Molecular insights and therapeutic targets for blood-brain barrier disruption in ischemic stroke: Critical role of matrix metalloproteinases and tissue-type plasminogen activator

Neurobiology of Disease

Volumn 38, Issue 3, 2010, Pages 376-385

  Jin, Rong ^a   Yang, Guojun ^b   Li, Guohong ^a  

^a Louisiana State University School of Medicine Shreveport   (United States)

^b NINGBO UNIVERSITY   (China)

Author keywords

Blood brain barrier; Ischemic stroke; MMPs; Neurovascular unit; Signaling pathways; TPA

Indexed keywords

ACTIVATED PROTEIN C; GELATINASE B; LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN; MATRIX METALLOPROTEINASE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; NEUROSERPIN; PLATELET DERIVED GROWTH FACTOR C; PROTEINASE ACTIVATED RECEPTOR 1; TISSUE PLASMINOGEN ACTIVATOR;

ACUTE DISEASE; BLOOD BRAIN BARRIER; BRAIN EDEMA; BRAIN INFARCTION; BRAIN ISCHEMIA; DISEASE MODEL; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG MEGADOSE; DRUG SAFETY; ENDOTHELIUM CELL; ENZYME ACTIVATION; ENZYME ACTIVITY; FIBRINOLYTIC THERAPY; HUMAN; LOW DRUG DOSE; NEUROPROTECTION; NEUROTOXICITY; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; REPERFUSION INJURY; REVIEW; SIGNAL TRANSDUCTION; SYSTEMIC CIRCULATION;

ANIMALS; BLOOD-AQUEOUS BARRIER; BRAIN ISCHEMIA; CAPILLARY PERMEABILITY; HUMANS; MATRIX METALLOPROTEINASES; SIGNAL TRANSDUCTION; STROKE; TISSUE PLASMINOGEN ACTIVATOR;

EID: 77952547253     PISSN: 09699961     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.nbd.2010.03.008     Document Type: Review

References (141)

