From the Department of Cardiovascular Pharmacology, SmithKline Beecham
Pharmaceuticals, King of Prussia, Pa.
Correspondence to Dr Anne M. Romanic, Department of Cardiovascular Pharmacology, UW2510, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd, King of Prussia, PA 19406. E-mail anne_romanic-1{at}sbphrd.com
Background and Purpose—Matrix
metalloproteinases (MMPs) are a family of proteolytic enzymes that
degrade the extracellular matrix and are implicated in numerous
pathological conditions including atherosclerosis,
inflammation, and tumor growth and metastasis. In the brain, the
endothelial cell wall, strengthened by tight junctions,
defines the blood-brain barrier (BBB). The extracellular matrix
molecules constitute the basement membrane underlying the vasculature
and play a critical role in maintaining the integrity of the BBB. After
focal stroke, there is a breakdown of the BBB with an associated
increase in vascular permeability, inflammatory cell influx, and
neuronal cell death. The present study was designed to investigate
the effects of MMP expression after stroke.
Methods—Focal stroke was produced by permanent middle cerebral
artery occlusion (MCAO) in the rat, and MMP protein expression was
measured by Western blot and zymogram analysis over a time
course ranging from 6 hours to 30 days (n=32). Immunohistochemistry at
1 and 5 days (n=8 and 6, respectively) was also utilized to
characterize the expression of several MMPs and related proteins after
stroke, including their cellular source. To test the hypothesis that
early increased MMP-9 expression is involved in ischemic brain
injury, a neutralizing monoclonal antibody directed against MMP-9 was
administered intravenously (n=7 per group) 1 hour before
MCAO, and infarct size was measured 24 hours later.
Results—MMP expression increased progressively over time after
stroke. After 12 hours, significant (P<0.05) MMP-9
activity was observed that reached maximum levels by 24 hours
(P<0.001), then persisted for 5 days at this level and
returned to basal (zero) levels by 15 days. On the basis of
morphological criteria, MMP-9 appeared to stain with
endothelial cells and neutrophils identified both
within and at the periphery of the infarct within 24 hours of focal
ischemia. After 5 days, MMP-9 appeared to stain with
macrophages present within the infarcted brain. MMP-2
activity was significantly (P<0.001) increased by 24
hours and was maximum after 5 days following MCAO. MMP-2 appeared to
stain with macrophages present within the infarcted region.
Unlike MMP-9 and MMP-2, tissue inhibitor of
metalloproteinase-1 was identified at comparable levels in both control
and ischemic tissue after MCAO. MMP-1 and MMP-3 could not be
detected in the brain after focal stroke. When an MMP-9–neutralizing
monoclonal antibody was administered systemically, animals exhibited
significantly reduced infarct size (ie, a 30% reduction compared with
non–immune antibody controls; P<0.05).
Conclusions—These results demonstrate that early increased MMP-9
expression in endothelial cells and infiltrating
neutrophils is a significant response to cerebral focal
ischemia and that selective inhibition of MMP-9 activity can
significantly reduce brain injury after stroke.
Department
of Neurology,
Johns Hopkins University School of Medicine,
Baltimore, Maryland
© 1998 American Heart Association, Inc.
