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 clinical investigations, and conclude with promising preclinical results that suggest glibenclamide may be an effective therapeutic option for ischemic and hemorrhagic stroke.
Highlights
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]
We provide an overview of the preclinical studies of glibenclamide therapy for Central nervous system (CNS) ischemia, 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
The protective effects of glibenclamide have been established in clinically relevant rodent models of ischemic and hemorrhagic CNS insults
Summary
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]. Activation of sulfonylurea receptor 1 (Sur1) regulated channels has been identified as a key molecular mechanism of cerebral edema following ischemic insults and, intriguingly, Sur inhibition has demonstrated novel protective anti-inflammatory effects in pre-clinical models of subarachnoid hemorrhage [8]. Targeted inhibition of Sur1-regulated channels by the sulfonylurea glibenclamide ( known as glyburide, US adopted name) may offer an effective new treatment option for both ischemic and hemorrhagic forms of stroke. We provide an overview of the preclinical studies of glibenclamide therapy for CNS ischemia, 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. While pathological involvement of Sur1–Trpm channels has been demonstrated in ischemic and hemorrhagic CNS injury, recent evidence supports a potential role of brain KATP channels in promoting neuroglial injury. Relatively low doses of drug can be used to obtain a favorable therapeutic effect in both ischemic and hemorrhagic stroke [33]
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