1. Abbott N.J., et al. Structure and function of the blood-brain barrier. Neurobiol. Dis. 2010, 37:13-25.
2. Adibhatla R.M., Hatcher J.F. Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies. CNS Neurol. Disord. Drug Targets 2008, 7:243-253.
3. András I.E., et al. The NMDA and AMPA/KA receptors are involved in glutamate-induced alterations of occludin expression and phosphorylation in brain endothelial cells. J. Cereb. Blood Flow Metab. 2007, 27:1431-1443.
4. Anthony D.C., et al. Differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke. Neuropathol. Appl. Neurobiol. 1997, 23:406-415.
5. Asahi M., et al. 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, 20:1681-1689.
6. Asahi M., et al. Matrix metalloproteinase 2 gene knockout has no effect on acute brain injury after focal ischemia. NeuroReport 2001, 12:3003-3007.
7. Asahi M., et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J. Neurosci. 2001, 21:7724-7732.
8. Balda M.S., et al. Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical-basolateral intramembrane diffusion barrier by expression of a mutant tight junction membrane protein. J. Cell. Biol. 1996, 134:1031-1049.
9. Barr T.L., et al. Blood-brain barrier disruption in humans is independently associated with increased matrix metalloproteinase-9. Stroke 2010, 41:E123-E128.
10. Bauer A.T., et al. Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement. Cereb. Blood Flow Metab. 2009, [Epub ahead of print].
11. Belayev L., et al. Quantitative evaluation of blood-brain barrier permeability following middle cerebral artery occlusion in rats. Brain Res. 1996, 739:88-96.
12. Benchenane K., et al. Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis. Circulation 2005, 111:2241-2249.
13. Benchenane K., et al. Oxygen glucose deprivation switches the transport of tPA across the blood-brain barrier from an LRP-dependent to an increased +LRP-independent process. Stroke 2005, 36:1065-1070.
14. Benchenane K., et al. Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory. J. Cell Sci. 2007, 120:578-585.
15. Bernard G.R., et al. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 2001, 344:699-709.
16. Bolton S.J., et al. Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood-brain barrier breakdown in vivo. Neuroscience 1998, 86:1245-1257.
17. Buck B.H., et al. Early neutrophilia is associated with volume of ischemic tissue in acute stroke. Stroke 2008, 39:355-360.
18. Candelario-Jalil E., et al. Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience 2009, 158:983-994.
19. Castellanos M., et al. Plasma metalloproteinase-9 concentration predicts hemorrhagic transformation in acute ischemic stroke. Stroke 2003, 34:40-46.
20. Castellanos M., et al. Serum cellular fibronectin and matrix metalloproteinase-9 as screening biomarkers for the prediction of parenchymal hematoma after thrombolytic therapy in acute ischemic stroke: a multicenter confirmatory study. Stroke 2007, 38:1855-1859.
21. Centonze D., et al. Tissue plasminogen activator is required for corticostriatal long-term potentiation. Eur. J. NeuroSci. 2002, 16:713-721.
22. Cera M.R., et al. JAM-A promotes neutrophil chemotaxis by controlling integrin internalization and recycling. J. Cell Sci. 2009, 122:268-277.
23. Chang D.I., et al. Activation systems for latent matrix metalloproteinase-2 are upregulated immediately after focal cerebral ischemia. J. Cereb. Blood Flow Metab. 2003, 23:1408-1419.
24. Chavakis T., et al. The junctional adhesion molecule-C promotes neutrophil transendothelial migration in vitro and in vivo. J. Biol. Chem. 2004, 279:55602-55608.
25. Chen B., et al. Severe blood-brain barrier disruption and surrounding tissue injury. Stroke 2009, 40:e666-e674.
26. Chen F., et al. Disruptions of occludin and claudin-5 in brain endothelial cells in vitro and in brains of mice with acute liver failure. Hepatology 2009, 50:1914-1923.
27. Cheng T., et al. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat. Med. 2003, 9:338-342.
28. Cheng T. Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nat. Med. 2006, 12:1278-1285.
29. Cinelli P., et al. Neuroserpin, a neuroprotective factor in focal ischemic stroke. Mol. Cell. Neurosci. 2001, 18:443-457.
30. Clark A.W., et al. Increased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia. Neurosci. Lett. 1997, 238:53-56.
31. Cronin C.A. Intravenous tissue plasminogen activator for stroke: a review of the ECASS III results in relation to prior clinical trials. J. Emerg. Med. 2010, 38:99-105.
32. Cunningham S.A., et al. JAM2 interacts with alpha4beta1: facilitation by JAM3. J. Biol. Chem. 2002, 277:27589-27592.
33. Cunningham L.A. Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 2005, 50:329-339.
34. Del Zoppo G.J. Stroke and neurovascular protection. N. Engl. J. Med. 2006, 354:553-555.
35. Dejana E., et al. The role of adherens junctions and VE-cadherin in the control of vascular permeability. J. Cell Sci. 2008, 121:2115-2122.
