Published online before print September 30, 2004, doi: 10.1161/01.STR.0000143219.16695.af
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 2004;35:2726.)
© 2004 American Heart Association, Inc.
Articles |
Mechanisms of Hemorrhagic Transformation After Tissue Plasminogen Activator Reperfusion Therapy for Ischemic Stroke
From the Departments of Radiology and Neurology (X.W., K.T., S.R.L., M.N., K.L.F., E.H.L.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; and the Stroke Program, Calgary Brain Institute and Department of Clinical Neurosciences (A.M.B), University of Calgary, Alberta, Canada.
Correspondence to Dr Eng H. Lo, Neuroprotection Research Laboratory, Harvard Medical School and Massachusetts General Hospital, MGH East 149-2401, Charlestown, MA 02129. E-mail Lo{at}helix.mgh.harvard.edu
 |
Abstract |
|---|
 Top Abstract IntroductionPleiotropic Actions of tPA...tPA-Matrix Metalloproteinase...References |
|---|
Reperfusion therapy with tissue plasminogen activator (tPA) is a rational therapy for acute ischemic stroke. Properly titrated use of tPA improves clinical outcomes. However, there is also an associated risk of hemorrhagic transformation after tPA therapy. Emerging data now suggest that some of these potentially neurotoxic side effects of tPA may be due to its signaling actions in the neurovascular unit. Besides its intended role in clot lysis, tPA is also an extracellular protease and signaling molecule in brain. tPA mediates matrix remodeling during brain development and plasticity. By interacting with the NMDA-type glutamate receptor, tPA may amplify potentially excitotoxic calcium currents. At selected concentrations, tPA may be vasoactive. Finally, by augmenting matrix metalloproteinase (MMP) dysregulation after stroke, tPA may degrade extracellular matrix integrity and increase risks of neurovascular cell death, blood–brain barrier leakage, edema, and hemorrhage. Understanding these pleiotropic actions of tPA may reveal new therapeutic opportunities for combination stroke therapy.
Key Words: blood—brain barrier • cerebral ischemia • hemorrhage • neuroprotection
|
Introduction |
|---|
|
TopAbstractIntroductionPleiotropic Actions of tPA...tPA-Matrix Metalloproteinase...References |
|---|
Arational approach to treat acute ischemic stroke is to rapidly reperfuse the affected brain tissue. Evidence from controlled clinical trials suggests that thrombolysis of the occluding clot with recombinant human tissue plasminogen activator (tPA) can successfully reperfuse ischemic brain.1,2 However, tPA therapy may work best if administered within a narrow 1- to 3-hour therapeutic window after stroke onset.3,4 Although some intriguing evidence exists to suggest that some patients may also benefit from later tPA treatments,5 the criteria for identifying these patient subsets need to be precisely defined.
To date, only 3% to 5% of patients receive tPA therapy for acute ischemic stroke. In part, this may be related to the elevated risks of symptomatic intracranial hemorrhage, and the resulting narrowed therapeutic time windows to lessen these complications of hemorrhagic transformation. Thus, the clinical problem at hand is how to increase the time window for tPA, decrease or eliminate the risks of cerebral hemorrhage, and ultimately to increase the overall efficacy of tPA reperfusion therapy. In this short review, we propose that tPA is a pleiotropic molecule. In addition to its intended role in clot lysis, tPA may also possess important signaling and protease actions in the neurovascular unit after stroke, some of which would be responsible for mediating hemorrhagic transformation in affected brain (Figure 1). We will discuss some accumulating evidence to support this hypothesis, with the hope that delineating some of these pathways may reveal new therapeutic opportunities for combination stroke therapies.
