMP-140. Nature 343, 757–760.CrossRefGoogle Scholar
  71. 71.
    Wagner D.D. (1993) Weibel-Palade body: The storage granule for von Willebrand factor and P-selectin. Thromb. Haemostasis 70, 105–110.Google Scholar
  72. 72.
    Baggiolini M (1998) Chemokines and leukocyte traffic. Nature 392, 565–568.PubMedCrossRefGoogle Scholar
  73. 73.
    Che X., Ye W., Panga L., Wu D.C., Yang G.Y. (2001) Monocyte chemoattractant protein-1 expressed in neurons and astrocytes during focal ischemia in mice. Brain Res. 902, 171–177.PubMedCrossRefGoogle Scholar
  74. 74.
    Wang X., Li X., Yaish-Ohad S., Sarau H.M., Barone F.C., and Feuerstein G.Z. (1999) Molecular cloning and expression of the rat monocyte chemotactic protein-3 gene: a possible role in stroke. Brain Res. Mol. Brain Res. 71, 304–312.PubMedCrossRefGoogle Scholar
  75. 75.
    Bajetto A., Bonavia R., Barbero S., and Schettini G. (2002) Characterization of chemokines and their receptors in the central nervous system: physiopathological implications. J. Neurochem. 82, 1311–1329.PubMedCrossRefGoogle Scholar
  76. 76.
    Couraud P.O. (1998) Infiltration of inflammatory cells through brain endothelium. Pathol. Biol. 46, 176–180.PubMedGoogle Scholar
  77. 77.
    Rosenberg G.A. (2002) Matrix metalloproteinases in neuroinflammation. Glia 39, 279–291.PubMedCrossRefGoogle Scholar
  78. 78.
    Wong D. and Dorovini-Zis K. (1992) Upregulation of intercellular adhesion molecule-1 (ICAM-1) expression in primary cultures of human brain microvessel endothelial cells by cytokines and lipopolysaccharide. J. Neuroimmunol. 39, 11–21.PubMedCrossRefGoogle Scholar
  79. 79.
    Adamson P., Etienne S., Couraud P.O., Calder V., and Greenwood J. (1999) Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a rho-dependent pathway. J. Immunol. 162, 2964–2973.PubMedGoogle Scholar
  80. 80.
    Etienne-Manneville S., Manneville J.B., Adamson P., Wilbourn B., Greenwood J., and Couraud P. O. (2000) ICAM-I-coupled cytoskeletal rearrangements and transendothelial lymphocyte migration involve intracellular calcium signaling in brain endothelial cell lines. J. Immunol. 165, 3375–3383.PubMedGoogle Scholar
  81. 81.
    Brown R.C. and Davis T.P. (2002) Calcium modulation of adherens and tight junction function: a potential mechanism for BBB disruption after stroke. Stroke 33, 1706–1711.PubMedCrossRefGoogle Scholar
  82. 82.
    Allport J.R., Ding H., Collins T., Gerritsen M.E., and Luscinkas F.W. (1997) Endothelial-dependent mechanisms regulate leukocyte transmigrationL a process involving the proteosome and disruption of vascular-endothelial -cadherin complex at endothelial cell-cell junctions. J. Exp. Med. 186, 517–527.PubMedCrossRefGoogle Scholar
  83. 83.
    Zhang Z.G., Zhang L., Jiang Q., Zhang R., Davies K., Powers C., et al. (2000) VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J. Clin. Investig 106, 829–838.PubMedGoogle Scholar
  84. 84.
    Zhang Z.G., Zhang L., Tsang W., Soltanian-Zadeh H., Morris D., Zhang R., et al. (2002) Correlation of VEGF and angiopoietin expression with disruption of blood-brain barrier and angiogenesis after focal cerebral ischemia. J. Cereb. Blood Flow Metab. 22, 379–392.PubMedCrossRefGoogle Scholar
  85. 85.
    Marti H.J., Bernaudin M., Bellail A., Schoch H., Euler M., Petit E., et al. (2000) Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia. Am. J. Pathol. 156, 965–976.PubMedGoogle Scholar
  86. 86.
    Croll S.D. and Wiegand S.J. (2001) Vascular growth factors in cerebral ischemia. Mol. Neurobiol. 23, 121–135.PubMedCrossRefGoogle Scholar
  87. 87.
    van Bruggen N., Thibodeaux H., Palmer J.T., Lee W.P., Fu L., Cairns B., et al. (1999) VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J. Clin. Investig 104, 1613–1620.PubMedCrossRefGoogle Scholar
  88. 88.
    Wagner S., Tagaya M., Koziol J.A., Quaranta V., and del Zoppo G.J. (1997) Rapid disruption of an astrocyte interaction with the extracellular matrix mediated by integrin alpha 6 beta 4 during focal cerebral ischemia/reperfusion. Stroke 28, 858–865.PubMedGoogle Scholar
  89. 89.
    Tagaya M., Haring H.P., Stuiver I., Wagner S., Abumiya T., Lucero J., et al. (2001) Rapid loss of microvascular integrin expression during focal brain ischemia reflects neuron injury. J. Cereb. Blood Flow Metab. 21, 835–846.PubMedCrossRefGoogle Scholar
  90. 90.