Original Contributions
Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats
Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size
Editorial Comment
Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size
This article has been cited by other articles:
 |
|
 |
|
  L Derex and N Nighoghossian Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: an update J. Neurol. Neurosurg. Psychiatry, October 1, 2008; 79(10): 1093 - 1099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Lockwood, C. Oner, Y. H. Uz, U. A. Kayisli, S. J. Huang, L. F. Buchwalder, W. Murk, E. F. Funai, and F. Schatz Matrix Metalloproteinase 9 (MMP9) Expression in Preeclamptic Decidua and MMP9 Induction by Tumor Necrosis Factor Alpha and Interleukin 1 Beta in Human First Trimester Decidual Cells Biol Reprod, June 1, 2008; 78(6): 1064 - 1072. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Tucker, H. Klassen, L. Yang, D. F. Chen, and M. J. Young Elevated MMP Expression in the MRL Mouse Retina Creates a Permissive Environment for Retinal Regeneration Invest. Ophthalmol. Vis. Sci., April 1, 2008; 49(4): 1686 - 1695. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Rosell, E. Cuadrado, A. Ortega-Aznar, M. Hernandez-Guillamon, E. H. Lo, and J. Montaner 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, April 1, 2008; 39(4): 1121 - 1126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. P. Obrenovitch Molecular Physiology of Preconditioning-Induced Brain Tolerance to Ischemia Physiol Rev, January 1, 2008; 88(1): 211 - 247. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Pedrazzi, M. Patrone, M. Passalacqua, E. Ranzato, D. Colamassaro, B. Sparatore, S. Pontremoli, and E. Melloni Selective Proinflammatory Activation of Astrocytes by High-Mobility Group Box 1 Protein Signaling J. Immunol., December 15, 2007; 179(12): 8525 - 8532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Cui, J. Chen, A. Zacharek, Y. Li, C. Roberts, A. Kapke, S. Savant-Bhonsale, and M. Chopp Nitric Oxide Donor Upregulation of Stromal Cell-Derived Factor-1/Chemokine (CXC Motif) Receptor 4 Enhances Bone Marrow Stromal Cell Migration into Ischemic Brain After Stroke Stem Cells, November 1, 2007; 25(11): 2777 - 2785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Forster, T. Kahles, S. Kietz, and D. Drenckhahn Dexamethasone induces the expression of metalloproteinase inhibitor TIMP-1 in the murine cerebral vascular endothelial cell line cEND J. Physiol., May 1, 2007; 580(3): 937 - 949. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Svedin, H. Hagberg, K. Savman, C. Zhu, and C. Mallard Matrix Metalloproteinase-9 Gene Knock-out Protects the Immature Brain after Cerebral Hypoxia-Ischemia J. Neurosci., February 14, 2007; 27(7): 1511 - 1518. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. del Zoppo, R. Milner, T. Mabuchi, S. Hung, X. Wang, G. I. Berg, and J. A. Koziol Microglial Activation and Matrix Protease Generation During Focal Cerebral Ischemia Stroke, February 1, 2007; 38(2): 646 - 651. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tsubokawa, I. Solaroglu, H. Yatsushige, J. Cahill, K. Yata, and J. H. Zhang Cathepsin and Calpain Inhibitor E64d Attenuates Matrix Metalloproteinase-9 Activity After Focal Cerebral Ischemia in Rats Stroke, July 1, 2006; 37(7): 1888 - 1894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Rosell, A. Ortega-Aznar, J. Alvarez-Sabin, I. Fernandez-Cadenas, M. Ribo, C. A. Molina, E. H. Lo, and J. Montaner Increased Brain Expression of Matrix Metalloproteinase-9 After Ischemic and Hemorrhagic Human Stroke Stroke, June 1, 2006; 37(6): 1399 - 1406. