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Glibenclamide in Cerebral Ischemia and Stroke

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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.

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Acknowledgments

This work was supported by Grants to JMS from the National Institute of Neurological Disorders and Stroke (NS061808) and the National Heart, Lung and Blood Institute (HL082517).

Conflict of interest

JMS holds a US patent (#7,285,574), “A novel non-selective cation channel in neural cells and methods for treating brain swelling,” and is a member of the scientific advisory board and holds shares in Remedy Pharmaceuticals. No support was provided by Remedy Pharmaceuticals to JMS or to other university-affiliated authors for this project.

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Authors and Affiliations

  1. Department of Neurosurgery, University of Maryland School of Medicine, 22 S. Greene St., Suite S12D, Baltimore, MD, 21201-1595, USA

    J. Marc Simard & Volodymyr Gerzanich

  2. Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA

    J. Marc Simard

  3. Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA

    J. Marc Simard

  4. Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA

    Barney J. Stern

  5. Division of Neurocritical Care, Department of Neurology, Yale University School of Medicine, New Haven, CT, USA

    Kevin N. Sheth

  6. Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    W. Taylor Kimberly

  7. Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA

    Gregory J. del Zoppo

  8. Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA

    Gregory J. del Zoppo

  9. Remedy Pharmaceuticals, Inc., New York, NY, USA

    Sven Jacobson

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  1. J. Marc Simard
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Simard, J.M., Sheth, K.N., Kimberly, W.T. et al. Glibenclamide in Cerebral Ischemia and Stroke. Neurocrit Care 20, 319–333 (2014). https://doi.org/10.1007/s12028-013-9923-1

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