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    Profile of intravenous glyburide for the prevention of cerebral edema following large hemispheric infarction: Evidence to date

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    Author
    King, Z.A.
    Sheth, K.N.
    Kimberly, W.T.
    Date
    2018
    Journal
    Drug Design, Development and Therapy
    Publisher
    Dove Medical Press Ltd.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://dx.doi.org/10.2147/DDDT.S150043
    Abstract
    Glyburide (also known as glibenclamide) is a second-generation sulfonylurea drug that inhibits sulfonylurea receptor 1 (Sur1) at nanomolar concentrations. Long used to target KATP (Sur1–Kir6.2) channels for the treatment of diabetes mellitus type 2, glyburide was recently repurposed to target Sur1–transient receptor potential melastatin 4 (Trpm4) channels in acute central nervous system injury. Discovered nearly two decades ago, SUR1–TRPM4 has emerged as a critical target in stroke, specifically in large hemispheric infarction, which is characterized by edema formation and life-threatening brain swelling. Following ischemia, SUR1–TRPM4 channels are transcriptionally upregulated in all cells of the neurovascular unit, including neurons, astrocytes, microglia, oligodendrocytes and microvascular endothelial cells. Work by several independent laboratories has linked SUR1–TRPM4 to edema formation, with blockade by glyburide reducing brain swelling and death in preclinical models. Recent work showed that, following ischemia, SUR1–TRPM4 co-assembles with aquaporin-4 to mediate cellular swelling of astrocytes, which contributes to brain swelling. Additionally, recent work linked SUR1–TRPM4 to secretion of matrix metalloproteinase-9 (MMP-9) induced by recombinant tissue plasminogen activator in activated brain endothelial cells, with blockade of SUR1–TRPM4 by glyburide reducing MMP-9 and hemorrhagic transformation in preclinical models with recombinant tissue plasminogen activator. The recently completed GAMES (Glyburide Advantage in Malignant Edema and Stroke) clinical trials on patients with large hemispheric infarctions treated with intravenous glyburide (RP-1127) revealed promising findings with regard to brain swelling (midline shift), MMP-9, functional outcomes and mortality. Here, we review key elements of the basic science, preclinical experiments and clinical studies, both retrospective and prospective, on glyburide in focal cerebral ischemia and stroke.
    Sponsors
    JMS is supported by grants from the Department of Veterans Affairs (I01BX002889), the Department of Defense (SCI170199), the National Heart, Lung and Blood Institute (R01HL082517) and the National Institute of Neurological Disorders and Stroke (NINDS) (R01NS060801; R01NS102589; R01NS105633).
    Keyword
    Brain swelling
    Cerebral ischemia
    Glyburide
    Malignant edema
    Matrix metalloproteinase-9
    Stroke
    Sulfonylurea receptor 1
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85057827338&doi=10.2147%2fDDDT.S150043&partnerID=40&md5=b39b9fc806a381760ac712dc6b975ada; http://hdl.handle.net/10713/9035
    ae974a485f413a2113503eed53cd6c53
    10.2147/DDDT.S150043
    Scopus Count
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    UMB Open Access Articles 2018

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