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Lominadze, A. M. Roberts, N. Tyagi, K. S. Moshal, and S. C. Tyagi Homocysteine causes cerebrovascular leakage in mice Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1206 - H1213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Eugenin, K. Osiecki, L. Lopez, H. Goldstein, T. M. Calderon, and J. W. Berman CCL2/Monocyte Chemoattractant Protein-1 Mediates Enhanced Transmigration of Human Immunodeficiency Virus (HIV)-Infected Leukocytes across the Blood-Brain Barrier: A Potential Mechanism of HIV-CNS Invasion and NeuroAIDS J. Neurosci., January 25, 2006; 26(4): 1098 - 1106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Gao, R. Taha, D. Gauvin, L. B. Othmen, Y. Wang, and G. Blaise Postoperative Cognitive Dysfunction After Cardiac Surgery Chest, November 1, 2005; 128(5): 3664 - 3670. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Haqqani, M. Nesic, E. Preston, E. Baumann, J. Kelly, and D. Stanimirovic Characterization of vascular protein expression patterns in cerebral ischemia/reperfusion using laser capture microdissection and ICAT-nanoLC-MS/MS FASEB J, November 1, 2005; 19(13): 1809 - 1821. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Gidday, Y. G. Gasche, J.-C. Copin, A. R. Shah, R. S. Perez, S. D. Shapiro, P. H. Chan, and T. S. Park Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H558 - H568. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Gu, J. Cui, S. Brown, R. Fridman, S. Mobashery, A. Y. Strongin, and S. A. Lipton A Highly Specific Inhibitor of Matrix Metalloproteinase-9 Rescues Laminin from Proteolysis and Neurons from Apoptosis in Transient Focal Cerebral Ischemia J. Neurosci., July 6, 2005; 25(27): 6401 - 6408. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Wang and S. E. Tsirka Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage Brain, July 1, 2005; 128(7): 1622 - 1633. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Rosell, J. Alvarez-Sabin, J. F. Arenillas, A. Rovira, P. Delgado, I. Fernandez-Cadenas, A. Penalba, C. A. Molina, and J. Montaner A Matrix Metalloproteinase Protein Array Reveals a Strong Relation Between MMP-9 and MMP-13 With Diffusion-Weighted Image Lesion Increase in Human Stroke Stroke, July 1, 2005; 36(7): 1415 - 1420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Mali, M. Cheng, and S. K. Chintala Intravitreous Injection of a Membrane Depolarization Agent Causes Retinal Degeneration Via Matrix Metalloproteinase-9 Invest. Ophthalmol. Vis. Sci., June 1, 2005; 46(6): 2125 - 2132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J Jimenez, W. Jy, L. M Mauro, L. L Horstman, E. R Ahn, Y. S Ahn, and A. Minagar Elevated endothelial microparticle--monocyte complexes induced by multiple sclerosis plasma and the inhibitory effects of interferon-{beta}1b on release of endothelial microparticles, formation and transendothelial migration of monocyte-endothelial microparticle complexes Multiple Sclerosis, June 1, 2005; 11(3): 310 - 315. [Abstract] [PDF]
|
|
|
|
|
|
T. M. Kauppinen and R. A. Swanson Poly(ADP-Ribose) Polymerase-1 Promotes Microglial Activation, Proliferation, and Matrix Metalloproteinase-9-Mediated Neuron Death J. Immunol., February 15, 2005; 174(4): 2288 - 2296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dittmar, G. Kiourkenidis, M. Horn, S. Bollwein, G. Bernhardt, G. A. Rosenberg, and T. Pfefferkorn Cerebral Ischemia, Matrix Metalloproteinases, and TNF-{alpha}: MMP Inhibitors May Act Not Exclusively by Reducing MMP Activity * Response Stroke, July 1, 2004; 35(7): e338 - e340. [Full Text] [PDF]
|
|
|
|
|
|
C. M. Maier, L. Hsieh, F. Yu, P. Bracci, and P. H. Chan Matrix Metalloproteinase-9 and Myeloperoxidase Expression: Quantitative Analysis by Antigen Immunohistochemistry in a Model of Transient Focal Cerebral Ischemia Stroke, May 1, 2004; 35(5): 1169 - 1174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. KJAeR Role of Extracellular Matrix in Adaptation of Tendon and Skeletal Muscle to Mechanical Loading Physiol Rev, April 1, 2004; 84(2): 649 - 698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. Hamann, D. Burggraf, H. K. Martens, M. Liebetrau, G. Jager, N. Wunderlich, M. DeGeorgia, and D. W. Krieger Mild to Moderate Hypothermia Prevents Microvascular Basal Lamina Antigen Loss in Experimental Focal Cerebral Ischemia Stroke, March 1, 2004; 35(3): 764 - 769. