This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Aoki, T. Articles by Lo, E. H. Search for Related Content PubMed PubMed Citation Articles by Aoki, T. Articles by Lo, E. H. Related Collections Animal models of human disease Embolic stroke Pathology of Stroke

(Stroke. 2002;33:2711.)
© 2002 American Heart Association, Inc.

Original Contributions

Blood-Brain Barrier Disruption and Matrix Metalloproteinase-9 Expression During Reperfusion Injury

Mechanical Versus Embolic Focal Ischemia in Spontaneously Hypertensive Rats

Toshiaki Aoki, PhD; Toshihisa Sumii, MD; Tatsuro Mori, MD; Xiaoying Wang, PhD Eng H. Lo, PhD

From the Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Charlestown, Mass.

Correspondence to Eng H. Lo, Neuroprotection Research Laboratory, Departments of Neurology and Radiology, Harvard Medical School, Massachusetts General Hospital East 149-2401, Charlestown, MA 02129. E-mail Lo{at}helix.mgh.harvard.edu

Background and Purpose— Most experimental models of cerebral ischemia use mechanical methods of occlusion and reperfusion. However, differences between mechanical reperfusion versus clot thrombolysis may influence reperfusion injury profiles. In this study we compared blood flow recovery, blood-brain barrier (BBB) permeability, and matrix metalloproteinase-9 (MMP-9) expression in cortex after mechanical versus thrombolytic reperfusion in rat focal ischemia.

Methods— Male spontaneously hypertensive rats were used. Mechanical ischemia/reperfusion was achieved with the use of an intraluminal filament to occlude the middle cerebral artery for 2 hours. Thrombolytic reperfusion was achieved by administering tissue plasminogen activator at 2 hours after embolic focal ischemia. Regional cortical blood flow was monitored by laser-Doppler flowmetry. BBB permeability in cortex was measured by Evans blue dye leakage. Cortical MMP-9 levels were assessed with zymography and immunohistochemistry.

Results— Blood flow recovery during mechanical reperfusion was complete in both central and peripheral areas of ischemic cortex. However, after thrombolysis, reperfusion was incomplete, with moderate recovery in the periphery only. BBB permeability was mainly increased in the central regions of the ischemic cortex after mechanical reperfusion but was increased in both central and peripheral areas after thrombolysis. Overall, MMP-9 levels were higher after embolic versus mechanical ischemia/reperfusion, even though ischemic injury was similar in both models at 24 hours.

Conclusions— There are significant differences in the profiles of blood flow recovery, BBB leakage, and MMP-9 upregulation in mechanical versus thrombolytic reperfusion after focal ischemia.

Key Words: brain edema • metalloproteinases • neuroprotection • stroke • tissue plasminogen activator

This article has been cited by other articles:

				F. A. DeLano and G. W. Schmid-Schonbein Proteinase Activity and Receptor Cleavage: Mechanism for Insulin Resistance in the Spontaneously Hypertensive Rat Hypertension, August 1, 2008; 52(2): 415 - 423. [Abstract] [Full Text] [PDF]

				O. Moldes, T. Sobrino, M. Millan, M. Castellanos, N. Perez de la Ossa, R. Leira, J. Serena, J. Vivancos, A. Davalos, and J. Castillo High Serum Levels of Endothelin-1 Predict Severe Cerebral Edema in Patients With Acute Ischemic Stroke Treated With t-PA Stroke, July 1, 2008; 39(7): 2006 - 2010. [Abstract] [Full Text] [PDF]

				K. Liu, S. Mori, H. K. Takahashi, Y. Tomono, H. Wake, T. Kanke, Y. Sato, N. Hiraga, N. Adachi, T. Yoshino, et al. Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats FASEB J, December 1, 2007; 21(14): 3904 - 3916. [Abstract] [Full Text] [PDF]

				C. Orset, R. Macrez, A. R. Young, D. Panthou, E. Angles-Cano, E. Maubert, V. Agin, and D. Vivien Mouse Model of In Situ Thromboembolic Stroke and Reperfusion Stroke, October 1, 2007; 38(10): 2771 - 2778. [Abstract] [Full Text] [PDF]

				M. Millan, T. Sobrino, M. Castellanos, F. Nombela, J. F. Arenillas, E. Riva, I. Cristobo, M. M. Garcia, J. Vivancos, J. Serena, et al. Increased Body Iron Stores Are Associated With Poor Outcome After Thrombolytic Treatment in Acute Stroke Stroke, January 1, 2007; 38(1): 90 - 95. [Abstract] [Full Text] [PDF]

