Int. J. Mol. Sci. 2015, 16, 4973-4984; doi:10.3390/ijms16034973 OPEN ACCESS
International Journal of
Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review
Glibenclamide for the Treatment of Ischemic and Hemorrhagic Stroke Nicholas Caffes 1, David B. Kurland 1, Volodymyr Gerzanich 1 and J. Marc Simard 1,2,3,* 1
2 3
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; E-Mails: [email protected] (N.C.); [email protected] (D.B.K.); [email protected] (V.G.) Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
* Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-410-328-0850; Fax: +1-410-328-0124. Academic Editor: Xiaofeng Jia Received: 12 January 2015 / Accepted: 26 February 2015 / Published: 4 March 2015
Abstract: 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
Int. J. Mol. Sci. 2015, 16
4974
clinical investigations, and conclude with promising preclinical results that suggest glibenclamide may be an effective therapeutic option for ischemic and hemorrhagic stroke. Keywords: ischemic stroke; subarachnoid hemorrhage; Sur1-Trpm4 channels; KATP channels; glibenclamide; cerebral edema; necrotic cell death
1. Introduction Each year, 5.5 million people die from an ischemic stroke, with 10%–12% suffering from “malignant infarctions”, rapidly progressing cerebral edema that compromises arterial inflow, culminating in further ischemic damage [1]. The prognosis for these patients is poor, with mortality rates as high as 60%–80% [1,2]. The only medication currently approved specifically for use in acute ischemic stroke is recombinant tissue plasminogen activator (rtPA); however, for many reasons, it is used in
International Journal of
Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review
Glibenclamide for the Treatment of Ischemic and Hemorrhagic Stroke Nicholas Caffes 1, David B. Kurland 1, Volodymyr Gerzanich 1 and J. Marc Simard 1,2,3,* 1
2 3
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; E-Mails: [email protected] (N.C.); [email protected] (D.B.K.); [email protected] (V.G.) Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
* Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-410-328-0850; Fax: +1-410-328-0124. Academic Editor: Xiaofeng Jia Received: 12 January 2015 / Accepted: 26 February 2015 / Published: 4 March 2015
Abstract: 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
Int. J. Mol. Sci. 2015, 16
4974
clinical investigations, and conclude with promising preclinical results that suggest glibenclamide may be an effective therapeutic option for ischemic and hemorrhagic stroke. Keywords: ischemic stroke; subarachnoid hemorrhage; Sur1-Trpm4 channels; KATP channels; glibenclamide; cerebral edema; necrotic cell death
1. Introduction Each year, 5.5 million people die from an ischemic stroke, with 10%–12% suffering from “malignant infarctions”, rapidly progressing cerebral edema that compromises arterial inflow, culminating in further ischemic damage [1]. The prognosis for these patients is poor, with mortality rates as high as 60%–80% [1,2]. The only medication currently approved specifically for use in acute ischemic stroke is recombinant tissue plasminogen activator (rtPA); however, for many reasons, it is used in
