Does inhibiting Sur1 complement rt-PA in cerebral ischemia?

  1. J. Marc Simard1,2,3,
  2. Zhihua Geng1,
  3. Frank L. Silver4,
  4. Kevin N. Sheth5,
  5. W. Taylor Kimberly6,
  6. Barney J. Stern5,
  7. Mario Colucci7,
  8. Volodymyr Gerzanich1

Article first published online: 20 SEP 2012

DOI: 10.1111/j.1749-6632.2012.06705.x

Issue

Annals of the New York Academy of Sciences

Annals of the New York Academy of Sciences

Additional Information

How to Cite

Simard, J. M., Geng, Z., Silver, F. L., Sheth, K. N., Kimberly, W. T., Stern, B. J., Colucci, M. and Gerzanich, V. (2012), Does inhibiting Sur1 complement rt-PA in cerebral ischemia?. Annals of the New York Academy of Sciences, 1268: 95–107. doi: 10.1111/j.1749-6632.2012.06705.x

Author Information

  1. 1

    Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland.

  2. 2

    Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland.

  3. 3

    Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland.

  4. 4

    Department of Medicine, Division of Neurology, University of Toronto, Toronto, Ontario, Canada.

  5. 5

    Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland.

  6. 6

    Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

  7. 7

    Department of Biomedical Sciences and Human Oncology, University of Aldo Moro, Bari, Italy

*Dr. J. Marc Simard, Department of Neurosurgery, University of Maryland School of Medicine, 22 S. Greene St., Suite S12D, Baltimore, MD 21201–1595. msimard@smail.umaryland.edu

Publication History

  1. Issue published online: 20 SEP 2012
  2. Article first published online: 20 SEP 2012

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Keywords:

  • rt-PA;
  • Sur1;
  • glyburide;
  • MMP-9;
  • cerebral ischemia;
  • stroke

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.

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