|
|
Pleiotropic Actions of tPA in Brain |
|---|
|
TopAbstractIntroductionPleiotropic Actions of tPA...tPA-Matrix Metalloproteinase...References |
|---|
tPA plays a central role in maintaining homeostatic control in the blood coagulation cascade. By cleaving the precursor molecule plasminogen, it produces the active enzyme plasmin, which then dissolves fibrin-based clots in focal cerebral ischemia. When given to the right patients, tPA effectively reperfuses ischemic brain and rescues tissue. However, in addition to the intended clot lysis effects in brain, tPA may also have other signaling properties.
tPA is intimately involved in extracellular matrix remodeling during brain development.6,7 By modifying the parenchymal matrix, tPA may mediate neuronal precursor migration, as well as neurite and axonal extension.8,9 In adult brain, tPA may play a critical role in long-term potentiation,10,11 possibly by microproteolysis of extracellular space that allows dynamic remodeling at the synaptic and dendritic levels.12 Knockout mice deficient in endogenous tPA show perturbed forms of long-term potentiation,13 whereas transgenic mice overexpressing tPA show enhanced long-term potentiation and learning.14 In a pathologic context, tPA may exacerbate deleterious learning, such as that which may occur during drug addiction. A recent study demonstrated that tPA may mediate the rewarding effects of morphine by regulating dopamine release in the affected nucleus accumbens.15 Matrix remodeling may also contribute to neuronal plasticity during delayed recovery from stroke and nervous tissue injury. TPA knockout mice show reduced morphological and functional recovery after sciatic nerve crush.16,17
One of the initial pieces of evidence that tPA may participate in stroke pathophysiology came from studies by Tsirka and colleagues, who showed that tPA knockout mice were resistant to kainate-induced excitotoxic lesions in the hippocampus.18 Subsequently, Lipton and colleagues showed that tPA knockout mice were similarly resistant to brain infarction after focal cerebral ischemia.19 It should be acknowledged, however, that these findings were somewhat dependent on model systems. In rat models, others have found that infusion of exogenous tPA did not increase infarcts after stroke.20,21 Nevertheless, the mechanisms by which tPA may amplify ischemic injury have been recently clarified. In cell culture systems, tPA may interact with the NR1 subunit of the NMDA receptor complex, thus amplifying damaging calcium currents during ischemic excitotoxicity22 (Figure 2). Furthermore, tPA (and plasmin) may also target nonfibrin substrates in brain extracellular matrix. For example, tPA amplifies excitotoxic neuron death in the hippocampus by degrading interneuronal laminin and disrupting prosurvival cell–matrix signaling.23 Finally, a recent study showed that clinically relevant concentrations of tPA can be potently vasoactive; at low 1 nmol/L concentrations tPA inhibits phenylephrine-induced vasoconstriction, whereas at high 20 nmol/L concentrations tPA augmented phenylephrine’s effects on vessel tone.24 Taken together, these data suggest important nonclot lysis roles for tPA and possibly other serine proteases in brain.
|
|
tPA–Matrix Metalloproteinase Interactions and Cerebral Hemorrhage |
|---|
|
TopAbstractIntroductionPleiotropic Actions of tPA...tPA-Matrix Metalloproteinase...References |
|---|
Accumulating data suggest that hemorrhagic transformation after tPA therapy in ischemic stroke may be related to dysregulated extracellular proteolysis within the neurovascular matrix.25,26,27 The candidate mediators are matrix metalloproteinases (MMPs), which comprise a large family of zinc endopeptidases responsible for remodeling almost all matrix substrates in brain.28,29 MMP-9 knockout mice are protected against brain trauma, spinal cord injury, and focal cerebral ischemia.30,31,32 Blood–brain barrier leakage is reduced in these knockout mice after injury.33 Furthermore, brain edema after intracerebral hemorrhage is reduced by MMP inhibtors.29 All of these data are consistent with the hypothesis that aberrant MMP-9 activity may be responsible for degrading neurovascular substrates in the neurovascular basal lamina.
