title: Does inhibiting Sur1 complement rt-PA in cerebral ischemia?
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.
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA. msimard@smail.umaryland.edu
authors.forename: J Marc
authors.initials: JM
authors.lastname: Simard
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Geng
authors.forename: Frank L
authors.initials: FL
authors.lastname: Silver
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Sheth
authors.forename: W Taylor
authors.initials: WT
authors.lastname: Kimberly
authors.forename: Barney J
authors.initials: BJ
authors.lastname: Stern
authors.forename: Mario
authors.initials: M
authors.lastname: Colucci
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Gerzanich
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001241:Aspirin / Q000009:adverse effects / Q000627:therapeutic use; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D002478:Cells, Cultured / Q000201:enzymology; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000517:prevention & control; D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D004357:Drug Synergism; D042783:Endothelial Cells / Q000201:enzymology; D005905:Glyburide / Q000494:pharmacology* / Q000627:therapeutic use; D006493:Heparin / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000502:physiology; D011446:Prospective Studies; D011955:Receptors, Drug / Q000037:antagonists & inhibitors* / Q000502:physiology; D011994:Recombinant Proteins / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D012189:Retrospective Studies; D012306:Risk; D064233:Sulfonylurea Receptors; D013752:Tetracycline / Q000494:pharmacology / Q000627:therapeutic use; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; D000975:Antioxidants; D007004:Hypoglycemic Agents; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D011994:Recombinant Proteins; D064233:Sulfonylurea Receptors; D006493:Heparin; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9; D013752:Tetracycline; D001241:Aspirin; D005905:Glyburide