    Zhang Z.G., Bower L., Zhang R.L., Chen S., Windham J.P., and Chopp M. (1999) Three-dimensional measurement of cerebral microvascular plasma perfusion, glial fibrillary acidic protein and microtubule associated protein-2 immunoreactivity after embolic stroke in rats: a double fluorescent labeled laser-scanning confocal microscopic study. Brain Res. 844, 55–66.PubMedCrossRefGoogle Scholar
  91. 91.
    Hamann G.F., Okada Y., Fitridge R., and del Zoppo G.J. (1995) Microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion. Stroke 26, 2120–2126.PubMedGoogle Scholar
  92. 92.
    Hamann G.F., Liebetrau M., Martens H., Burggraf D., Kloss C.U., Bultemeier G., et al. (2002) Microvascular basal lamina injury after experimental focal cerebral ischemia and reperfusion in the rat. J. Cereb. Blood Flow Metab. 22, 526–533.PubMedCrossRefGoogle Scholar
  93. 93.
    Hamann G.F., Okada Y., and del Zoppo G.J. (1996) Hemorrhagic transformation and microvascular integrity during focal cerebral ischemia/reperfusion. J. Cereb. Blood Flow Metab. 16, 1373–1378.PubMedCrossRefGoogle Scholar
  94. 94.
    del Zoppo G.J., von Kummer R., and Hamann G.F. (1998) Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke. J. Neurol. Neurosurg. Psychiatry 65, 1–9.PubMedGoogle Scholar
  95. 95.
    Gasche Y., Copin J-C., Sugawara T., Fujimura K, and Chan P.H. (2001) Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 21, 1393–1400.PubMedCrossRefGoogle Scholar
  96. 96.
    Lo E.H., Wang X., and Cuzner M.L. (2002) Extracellular proteolysis in brain injury and inflammation:role for plasminogen activators and matrix metalloproteinases. J. Neurosci. Res. 69, 1–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Armao D., Kornfeld M., Estrada E.Y., Grossetete M., and Rosenberg G.A. (1997) Neutral proteases and disruption of the blood-brain barrier in rat. Brain Res. 767, 259–264.PubMedCrossRefGoogle Scholar
  98. 98.
    Asahi M., Wang X., Mori T., Sumii T., Jung J-C., Moskowitz M.A., et al. (2001) Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J. Neurosci. 21, 7724–7732.PubMedGoogle Scholar
  99. 99.
    Asahi M., Asahi K., Jung J.C., del Zoppo G.J., Fini M.E., and Lo E.H. (2000) Role for matrix metalloproteinase 9 after focal cerebral ischemia:effects of gene knockout and enzyme inhibition with BB-94. J. Cereb Blood Flow Metab. 20, 1681–1689.PubMedCrossRefGoogle Scholar
  100. 100.
    Fujimura M., Gasche Y., Morita-Fujimura Y., Massengale J., Kawase M., and Chan P.H. (1999) Early appearance of activated matrix metalloproteinase 9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion. Brain Res. 842, 92–100.PubMedCrossRefGoogle Scholar
  101. 101.
    Heo J.H., Lucero J., Abumiya T., Koizol J.A., Copeland B.R., and del Zoppo G.J. (1999) Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J. Cereb. Blood Flow Metab. 19, 624–633.PubMedCrossRefGoogle Scholar
  102. 102.
    Mun-Bryce S. and Rosenberg G.A. (1998) Matrix metalloproteinases in cerebro-vascular disease. J. Cereb. Blood Flow Metab. 18, 1163–1172.PubMedCrossRefGoogle Scholar
  103. 103.
    Rosenberg G.A., Navratil M., Barone F., and Feuerstein G. (1996) Proteolytic cascade enzymes increase in focal cerebral ischemia in rat. J. Cereb. Blood Flow Metab. 16, 360–366.PubMedCrossRefGoogle Scholar
  104. 104.
    Anthony D.C., Miller K.M., Fearn S., Townsend M.J., Opdennaker G., Wells G.M.A., et al. (1998) Matrix metalloproteinase expression in an experimentally induced DTH model of multiple sclerosis in rat CNS. J. Neuroimmunol. 87, 62–72.PubMedCrossRefGoogle Scholar
  105. 105.
    Rosenberg G.A., Estrada E.Y., and Dencoff J.E. (1998) Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke 29, 2189–2195.PubMedGoogle Scholar
  106. 106.
    Jiang X., Namura S., and Nagata I. (2001) Matrix metalloproteinase inhibitor KB-R7785 attenuates brain damage resulting from permanent focal cerebral ischemia in mice. Neurosci. Lett. 305, 41–44.PubMedCrossRefGoogle Scholar
  107. 107.
    Romanic A.M., White R.F., Arleth A.J., Ohlstein E.H., and Barone F.C. (1998) Matrix metalloproteinase expression increases after cerebral focal ischemia in rats:inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke 29, 1020–1030.PubMedGoogle Scholar
  108. 108.