The connection between tPA and MMP-9 comes from various pharmacologic, genetic and clinical studies. Broad-spectrum MMP inhibitors significantly reduce the incidence34 and severity35 of tPA-associated cerebral hemorrhage in animal models of clot-based embolic stroke. Administration of exogenous tPA significantly amplified the ischemic levels of MMP-9 in hypertensive rats after transient focal cerebral ischemia35,36 (Figure 3). Correspondingly, ischemic brain MMP-9 levels were reduced in tPA knockout mice.37 Emerging clinical data support this hypothesis as well. Although the indirect confounds of stroke severity versus causality will need to be clarified, stroke patients with elevated plasma levels of MMP-9 have greater brain injury and poor neurologic outcome,38 and MMP-9 levels are increased in patients who receive tPA.39 Finally, patients with higher plasma MMP-9 levels are more likely to undergo hemorrhagic transformation after tPA.40
|
How does tPA amplify MMP-9? Because the MMP-9 gene promoter possesses activator protein-1 and nuclear factor-
B transcription factor sites,37 this may be nonspecifically related to oxidative stress induced by reperfusion injury. However, emerging data suggest that more specific signaling mechanisms may also be involved. tPA is now recognized as a cell signaling molecule in brain. As discussed earlier, tPA-mediated modification of N-methyl-D-aspartate (NMDA) calcium currents may contribute to cell signaling. In neurons and astrocytes, tPA is capable of activating intracellular protein kinase cascades.41,42 Recent studies also suggest a role for the low density lipoprotein receptor–related protein (LRP). LRP is a member of the large lipoprotein receptor gene family that is expressed in brain endothelial cells, neurons, and astrocytes. LRP is a receptor for tPA, possesses cell signaling properties, and is already implicated in vascular correlates of ApoE and amyloid processing.43 In human brain endothelial cell cultures, recombinant tPA upregulated MMP-9 mRNA and protein, whereas this tPA-induced MMP-9 response was decreased in endothelial cells treated with RNA interference to suppress LRP37 (Figure 4). These data suggest that LRP-mediated upregulation of MMPs after tPA may degrade neurovascular matrix after stroke, thus leading to hemorrhagic transformation. Furthermore, endothelial cell death may also be triggered by the ensuing disruption of cell–matrix homeostasis. Cerebral endothelial cells underwent anoikis-like death after hypoxia-reoxygenation, and this cell death was mediated by MMP-induced degradation of fibronectin matrix and prosurvival integrin signaling.44 Hence tPA-induced MMPs may also induce cell death within the neurovascular unit. It should be acknowledged that, in keeping with tPA’s pleiotropic actions, multiple signaling pathways may ultimately contribute. Indeed, it has been shown that direct intraventricular injections of tPA into mouse brain may bind LRP and also increase blood–brain barrier permeability in an MMP-independent manner as well.45
|
Targeting tPA–MMP interactions may suggest new approaches for combination stroke therapy. In a rat model of focal stroke, cotreatment with tPA plus MMP inhibitors ameliorated reperfusion injury.46 Inteferon-ß downregulates MMPs, suggesting yet another therapeutic combination.47 Alternatively, blocking neurotoxic properties of tPA with neuroserpin (ie, neuronal serine protease inhibitor) increased the time-to-treatment window for thrombolysis in rat stroke models.48 Finally, there may be thrombolytic agents such as microplasmin49 or vampire bat salivary plasminogen activator50 that may not trigger MMP dysregulation or enhance excitotoxic neurodegeneration. Any approach to optimize tPA thrombolysis may reduce risks of hemorrhage, lengthen the time-to-treatment windows, and enhance the efficacy and safety of reperfusion therapy for stroke.
|
Acknowledgments |
|---|
This work is supported in part by National Institutes of Health grants P50-NS10828, R01-NS37074, R01-NS38731, and R01-NS40529.