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-R. Lee, K. Tsuji, S.-R. Lee, and E. H. Lo Role of Matrix Metalloproteinases in Delayed Neuronal Damage after Transient Global Cerebral Ischemia J. Neurosci., January 21, 2004; 24(3): 671 - 678. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Yamani, R. C. Starling, D. J. Cook, E. M. Tuzcu, A. Abdo, P. Paul, K. Powell, N. B. Ratliff, Y. Yu, P. M. McCarthy, et al. Donor Spontaneous Intracerebral Hemorrhage Is Associated With Systemic Activation of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 and Subsequent Development of Coronary Vasculopathy in the Heart Transplant Recipient Circulation, October 7, 2003; 108(14): 1724 - 1728. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W. Kim, Y. Gasche, S. Grzeschik, J.-C. Copin, C. M. Maier, and P. H. Chan Neurodegeneration in Striatum Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Role of Matrix Metalloproteinase-9 in Early Blood-Brain Barrier Disruption? J. Neurosci., September 24, 2003; 23(25): 8733 - 8742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Horstmann, P. Kalb, J. Koziol, H. Gardner, and S. Wagner Profiles of Matrix Metalloproteinases, Their Inhibitors, and Laminin in Stroke Patients: Influence of Different Therapies Stroke, September 1, 2003; 34(9): 2165 - 2170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. T. Askari, M.-L. Brennan, X. Zhou, J. Drinko, A. Morehead, J. D. Thomas, E. J. Topol, S. L. Hazen, and M. S. Penn Myeloperoxidase and Plasminogen Activator Inhibitor 1 Play a Central Role in Ventricular Remodeling after Myocardial Infarction J. Exp. Med., March 3, 2003; 197(5): 615 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Montaner, C. A. Molina, J. Monasterio, S. Abilleira, J. F. Arenillas, M. Ribo, M. Quintana;, and J. Alvarez-Sabin Matrix Metalloproteinase-9 Pretreatment Level Predicts Intracranial Hemorrhagic Complications After Thrombolysis in Human Stroke Circulation, February 4, 2003; 107(4): 598 - 603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Castellanos, R. Leira, J. Serena, J. M. Pumar, I. Lizasoain, J. Castillo, A. Davalos, and G. F. Hamann Plasma Metalloproteinase-9 Concentration Predicts Hemorrhagic Transformation in Acute Ischemic Stroke * Editorial Comment Stroke, January 1, 2003; 34(1): 40 - 46. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Chintala, X. Zhang, J. S. Austin, and M. E. Fini Deficiency in Matrix Metalloproteinase Gelatinase B (MMP-9) Protects against Retinal Ganglion Cell Death after Optic Nerve Ligation J. Biol. Chem., November 27, 2002; 277(49): 47461 - 47468. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Noble, F. Donovan, T. Igarashi, S. Goussev, and Z. Werb Matrix Metalloproteinases Limit Functional Recovery after Spinal Cord Injury by Modulation of Early Vascular Events J. Neurosci., September 1, 2002; 22(17): 7526 - 7535. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Gu, M. Kaul, B. Yan, S. J. Kridel, J. Cui, A. Strongin, J. W. Smith, R. C. Liddington, and S. A. Lipton S-Nitrosylation of Matrix Metalloproteinases: Signaling Pathway to Neuronal Cell Death Science, August 16, 2002; 297(5584): 1186 - 1190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sumii and E. H. Lo Involvement of Matrix Metalloproteinase in Thrombolysis-Associated Hemorrhagic Transformation After Embolic Focal Ischemia in Rats Stroke, March 1, 2002; 33(3): 831 - 836. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Szklarczyk, J. Lapinska, M. Rylski, R. D. G. McKay, and L. Kaczmarek Matrix Metalloproteinase-9 Undergoes Expression and Activation during Dendritic Remodeling in Adult Hippocampus J. Neurosci., February 1, 2002; 22(3): 920 - 930. