Neurocritical Care

, Volume 20, Issue 2, pp 319–333

Glibenclamide in Cerebral Ischemia and Stroke

  • J. Marc Simard
  • Kevin N. Sheth
  • W. Taylor Kimberly
  • Barney J. Stern
  • Gregory J. del Zoppo
  • Sven Jacobson
  • Volodymyr Gerzanich
Review Article

DOI: 10.1007/s12028-013-9923-1

Cite this article as:
Simard, J.M., Sheth, K.N., Kimberly, W.T. et al. Neurocrit Care (2014) 20: 319. doi:10.1007/s12028-013-9923-1

Abstract

The sulfonylurea receptor 1 (Sur1)–transient receptor potential 4 (Trpm4) channel is an important molecular element in focal cerebral ischemia. The channel is upregulated in all cells of the neurovascular unit following ischemia, and is linked to microvascular dysfunction that manifests as edema formation and secondary hemorrhage, which cause brain swelling. Activation of the channel is a major molecular mechanism of cytotoxic edema and “accidental necrotic cell death.” Blockade of Sur1 using glibenclamide has been studied in different types of rat models of stroke: (i) in conventional non-lethal models (thromboembolic, 1–2 h temporary, or permanent middle cerebral artery occlusion), glibenclamide reduces brain swelling and infarct volume and improves neurological function; (ii) in lethal models of malignant cerebral edema, glibenclamide reduces edema, brain swelling, and mortality; (iii) in models with rtPA, glibenclamide reduces swelling, hemorrhagic transformation, and death. Retrospective studies of diabetic patients who present with stroke have shown that those whose diabetes is managed with a sulfonylurea drug and who are maintained on the sulfonylurea drug during hospitalization for stroke have better outcomes at discharge and are less likely to suffer hemorrhagic transformation. Here, we provide a comprehensive review of the basic science, preclinical experiments, and retrospective clinical studies on glibenclamide in focal cerebral ischemia and stroke. We also compare the preclinical work in stroke models to the updated recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR). The findings reviewed here provide a strong foundation for a translational research program to study glibenclamide in patients with ischemic stroke.

Keywords

Cerebral ischemia Stroke Sur1 Sur1–Trpm4 channel Glibenclamide RP-1127 Stroke Therapy Academic Industry Roundtable (STAIR) 

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • J. Marc Simard
    • 1
    • 2
    • 3
  • Kevin N. Sheth
    • 5
  • W. Taylor Kimberly
    • 6
  • Barney J. Stern
    • 4
  • Gregory J. del Zoppo
    • 7
    • 8
  • Sven Jacobson
    • 9
  • Volodymyr Gerzanich
    • 1
  1. 1.Department of NeurosurgeryUniversity of Maryland School of MedicineBaltimoreUSA
  2. 2.Department of PathologyUniversity of Maryland School of MedicineBaltimoreUSA
  3. 3.Department of PhysiologyUniversity of Maryland School of MedicineBaltimoreUSA
  4. 4.Department of NeurologyUniversity of Maryland School of MedicineBaltimoreUSA
  5. 5.Division of Neurocritical Care, Department of NeurologyYale University School of MedicineNew HavenUSA
  6. 6.Division of Neurocritical Care and Emergency Neurology, Department of NeurologyMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  7. 7.Division of Hematology, Department of MedicineUniversity of Washington School of MedicineSeattleUSA
  8. 8.Department of NeurologyUniversity of Washington School of MedicineSeattleUSA
  9. 9.Remedy Pharmaceuticals, Inc.New YorkUSA

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