36. Del Maschio A., et al. Leukocyte recruitment in the cerebrospinal fluid of mice with experimental meningitis is inhibited by an antibody to junctional adhesion molecule (JAM). J. Exp. Med. 1999, 190:1351-1356.
37. Derex L., Nighoghossian N. Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: an update. J. Neurol. Neurosurg. Psychiatry 2008, 79:1093-1099.
38. Emsley H.C., et al. An early and sustained peripheral inflammatory response in acute ischaemic stroke: relationships with infection and atherosclerosis. J. Neuroimmunol. 2003, 139:93-101.
39. Fanning A.S., et al. The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J. Biol. Chem. 1998, 273:29745-29753.
40. Feistritzer C., Riewald M. Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 2005, 105:3178-3184.
41. Feldman G.J., et al. Occludin: structure, function and regulation. Adv. Drug Deliv. Rev. 2005, 57:883-917.
42. Fredriksson L., et al. Tissue plasminogen activator is a potent activator of PDGF-CC. EMBO J. 2004, 23:3793-3802.
43. Fredriksson L., et al. Structural requirements for activation of latent platelet-derived growth factor CC by tissue plasminogen activator. J. Biol. Chem. 2005, 280:26856-26862.
44. Furuse M., et al. Manner of interaction of heterogeneous claudin species within and between tight junction strands. J. Cell Biol. 1999, 147:891-903.
45. Gasche Y., et al. Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood-brain barrier dysfunction. J. Cereb. Blood Flow Metab. 1999, 119:1020-1028.
46. Gasche Y., et al. Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 2001, 21:1393-1400.
47. Gidday J.M., et al. Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am. J. Physiol. Heart Circ. Physiol. 2005, 289:H558-H568.
48. Gravanis I., Tsirka S.E. Tissue-type plasminogen activator as a therapeutic target in stroke. Expert Opin. Ther. Targets 2008, 12:159-170.
49. Guo H., et al. Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron 2004, 41:563-572.
50. Guo S., Lo E.H. Dysfunctional cell-cell signaling in the neurovascular unit as a paradigm for central nervous system disease. Stroke 2009, 40:S4-S7.
51. Gurney K.J., et al. Blood-brain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation. Neurobiol. Dis. 2006, 23:87-96.
52. Haorah J., et al. Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood-brain barrier dysfunction. J. Neurochem. 2007, 101:566-576.
53. Haskins J., et al. ZO-3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO-1 and occludin. J. Cell Biol. 1998, 1412:199-208.
54. Hawkins B.T., Davis T.P. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol. Rev. 2005, 57:173-185.
55. Heo J.H., et al. Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J. Cereb. Blood Flow Metab. 1999, 19:624-633.
56. Herz J., Strickland D.K. LRP: a multifunctional scavenger and signaling receptor. J. Clin. Invest. 2001, 108:779-784.
57. Hirase T., et al. Occludin as a possible determinant of tight junction permeability in endothelial cells. J. Cell Sci. 1997, 110:1603-1613.
58. Horstmann S., et al. Profiles of matrix metalloproteinases, their inhibitors, and laminin in stroke patients: influence of different therapies. Stroke 2003, 234:2165-2170.
59. Huang Z.G., et al. Biphasic opening of the blood-brain barrier following transient focal ischemia: effects of hypothermia. Can. J. Neurol. Sci. 1999, 26:298-304.
60. Jian Liu K., Rosenberg G.A. Matrix metalloproteinases and free radicals in cerebral ischemia. Free Radic. Biol. Med. 2005, 39:71-80.
61. Jin R., et al. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J. Leukoc. Biol. 2010, [Epub ahead of print].
62. Justicia C., et al. Neutrophil infiltration increases matrix metalloproteinase-9 in the ischemic brain after occlusion/reperfusion of the middle cerebral artery in rats. J. Cereb. Blood Flow Metab. 2003, 23:1430-1440.
63. Kago T., et al. Cerebral ischemia enhances tyrosine phosphorylation of occludin in brain capillaries. Biochem. Biophys. Res. Commun. 2006, 339:1197-1203.
64. Kale G., et al. Tyrosine phosphorylation of occludin attenuates its interactions with ZO-1, ZO-2, and ZO-3. Biochem. Biophys. Res. Commun. 2003, 302:324-329.
65. Keiper T., et al. The role of junctional adhesion molecule-C (JAM-C) in oxidized LDL-mediated leukocyte recruitment. FASEB J. 2005, 19:2078-2080.
66. Kelly P.J., et al. Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke: the Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) study. Stroke 2008, 39:100-104.
67. Kim Y.H., et al. Nonproteolytic neuroprotection by human recombinant tissue plasminogen activator. Science 1999, 284:647-665.
68. Kuroiwa T., et al. The biphasic opening of the blood-brain barrier to proteins following temporary middle cerebral artery occlusion. Acta Neuropathol. 1985, 68(68):122-129.
69. Kvajo M., et al. Regulation of brain proteolytic activity is necessary for the in vivo function of NMDA receptors. J. Neurosci. 2004, 24:9734-9743.
70. Lai C.H., et al. Critical role of actin in modulating BBB permeability. Brain Res. Brain Res. Rev. 2005, 50:7-13.