				K.-J. Yin, J. R. Cirrito, P. Yan, X. Hu, Q. Xiao, X. Pan, R. Bateman, H. Song, F.-F. Hsu, J. Turk, et al. Matrix Metalloproteinases Expressed by Astrocytes Mediate Extracellular Amyloid-beta Peptide Catabolism J. Neurosci., October 25, 2006; 26(43): 10939 - 10948. [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]

				S.-H. Lee, B. J. Kim, and J.-K. Roh Silent microbleeds are associated with volume of primary intracerebral hemorrhage Neurology, February 14, 2006; 66(3): 430 - 432. [Abstract] [Full Text] [PDF]

				R. Polavarapu, M. C. Gongora, J. A. Winkles, and M. Yepes Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Increases the Permeability of the Neurovascular Unit through Nuclear Factor-{kappa}B Pathway Activation J. Neurosci., November 2, 2005; 25(44): 10094 - 10100. [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]

				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]

				K. Benchenane, V. Berezowski, C. Ali, M. Fernandez-Monreal, J. P. Lopez-Atalaya, J. Brillault, J. Chuquet, A. Nouvelot, E. T. MacKenzie, G. Bu, et al. Tissue-Type Plasminogen Activator Crosses the Intact Blood-Brain Barrier by Low-Density Lipoprotein Receptor-Related Protein-Mediated Transcytosis Circulation, May 3, 2005; 111(17): 2241 - 2249. [Abstract] [Full Text] [PDF]

				K. Benchenane, V. Berezowski, M. Fernandez-Monreal, J. Brillault, S. Valable, M.-P. Dehouck, R. Cecchelli, D. Vivien, O. Touzani, and C. Ali Oxygen Glucose Deprivation Switches the Transport of tPA Across the Blood-Brain Barrier From an LRP-Dependent to an Increased LRP-Independent Process Stroke, May 1, 2005; 36(5): 1059 - 1064. [Abstract] [Full Text] [PDF]

				R. Noor, C. X. Wang, and A. Shuaib Hyperthermia Masks the Neuroprotective Effects of Tissue Plaminogen Activator Stroke, March 1, 2005; 36(3): 665 - 669. [Abstract] [Full Text] [PDF]

				Y. Silva, R. Leira, J. Tejada, J. M. Lainez, J. Castillo, A. Davalos, and by the Stroke Project, Cerebrovascular Diseases Gr Molecular Signatures of Vascular Injury Are Associated With Early Growth of Intracerebral Hemorrhage Stroke, January 1, 2005; 36(1): 86 - 91. [Abstract] [Full Text] [PDF]

				T. A. Sutton, K. J. Kelly, H. E. Mang, Z. Plotkin, R. M. Sandoval, and P. C. Dagher Minocycline reduces renal microvascular leakage in a rat model of ischemic renal injury Am J Physiol Renal Physiol, January 1, 2005; 288(1): F91 - F97. [Abstract] [Full Text] [PDF]

				M. Yepes and D. A. Lawrence New Functions for an Old Enzyme: Nonhemostatic Roles for Tissue-Type Plasminogen Activator in the Central Nervous System Experimental Biology and Medicine, December 1, 2004; 229(11): 1097 - 1104. [Abstract] [Full Text] [PDF]

				X. Wang, K. Tsuji, S.-R. Lee, M. Ning, K. L. Furie, A. M. Buchan, and E. H. Lo Mechanisms of Hemorrhagic Transformation After Tissue Plasminogen Activator Reperfusion Therapy for Ischemic Stroke Stroke, November 1, 2004; 35(11_suppl_1): 2726 - 2730. [Abstract] [Full Text] [PDF]

				J. A. Bittl and L. R. Caplan Stroke after percutaneous coronary interventions J. Am. Coll. Cardiol., April 7, 2004; 43(7): 1168 - 1169. [Full Text] [PDF]

				E. H. Lo, J. P. Broderick, and M. A. Moskowitz tPA and Proteolysis in the Neurovascular Unit Stroke, February 1, 2004; 35(2): 354 - 356. [Full Text] [PDF]

				S. Gautier, O. Petrault, P. Gele, M. Laprais, M. Bastide, A. Bauters, D. Deplanque, B. Jude, J. Caron, and R. Bordet Involvement of Thrombolysis in Recombinant Tissue Plasminogen Activator-Induced Cerebral Hemorrhages and Effect on Infarct Volume and Postischemic Endothelial Function Stroke, December 1, 2003; 34(12): 2975 - 2979. [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]

				T. Pfefferkorn and G. A. Rosenberg Closure of the Blood-Brain Barrier by Matrix Metalloproteinase Inhibition Reduces rtPA-Mediated Mortality in Cerebral Ischemia With Delayed Reperfusion Stroke, August 1, 2003; 34(8): 2025 - 2030. [Abstract] [Full Text] [PDF]