Received June 18, 2004; accepted August 5, 2004.
|
References |
|---|
|
TopAbstractIntroductionPleiotropic Actions of tPA...tPA-Matrix Metalloproteinase...References |
|---|
1. NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333: 1581–1587.
2. Hacke W, Brott T, Caplan L, Meier D, Fieschi C, von Kummer R, Donnan G, Heiss WD, Wahlgren NG, Spranger M, Boysen G, Marler JR. Thrombolysis in acute ischemic stroke: controlled trials and clinical experience. Neurology. 1999; 53: S3–S14.
3. Marler JR, Goldstein LB. Stroke: tPA and the clinic. Science. 2003; 301: 1677.
4. Wardlaw JM, Sandercock PA, Berge E. Thrombolytic therapy with recombinant tissue plasminogen activator for acute ischemic stroke: where do we go from here? A cumulative meta-analysis. Stroke. 2003; 34: 1437–1442.
5. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G, Bluhmki E, Wilhelm M, Hamilton S; ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004; 363: 768–774.[CrossRef][Medline] [Order article via Infotrieve]
6. Sumi Y, Dent MA, Owen DE, Seeley PJ, Morris RJ. The expression of tissue and urokinase plasminogen activators in neural development suggests different modes of proteolytic involvement in neuronal growth. Development. 1992; 116: 625–637.[Abstract]
7. Carroll PM, Tsirka SE, Richards WG, Frohman MA, Strickland S. The mouse tissue plasminogen activator gene 5'-flanking region directs appropriate expression in development and seizure-enhanced response in the CNS. Development. 1994; 120: 3173–3183.[Abstract]
8. Ware JH, DiBennedetto AJ, Pittman RN. Localization of tissue plasminogen activator mRNA in the developing rat cerebellum and effects of inhibiting tissue plasminogen activator on granule cell migration. J Neurobiol. 1995; 28: 9–22.[CrossRef][Medline] [Order article via Infotrieve]
9. Seeds NW, Basham ME, Haffke SP. Neuronal migration is retarded in mice lacking the tissue plasminogen activator gene. Proc Natl Acad Sci U S A. 1999; 96: 14118–14123.
10. Qian Z, Gilbert ME, Colicos MA, Kandel ER, Kuhl D. Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation. Nature. 1993; 361: 453–457.[CrossRef][Medline] [Order article via Infotrieve]
11. Centonze D, Napolitano M, Saulle E, Gubellini P, Piconni B, Martorana A, Pisai A, Gulino A, Bernadi G, Calabresi P. Tissue plasminogen activator is required for corticostriatal long term potentiation. Eur J Neurosci. 2002; 16: 713–721.[CrossRef][Medline] [Order article via Infotrieve]
12. Sappino AP, Madani R, Huarte J, Belin D, Kiss JZ, Wohlwend A, Vassalli JD. Extracellular proteolysis in the adult murine brain. J Clin Invest. 1993; 92: 679–685.
13. Huang YY, Bach ME, Lipp HP, Zhuo M, Wolfer DP, Hawkins RD, Schoonjans L, Kandel ER, Godfraind JM, Mulligan R, Collen D, Carmeliet P. Mice lacking tissue plasminogen activator show a selective interference with late phase long term potentiation in Schaffer collateral and mossy fiber pathways. Proc Natl Acad Sci U S A. 1996; 93: 8699–8704.
14. Madani R, Hulo S, Toni N, Madani H, Steimer T, Muller D, Vassalli JD. Enhanced hippocampal long-term potentiation and learning by increased neuronal expression of tissue-type plasminogen activator in transgenic mice. EMBO J. 1999; 18: 3007–3012.[CrossRef][Medline] [Order article via Infotrieve]
15. Nagai T, Yamada K, Yoshimura M, Ishikawa K, Miyamoto Y, Hashimoto K, Noda Y, Nitta A, Nabeshima T. The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release. Proc Natl Acad Sci U S A. 2004; 101: 3650–3655.