71. Lebeurrier N., et al. The brain-specific tissue-type plasminogen activator inhibitor, neuroserpin, protects neurons against excitotoxicity both in vitro and in vivo. Mol. Cell. Neurosci. 2005, 30:552-558.
72. Lee C.Z., et al. Matrix metalloproteinase-9 inhibition attenuates vascular endothelial growth factor-induced intracerebral hemorrhage. Stroke 2007, 38:2563-2568.
73. Lee H.Y., et al. Non-proteolytic neurotrophic effects of tissue plasminogen activator on cultured mouse cerebrocortical neurons. J. Neurochem. 2007, 101:1236-1247.
74. Levin E.G., del Zoppo G.J. Localization of tissue plasminogen activator in the endothelium of a limited number of vessels. Am. J. Pathol. 1994, 144:855-861.
75. Li X., et al. PDGF-C is a new protease-activated ligand for the PDGF-Α receptor. Nat. Cell Biol. 2000, 2:302-309.
76. Liu D., et al. Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. Nat. Med. 2004, 10:1379-1383.
77. Liu L.B., et al. Bradykinin increases blood-tumor barrier permeability by down-regulating the expression levels of ZO-1, occludin, and claudin-5 and rearranging actin cytoskeleton. J. Neurosci. Res. 2008, 86:1153-1168.
78. Liu W., et al. Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia. J. Neurochem. 2009, 108:811-820.
79. López-Atalaya J.P., et al. Recombinant Desmodus rotundus salivary plasminogen activator crosses the blood-brain barrier through a low-density lipoprotein receptor-related protein-dependent mechanism without exerting neurotoxic effects. Stroke 2007, 38:1036-1043.
80. Lopez-Atalaya J.P., et al. Toward safer thrombolytic agents in stroke: molecular requirements for NMDA receptor-mediated neurotoxicity. J. Cereb. Blood Flow Metab. 2008, 28:1212-1221.
81. Lucivero V., et al. Different roles of matrix metalloproteinases-2 and -9 after human ischaemic stroke. Neurol. Sci. 2007, 28:165-170.
82. Ludwig R.J., et al. Junctional adhesion molecule (JAM)-B supports lymphocyte rolling and adhesion through interaction with alpha4beta1 integrin. Immunology 2009, 128:196-205.
83. Martin-Padura I., et al. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J. Cell Biol. 1998, 142:117-127.
84. Mataga N., et al. Permissive proteolytic activity for visual cortical plasticity. Proc. Natl. Acad. Sci. U. S. A. 2002, 99:7717-7721.
85. McColl B.W., et al. Systemic inflammatory stimulus potentiates the acute phase and CXC chemokine responses to experimental stroke and exacerbates brain damage via interleukin-1- and neutrophil-dependent mechanisms. J. Neurosci. 2007, 27:4403-4412.
86. McColl B.W., et al. Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. J. Neurosci. 2008, 28:9451-9462.
87. Michaluk P., et al. Matrix metalloproteinase-9 controls NMDA receptor surface diffusion through integrin beta1 signaling. J. Neurosci. 2009, 29:6007-6012.
88. Miranda E., Lomas D.A. Neuroserpin: a serpin to think about. Cell. Mol. Life Sci. 2006, 63:709-722.
89. Montaner J., et al. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 2003, 107:598-603.
90. Murakami T., et al. Occludin phosphorylation and ubiquitination regulate tight junction trafficking and vascular endothelial growth factor-induced permeability. J. Biol. Chem. 2009, 284:21036-22146.
91. Nassar T., et al. Binding of urokinase to low density lipoprotein-related receptor (LRP) regulates vascular smooth muscle cell contraction. J. Biol. Chem. 2002, 277:40499-40504.
92. Nicole O., et al. The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling. Nat. Med. 2001, 7:59-64.
93. Nitta T., et al. Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J. Cell Biol. 2003, 161:653-660.
94. Piontek J., et al. Formation of tight junction: determinants of homophilic interaction between classic claudins. Faseb J. 2008, 22:146-158.
95. Planas A.M. Expression and activation of matrix metalloproteinase-2 and -9 in rat brain after transient focal cerebral ischemia. Neurobiol. Dis. 2001, 8:834-846.
96. Polavarapu R., et al. Tissue-type plasminogen activator-mediated shedding of astrocytic low-density lipoprotein receptor-related protein increases the permeability of the neurovascular unit. Blood 2007, 109:3270-3278.
97. Qian Z., et al. Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation. Nature 1993, 361:453-457.
98. Rao R.K., et al. Tyrosine phosphorylation and dissociation of occludin-ZO-1 and E-cadherin-beta-catenin complexes from the cytoskeleton by oxidative stress. Biochem. J. 2002, 368:471-481.
99. Rosell A., et al. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke 2006, 37:1399-1406.
100. Rosell A., Lo E.H. Multiphasic roles for matrix metalloproteinases after stroke. Curr. Opin. Pharmacol. 2008, 1:82-89.
101. Rosell A., et al. Mechanisms and markers for hemorrhagic transformation after stroke. Acta Neurochir. Suppl. 2008, 105:173-178.
102. Rosell A., et al. MMP-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke 2008, 39:1121-1126.
103. Rosenberg G.A., et al. TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase. Brain Res. 1992, 576:203-207.
