Abstract
Hemorrhagic transformation (HT) associated with recombinant tissue plasminogen activator (rt-PA) complicates and limits its use in stroke. Here, we provide a focused review on the involvement of matrix metalloproteinase 9 (MMP-9) in rt-PA-associated HT in cerebral ischemia, and we review emerging evidence that the selective inhibitor of the sulfonylurea receptor 1 (Sur1), glibenclamide (U.S. adopted name, glyburide), may provide protection against rt-PA-associated HT in cerebral ischemia. Glyburide inhibits activation of MMP-9, ameliorates edema formation, swelling, and symptomatic hemorrhagic transformation, and improves preclinical outcomes in several clinically relevant models of stroke, both without and with rt-PA treatment. A retrospective clinical study comparing outcomes in diabetic patients with stroke treated with rt-PA showed that those who were previously on and were maintained on a sulfonylurea fared significantly better than those whose diabetes was managed without sulfonylureas. Inhibition of Sur1 with injectable glyburide holds promise for ameliorating rt-PA-associated HT in stroke.
© 2012 New York Academy of Sciences.
MeSH terms
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ATP-Binding Cassette Transporters / antagonists & inhibitors*
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ATP-Binding Cassette Transporters / physiology
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Animals
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Antioxidants / pharmacology*
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Antioxidants / therapeutic use
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Aspirin / adverse effects
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Aspirin / therapeutic use
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Brain Ischemia / complications
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Brain Ischemia / drug therapy*
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Cells, Cultured / enzymology
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Cerebral Hemorrhage / etiology
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Cerebral Hemorrhage / prevention & control
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Clinical Trials as Topic
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Diabetes Mellitus, Type 2 / complications
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Diabetes Mellitus, Type 2 / drug therapy*
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Drug Synergism
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Endothelial Cells / enzymology
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Glyburide / pharmacology*
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Glyburide / therapeutic use
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Heparin / adverse effects
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Heparin / therapeutic use
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Humans
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Hypoglycemic Agents / pharmacology*
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Hypoglycemic Agents / therapeutic use
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Matrix Metalloproteinase 9 / deficiency
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Matrix Metalloproteinase 9 / physiology*
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Mice
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Mice, Knockout
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Potassium Channels, Inwardly Rectifying / antagonists & inhibitors*
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Potassium Channels, Inwardly Rectifying / physiology
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Prospective Studies
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Receptors, Drug / antagonists & inhibitors*
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Receptors, Drug / physiology
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Recombinant Proteins / adverse effects
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Recombinant Proteins / pharmacology
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Recombinant Proteins / therapeutic use
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Retrospective Studies
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Risk
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Sulfonylurea Receptors
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Tetracycline / pharmacology
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Tetracycline / therapeutic use
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Tissue Plasminogen Activator / adverse effects
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Tissue Plasminogen Activator / pharmacology*
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Tissue Plasminogen Activator / therapeutic use
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Treatment Outcome
Substances
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ABCC8 protein, human
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ATP-Binding Cassette Transporters
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Abcc8 protein, mouse
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Antioxidants
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Hypoglycemic Agents
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Potassium Channels, Inwardly Rectifying
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Receptors, Drug
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Recombinant Proteins
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Sulfonylurea Receptors
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Heparin
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Tissue Plasminogen Activator
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Matrix Metalloproteinase 9
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Tetracycline
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Aspirin
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Glyburide