16. Siconolfi LB, Seeds NW. Mice lacking tPA, uPA, or plasminogen genes showed delayed functional recovery after sciatic nerve crush. J Neurosci. 2001; 21: 4348–4355.
17. Siconolfi LB, Seeds NW. Induction of the plasminogen activator system accompanies peripheral nerve regeneration after sciatic nerve crush. J Neurosci. 2001; 21: 4336–4347.
18. Tsirka SE, Rogove AD, Strickland S. Neuronal cell death and TPA. Nature. 1996; 384: 123–124.[Medline] [Order article via Infotrieve]
19. Wang YF, Tsirka SE, Strickland S, Steig PE, Soriano SG, Lipton SA. TPA increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nature Med. 1998; 4: 228–231.[CrossRef][Medline] [Order article via Infotrieve]
20. Klein GM, Li H, Sun P, Buchan AM. Tissue plasminogen activator does not increase neuronal damage in rat models of global and focal ischemia. Neurology. 1999; 52: 1381–1384.
21. Meng W, Wang X, Ashahi M, Kano T, Asahi K. Acherman RH, Lo EH. Effects of tissue type plasminogen activator in embolic versus mechanical models of focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 1999; 19: 1316–1321.[CrossRef][Medline] [Order article via Infotrieve]
22. Nicole O, Docagne F, Ali C, Margail I, Carmeliet P, MacKenzie ET, Vivien D, Buisson A. The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling. Nature Med. 2001; 7: 59–64.[CrossRef][Medline] [Order article via Infotrieve]
23. Indyk JA, Chen ZL, Tsirka SE, Strickland S. Laminin chain expression suggests that laminin-10 is a major isoform in the mouse hippocampus and is degraded by the tissue plasminogen activator/plasmin protease cascade during excitotoxic injury. Neuroscience. 2003; 116: 359–371.[CrossRef][Medline] [Order article via Infotrieve]
24. Nasser T, Akkawi S, Shina A, Haj-Yehia A, Bdeir K, Tarshis M, Heyman SN, Higazi AA. In vitro and in vivo effects of tPA and PAI-1 on blood vessel tone. Blood. 2004; 103: 897–902.
25. Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 2003; 4: 399–415.[Medline] [Order article via Infotrieve]
26. Lo EH, Broderick JP, Moskowitz MA. tPA and proteolysis in the neurovascular unit. Stroke. 2004; 35: 354–356.
27. del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab. 2003; 23: 879–894.[CrossRef][Medline] [Order article via Infotrieve]
28. Yong VW, Power C, Forsyth P, Edwards DR. Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci. 2001; 2: 502–511.[CrossRef][Medline] [Order article via Infotrieve]
29. Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia. 2002; 39: 279–291.[CrossRef][Medline] [Order article via Infotrieve]
30. Wang X, Jung J, Asahi M, Chwang W, Russo L, Moskowitz MA, Dixon CE, Fini ME, Lo EH. Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci. 2000; 20: 7037–7042.
31. Gursoy-Odzemir Y, Qiu J, Matsuoka N, Bolay H, Bermpohl D, Jin H, Wang X, Rosenberg GA, Lo EH, Moskowitz MA. Cortical spreading depression activates and upregulates matrix metalloproteinase-9. J Clin Invest. 2004; 113: 1447–1455.[CrossRef][Medline] [Order article via Infotrieve]
32. 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: 1681–1689.[CrossRef][Medline] [Order article via Infotrieve]
33. Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, Fini ME, Lo EH. 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.
34. Lapchak PA, Chapman DF, Zivin JA. Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke. 2000; 31: 3034–3040.
35. Sumii T, Lo EH. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke. 2002; 33: 831–836.
36. Aoki T, Sumii T, Mori T, Wang X, Lo EH. Blood–brain barrier disruption and matrix metalloproteinase-9 expression during reperfusion injury: mechanical versus embolic focal ischemia in spontaneously hypertensive rats. Stroke. 2002; 33: 2711–2717.
