title: Glibenclamide in cerebral ischemia and stroke.
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.
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, 22 S. Greene St., Suite S12D, Baltimore, MD, 21201-1595, USA, msimard@smail.umaryland.edu.
authors.forename: J Marc
authors.initials: JM
authors.lastname: Simard
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Sheth
authors.forename: W Taylor
authors.initials: WT
authors.lastname: Kimberly
authors.forename: Barney J
authors.initials: BJ
authors.lastname: Stern
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: del Zoppo
authors.forename: Sven
authors.initials: S
authors.lastname: Jacobson
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Gerzanich
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000188:drug therapy; D002545:Brain Ischemia / Q000188:drug therapy*; D005905:Glyburide / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D020521:Stroke / Q000188:drug therapy*
chemical_list: D007004:Hypoglycemic Agents; D005905:Glyburide