Does inhibiting Sur1 complement rt-PA in cerebral ischemia?

J. Marc Simard, Zhihua Geng, Frank L. Silver, Kevin N. Sheth, W. Taylor Kimberly, Barney J. Stern, Mario Colucci, Volodymyr Gerzanich

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)95-107
Number of pages13
JournalAnnals of the New York Academy of Sciences
Volume1268
Issue number1
DOIs
StatePublished - Sep 2012
Externally publishedYes

Keywords

  • Cerebral ischemia
  • Glyburide
  • MMP-9
  • Rt-PA
  • Stroke
  • Sur1

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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