37. Wang X, Lee SR, Arai K, Lee SR, Tsuji K, Rebeck GW, Lo EH. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med. 2003; 9: 1313–1317.[CrossRef][Medline] [Order article via Infotrieve]
38. Castellanos M, Leira R, Serena J, Pumar JM, Lizasoain I, Castillo J, Davalos A. Plasma metalloproteinase-9 concentration predicts hemorrhagic transformation in acute ischemic stroke. Stroke. 2003; 34: 40–46.
39. Horstmann S, Kalb P, Koziol J, Gardner H, Wagner S. Profiles of matrix metalloproteinases, their inhibitors, and laminin in stroke patients: influence of different therapies. Stroke. 2003; 34: 2165–2170.
40. Montaner J, Molina CA, Monasterio J, Abilleira S, Arenillas JF, Ribo M, Quintana M, Alvarez-Sabin J. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation. 2003; 107: 598–603.
41. Siao CJ, Tsirka SE. Tissue plasminogen activator mediates microglial activation via its finger domain through annexin II. J Neurosci. 2002; 22: 3352–3358.
42. Son H, Seuk Kim J, Mogg Kim J, Lee SH, Lee YS. Reciprocal actions of NCAM and tPA via a Ras-dependent MAPK activation in rat hippocampal neurons. Biochem Biophys Res Commun. 2002; 298: 262–268.[CrossRef][Medline] [Order article via Infotrieve]
43. Herz J, Strickland DK. LRP: a multifunctional scavenger and signaling receptor. J Clin Invest. 2001; 108: 779–784.[CrossRef][Medline] [Order article via Infotrieve]
44. Lee S, Lo EH. Induction of cerebral endothelial cell death by matrix metalloproteinase-mediated anoikis. J Cereb Blood Flow Metab. 2004; 24: 720–727.[CrossRef][Medline] [Order article via Infotrieve]
45. Yepes M, Sandkvist M, Moore EG, Bugge TH, Strickland DK, Lawrence DA. Tissue type plasminogen activator induces opening of the blood–brain barrier via the LDL receptor related protein. J Clin Invest. 2003; 112: 1533–1540.[CrossRef][Medline] [Order article via Infotrieve]
46. Pfefferkon T, Rosenberg GA. Closure of the blood–brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion. Stroke. 2003; 34: 2025–2030.
47. Veldhius WB, Floris S, van der Meide PH, Vos IM, de Vries HE, Dijkstra CD, Bar PR, Nicolay K. Inteferon-ß prevents cytokine-induced neutrophil infiltration and attenuates blood–brain barrier disruption. J Cereb Blood Flow Metab. 2003; 23: 1060–1069.[CrossRef][Medline] [Order article via Infotrieve]
48. Zhang L, Zhang L, Yepes M, Jiang Q, Li Q, Arniego P, Coleman TA, Lawrence DA, Chopp M. Adjuvant treatment with neuroserpin increases the therapeutic window for tPA adminstration in a rat model of embolic stroke. Circulation. 2002; 106: 740–745.
49. Lapchak PA, Arujo DM, Pakola S, Song D, Wei J, Zivin JA. Microplasmin: a novel thrombolytic that improves behavioral outcome after embolic strokes in rabbits. Stroke. 2002; 33: 2279–2284.
50. Liberatore GT, Samson A, Bladin C, Schleuning WD, Medcalf RL. Vampire bat salivary plasminogen activator (desmoteplase): a unique fibrinolytic enzyme that does not promote neurodegeneration. Stroke. 2003; 34: 537–543.
