Glibenclamide for the treatment of ischemic and hemorrhagic stroke.
Ischemic and hemorrhagic strokes are associated with severe functional disability and high mortality. Except for recombinant tissue plasminogen activator, therapies targeting the underlying pathophysiology of central nervous system (CNS) ischemia and hemorrhage are strikingly lacking. Sur1-regulated channels play essential roles in necrotic cell death and cerebral edema following ischemic insults, and in neuroinflammation after hemorrhagic injuries. Inhibiting endothelial, neuronal, astrocytic and oligodendroglial sulfonylurea receptor 1-transient receptor potential melastatin 4 (Sur1-Trpm4) channels and, in some cases, microglial KATP (Sur1-Kir6.2) channels, with glibenclamide is protective in a variety of contexts. Robust preclinical studies have shown that glibenclamide and other sulfonylurea agents reduce infarct volumes, edema and hemorrhagic conversion, and improve outcomes in rodent models of ischemic stroke. Retrospective studies suggest that diabetic patients on sulfonylurea drugs at stroke presentation fare better if they continue on drug. Additional laboratory investigations have implicated Sur1 in the pathophysiology of hemorrhagic CNS insults. In clinically relevant models of subarachnoid hemorrhage, glibenclamide reduces adverse neuroinflammatory and behavioral outcomes. Here, we provide an overview of the preclinical studies of glibenclamide therapy for CNS ischemia and hemorrhage, discuss the available data from clinical investigations, and conclude with promising preclinical results that suggest glibenclamide may be an effective therapeutic option for ischemic and hemorrhagic stroke.
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. nicholas.caffes@som.umaryland.edu.
Nicholas
N
Caffes
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. kurland.davidb@gmail.com.
David B
DB
Kurland
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. vgerzanich@smail.umaryland.edu.
Volodymyr
V
Gerzanich
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. msimard@smail.umaryland.edu.|Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. msimard@smail.umaryland.edu.|Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. msimard@smail.umaryland.edu.
J Marc
JM
Simard
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D005905:Glyburide / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D054086:KATP Channels / Q000737:chemistry / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy*; D064233:Sulfonylurea Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism
C577507:ABCC8 protein, human; D007004:Hypoglycemic Agents; D054086:KATP Channels; D064233:Sulfonylurea Receptors; D005905:Glyburide