    Lapchak P.A., Chapman D.F., and Zivin J.A. (2000) Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke 31, 3034–3040.PubMedGoogle Scholar
  109. 109.
    Rosenberg G.A., Estrada E.Y., Dencoff J.E., and Stetler-Stevenson W.G. (1995) Tumor necrosis factor-alpha-induced gelatinase B causes delayed opening of blood-brain barrier: an expanded therapeutic window. Brain Res. 703, 151–155.PubMedCrossRefGoogle Scholar
  110. 110.
    Lee S. and Lo E.H. (2003) Induction of caspase-mediated cell death by matrix metalloproteinase after hypoxia-reoxygenation in human brain microvascular endothelial cells. Stroke 34, 250 (abstr).CrossRefGoogle Scholar
  111. 111.
    Fini M.E., Cook J.R., Mohan R., and Brinckerhoff C.E. (1998) Regulation of matrix metalloproteinase gene expression, in Matrix Metalloproteinases (Parks W.C. and Mecham R.P.) Academic Press, New York, NY pp. 299–356.Google Scholar
  112. 112.
    Wang X., Mori T., Jung J-C., Fini M.E., and Lo E.H. (2002) Secretion of matrix metalloproteinase-2 and -9 after mechanical trauma injury in rat cortical cultures and involvement of MAP kinase. J. Neurotrauma 19, 615–625.PubMedCrossRefGoogle Scholar
  113. 113.
    Morita-Fujimura Y., Fujimura M., Gasche Y., Copin J., and Chan P.H. (1999) Overexpression of copper and zinc superoxide dismutase in transgenic mice prevents the induction and activation of matrix metalloproteinases after cold injury induced brain trauma. J. Cereb. Blood Flow Metab. 20, 130–138.CrossRefGoogle Scholar
  114. 114.
    Ahn M.Y., Zhang Z.G., Tsang W., and Chopp M. (1999) Endogenous plasminogen activator expression after embolic focal cerebral ischemia in mice. Brain Res. 837, 169–176.PubMedCrossRefGoogle Scholar
  115. 115.
    Hosomi N., Lucero J., Heo J.H., Koziol J.A., Copeland B.R., and del Zoppo G.J. (2001) Rapid differential endogenous plasminogen activator expression after acute middle cerebral aretry occlusion. Stroke 32, 1341–1348.PubMedGoogle Scholar
  116. 116.
    Yepes M., Sankvist M., Wong M.K.K., Coleman T.A., Smith E., Cohan S.L., et al. (2000) Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis. Blood 96, 569–576.PubMedGoogle Scholar
  117. 117.
    NINDS rt-PA Stroke Study Group. (1995) Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 333, 1581–1587.CrossRefGoogle Scholar
  118. 118.
    Larrue V., von Kummer R., del Zoppo G., and Bluhmki E. (1999) Hemorrhagic transformation in acute ischemic stroke:potential contributing factors in the ECASS study. Stroke 28, 957–960.Google Scholar
  119. 119.
    NINDS rt-PA Stroke Study Group. (1997) Intracerebral hemorrhage after intravenous TPA therapy for ischemic stroke. Stroke 28, 2109–2118.Google Scholar
  120. 120.
    Sumii T. and Lo E.H. (2002) Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke 33, 831–836.PubMedCrossRefGoogle Scholar
  121. 121.
    Montaner J., Alvarez-Sabin J., Molina C.A., Angles A., Abilliera S., Arenillas J., et al. (2001) Matrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke. Stroke 32, 2762–2767.PubMedGoogle Scholar
  122. 122.
    Maeda M., Furuichi Y., Uetama N., Moriguchi A., Satoh N., Matsuoka N., et al. (2002) A combined treatment with tacrolimus (FK506) and recombinant tissue plasminogen activator for thrombotic focal cerebral ischemia in rats: increased neuroprotective efficacy and extended therapeutic time window. J. Cereb. Blood Flow Metab. 22, 1205–1211.PubMedCrossRefGoogle Scholar
  123. 123.
    Pozzi A., Moberg P.E., Miles L.A., Wagner S., Soloway P., and Gardner H.A. (2000) Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization. Proc. Natl. Acad. Sci. USA 97, 2202–2207.PubMedCrossRefGoogle Scholar
  124. 124.
    Aoudjit F., Ptoworowski E.F., and St-Pierre Y. (1998) Bi-directional induction of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 during T lymphoma/endothelial cell contact: implication of ICAM-1. J. Immunol. 160, 2967–2973.PubMedGoogle Scholar
  125. 125.
    May A.E., Kalsch T., Maasberg S., Herouy Y., Schmidt R., and Gawaz M. (2002) Engagement of glycoprotein IIb/IIa (alpha-IIb/beta-3) on platelets upregulates CD40L and triggers CD40L-dependent matrix degradation by endothelial cells. Circulation 106, 2111–2117.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  1. 1.Neuroprotection Research Laboratory, Departments of Neurology and RadiologyMassachusetts General HospitalBoston
  2. 2.Program in NeuroscienceHarvard Medical SchoolBoston

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