This article has been cited by other articles:
 |
|
 |
|
  L. S. Machado, I. Y. Sazonova, A. Kozak, D. C. Wiley, A. B. El-Remessy, A. Ergul, D. C. Hess, J. L. Waller, and S. C. Fagan Minocycline and Tissue-Type Plasminogen Activator for Stroke: Assessment of Interaction Potential Stroke, September 1, 2009; 40(9): 3028 - 3033. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Foerch, J. Montaner, K. L. Furie, M. M. Ning, and E. H. Lo Invited Article: Searching for oracles?: Blood biomarkers in acute stroke Neurology, August 4, 2009; 73(5): 393 - 399. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. D. Roussel, R. Macrez, A. Jullienne, V. Agin, E. Maubert, L. Dauphinot, M.-C. Potier, L. Plawinski, H. Castel, Y. Hommet, et al. Age and albumin D site-binding protein control tissue plasminogen activator levels: neurotoxic impact Brain, August 1, 2009; 132(8): 2219 - 2230. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Danielyan, K. Ganguly, B.-S. Ding, D. Atochin, S. Zaitsev, J.-C. Murciano, P. L. Huang, S. E. Kasner, D. B. Cines, and V. R. Muzykantov Cerebrovascular Thromboprophylaxis in Mice by Erythrocyte-Coupled Tissue-Type Plasminogen Activator Circulation, September 30, 2008; 118(14): 1442 - 1449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Cuadrado, L. Ortega, M. Hernandez-Guillamon, A. Penalba, I. Fernandez-Cadenas, A. Rosell, and J. Montaner Tissue plasminogen activator (t-PA) promotes neutrophil degranulation and MMP-9 release J. Leukoc. Biol., July 1, 2008; 84(1): 207 - 214. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.J. Dickinson Intracerebral haemorrhage revisited QJM, November 1, 2007; 100(11): 715 - 719. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Z. Lee, Z. Xue, Y. Zhu, G.-Y. Yang, and W. L. Young Matrix Metalloproteinase-9 Inhibition Attenuates Vascular Endothelial Growth Factor-Induced Intracerebral Hemorrhage Stroke, September 1, 2007; 38(9): 2563 - 2568. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Chen, Y. Suzuki, N. Nagai, X. Sun, H. Wang, J. Yu, G. Marchal, and Y. Ni Microplasmin and Tissue Plasminogen Activator: Comparison of Therapeutic Effects in Rat Stroke Model at Multiparametric MR Imaging Radiology, August 1, 2007; 244(2): 429 - 438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Castellanos, T. Sobrino, M. Millan, M. Garcia, J. Arenillas, F. Nombela, D. Brea, N. Perez de la Ossa, J. Serena, J. Vivancos, 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, June 1, 2007; 38(6): 1855 - 1859. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B.-Q. Zhao, E. Tejima, and E. H. Lo Neurovascular Proteases in Brain Injury, Hemorrhage and Remodeling After Stroke Stroke, February 1, 2007; 38(2): 748 - 752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Khatri, L. R. Wechsler, and J. P. Broderick Intracranial Hemorrhage Associated With Revascularization Therapies Stroke, February 1, 2007; 38(2): 431 - 440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ning, K. L. Furie, W. J. Koroshetz, H. Lee, M. Barron, M. Lederer, X. Wang, M. Zhu, A. G. Sorensen, E. H. Lo, et al. Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke Neurology, May 23, 2006; 66(10): 1550 - 1555. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-L. Xu, L. Salter-Cid, M. D. Linnik, E. Y. Wang, C. Paisansathan, and D. A. Pelligrino Vascular Adhesion Protein-1 Plays an Important Role in Postischemic Inflammation and Neuropathology in Diabetic, Estrogen-Treated Ovariectomized Female Rats Subjected to Transient Forebrain Ischemia J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 19 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tsuji, T. Aoki, E. Tejima, K. Arai, S.-R. Lee, D. N. Atochin, P. L. Huang, X. Wang, J. Montaner, and E. H. Lo Tissue Plasminogen Activator Promotes Matrix Metalloproteinase-9 Upregulation After Focal Cerebral Ischemia Stroke, September 1, 2005; 36(9): 1954 - 1959. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||