104. Rosenberg G.A., et al. Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke 1998, 29:2189-2195.
105. Rosenberg G.A., Yang Y. Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg. Focus 2007, 22:E4.
106. Saitou M., et al. Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol. Biol. Cell 2000, 11:4131-4142.
107. Salles F.J., Strickland S. Localization and regulation of the tissue plasminogen activator-plasmin system in the hippocampus. J. Neurosci. 2002, 22:2125-2134.
108. Samson A.L., Medcalf R.L. Tissue-type plasminogen activator: a multifaceted modulator of neurotransmission and synaptic plasticity. Neuron 2006, 50:673-678.
109. Sandoval K.E., Witt K.A. Blood-brain barrier tight junction permeability and ischemic stroke. Neurobiol. Dis. 2008, 32:200-219.
110. Santoso S., et al. The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1. J. Exp. Med. 2002, 196:679-691.
111. Sappino A.P., et al. Extracellular proteolysis in the adult murine brain. J. Clin. Invest. 1993, 92:679-685.
112. Seeds N.W., et al. Tissue plasminogen activator induction in Purkinje neurons after cerebellar motor learning. Science 1995, 270:1992-1994.
113. Sharp F.R., et al. Multiple molecular penumbras after focal cerebral ischemia. J. Cereb. Blood Flow Metab. 2000, 20:1011-1032.
114. Siao C.J., et al. Cell type-specific roles for tissue plasminogen activator released by neurons or microglia after excitotoxic injury. J. Neurosci. 2003, 23:3234-3242.
115. Sole S., et al. Activation of matrix metalloproteinase-3 and agrin cleavage in cerebral ischemia/reperfusion. J. Neuropathol. Exp. Neurol. 2004, 63:338-349.
116. Soma T., et al. Thr(207) of claudin-5 is involved in size-selective loosening of the endothelial barrier by cyclic AMP. Exp. Cell Res. 2004, 300:202-212.
117. Su E.J., et al. Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat. Med. 2008, 14:731-737.
118. Suzuki Y., et al. Stromelysin-1 (MMP-3) is critical for intracranial bleeding after t-PA treatment of stroke in mice. J. Thromb. Haemost. 2007, 5:1732-1739.
119. Suzuki Y., et al. Tissue-type plasminogen activator (t-PA) induces stromelysin-1 (MMP-3) in endothelial cells through activation of lipoprotein receptor-related protein. Blood 2009, 114:3352-3358.
120. Taddei A., et al. Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5. Nat. Cell Biol. 2008, 10:923-934.
121. Thiyagarajan M., et al. Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1. J. Neurosci. 2008, 28:12788-12797.
122. Tsirka S.E., et al. Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 1995, 377:340-344.
123. Tsirka S.E., et al. An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus. J. Neurosci. 1997, 17:543-552.
124. Tsuji K., et al. Tissue plasminogen activator promotes matrix metalloproteinase-9 upregulation after focal cerebral ischemia. Stroke 2005, 36:1954-1959.
125. Tsukita S., Furuse M. Occludin and claudins in tight-junction strands: leading or supporting players?. Trends. Cell Biol. 1999, 9:268-273.
126. Wang X., et al. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat. Med. 2003, 9:1313-1317.
127. Wang Y.F., et al. Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nat. Med. 1998, 4:228-231.
128. Weber C., et al. The role of junctional adhesion molecules in vascular inflammation. Nat. Rev. Immunol. 2007, 7:467-477.
129. Yamamoto M., et al. Phosphorylation of claudin-5 and occludin by rho kinase in brain endothelial cells. Am. J. Pathol. 2008, 172:521-533.
130. Yang Y., et al. 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, 27:697-709.
131. Yepes M., et al. Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis. Blood 2000, 96:569-576.
132. Yepes M., et al. Regulation of seizure spreading by neuroserpin and tissue-type plasminogen activator is plasminogen-independent. J. Clin. Invest. 2002, 109:1571-1578.
133. Yepes M., et al. Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. J Clin Invest. 2003, 112:1533-1540.
134. Yepes M., et al. Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic. Trends Neurosci. 2009, 32:48-55.
135. Zeller J.A., et al. Platelet-leukocyte interaction and platelet activation in acute stroke with and without preceding infection. Arterioscler. Thromb. Vasc. Biol. 2005, 25:1519-1523.
136. Zhang X., et al. Tissue-type plasminogen activator and the low-density lipoprotein receptor-related protein mediate cerebral ischemia-induced nuclear factor-kappaB pathway activation. Am. J. Pathol. 2007, 171:1281-1290.
137. Zhang Z., et al. Adjuvant treatment with neuroserpin increases the therapeutic window for tissue-type plasminogen activator administration in a rat model of embolic stroke. Circulation 2002, 106:740-745.
138. Zhao B.Q., et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat. Med. 2006, 12:441-445.
139. Zlokovic B.V., et al. Functional recovery after embolic stroke in rodents by activated protein C. Ann. Neurol. 2005, 58:474-477.
140. Zlokovic B.V. Remodeling after stroke. Nat. Med. 2006, 12:390-391.
141. Zlokovic B.V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008, 57:178-201.