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Montaner, J. Alvarez-Sabin, C.A. Molina, A. Angles, S. Abilleira, J. Arenillas, and J. Monasterio Matrix Metalloproteinase Expression Is Related to Hemorrhagic Transformation After Cardioembolic Stroke Stroke, December 1, 2001; 32(12): 2762 - 2767. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Morris, L. Zhang, Z. G. Zhang, M. Lu, K. L. Berens, P. M. Brown, and M. Chopp Extension of the Therapeutic Window for Recombinant Tissue Plasminogen Activator With Argatroban in a Rat Model of Embolic Stroke Stroke, November 1, 2001; 32(11): 2635 - 2640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Asahi, X. Wang, T. Mori, T. Sumii, J.-C. Jung, M. A. Moskowitz, M. E. Fini, and E. H. Lo Effects of Matrix Metalloproteinase-9 Gene Knock-Out on the Proteolysis of Blood-Brain Barrier and White Matter Components after Cerebral Ischemia J. Neurosci., October 1, 2001; 21(19): 7724 - 7732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Montaner, J. Alvarez-Sabin, C. Molina, A. Angles, S. Abilleira, J. Arenillas, M. A. Gonzalez, and J. Monasterio Matrix Metalloproteinase Expression After Human Cardioembolic Stroke: Temporal Profile and Relation to Neurological Impairment Stroke, August 1, 2001; 32(8): 1759 - 1766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Lemons, J. D. Sandy, D. K. Anderson, and D. R. Howland Intact Aggrecan and Fragments Generated by Both Aggrecanse and Metalloproteinase-Like Activities Are Present in the Developing and Adult Rat Spinal Cord and Their Relative Abundance Is Altered by Injury J. Neurosci., July 1, 2001; 21(13): 4772 - 4781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Lapchak, D. F. Chapman, J. A. Zivin, and C. Y. Hsu Metalloproteinase Inhibition Reduces Thrombolytic (Tissue Plasminogen Activator)-Induced Hemorrhage After Thromboembolic Stroke Editorial Comment Stroke, December 1, 2000; 31(12): 3034 - 3040. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wang, J. Jung, M. Asahi, W. Chwang, L. Russo, M. A. Moskowitz, C. E. Dixon, M. E. Fini, and E. H. Lo Effects of Matrix Metalloproteinase-9 Gene Knock-Out on Morphological and Motor Outcomes after Traumatic Brain Injury J. Neurosci., September 15, 2000; 20(18): 7037 - 7042. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Lu, Z. Gunja-Smith, J. F. Woessner, P. C. Ursell, T. Nissen, R. E. Galardy, Y. Xu, P. Zhu, and G. G. Schwartz Matrix metalloproteinases and collagen ultrastructure in moderate myocardial ischemia and reperfusion in vivo Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H601 - H609. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. Mautes, M. R Weinzierl, F. Donovan, and L. J Noble Vascular Events After Spinal Cord Injury: Contribution to Secondary Pathogenesis Physical Therapy, July 1, 2000; 80(7): 673 - 687. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Tucker, M. Kihiko, J. N. Caldwell, S. Wright, T. Kawarabayashi, D. Price, D. Walker, S. Scheff, J. P. McGillis, R. E. Rydel, et al. The Plasmin System Is Induced by and Degrades Amyloid-beta Aggregates J. Neurosci., June 1, 2000; 20(11): 3937 - 3946. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Leib, D. Leppert, J. Clements, and M. G. Tauber Matrix Metalloproteinases Contribute to Brain Damage in Experimental Pneumococcal Meningitis Infect. Immun., February 1, 2000; 68(2): 615 - 620. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Yrjanheikki, T. Tikka, R. Keinanen, G. Goldsteins, P. H. Chan, and J. Koistinaho A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window PNAS, November 9, 1999; 96(23): 13496 - 13500. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Lipton Ischemic Cell Death in Brain Neurons Physiol Rev, October 1, 1999; 79(4): 1431 - 1568. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-S. Silvestre, Z. Mallat, R. Tamarat, M. Duriez, A. Tedgui, and B. I. Levy Regulation of Matrix Metalloproteinase Activity in Ischemic Tissue by Interleukin-10: Role in Ischemia-Induced Angiogenesis Circ. Res., August 3, 2001; 89(3): 259 - 264. [Abstract] [Full Text] [PDF]
|
|