Abstract
First introduced into clinical practice in 1969, glibenclamide (US adopted name, glyburide) is known best for its use in the treatment of diabetes mellitus type 2, where it is used to promote the release of insulin by blocking pancreatic KATP [sulfonylurea receptor 1 (Sur1)-Kir6.2] channels. During the last decade, glibenclamide has received renewed attention due to its pleiotropic protective effects in acute CNS injury. Acting via inhibition of the recently characterized Sur1-Trpm4 channel (formerly, the Sur1-regulated NCCa-ATP channel) and, in some cases, via brain KATP channels, glibenclamide has been shown to be beneficial in several clinically relevant rodent models of ischemic and hemorrhagic stroke, traumatic brain injury, spinal cord injury, neonatal encephalopathy of prematurity, and metastatic brain tumor. Glibenclamide acts on microvessels to reduce edema formation and secondary hemorrhage, it inhibits necrotic cell death, it exerts potent anti-inflammatory effects and it promotes neurogenesis—all via inhibition of Sur1. Two clinical trials, one in TBI and one in stroke, currently are underway. These recent findings, which implicate Sur1 in a number of acute pathological conditions involving the CNS, present new opportunities to use glibenclamide, a well-known, safe pharmaceutical agent, for medical conditions that heretofore had few or no treatment options.
Highlights
Glibenclamide (US adopted name, glyburide) is a member of the sulfonylurea class of drugs and has been in clinical use as an oral hypoglycemic agent since the 1960s [1]
Focal cerebral ischemia is associated with progressive microvascular dysfunction that is manifested initially by the formation of ionic edema, which may be followed by formation of vasogenic edema and, if severe enough, may be followed by the catastrophic structural failure of capillaries—so-called, “hemorrhagic transformation” of an ischemic stroke [39]
Sur1-Trpm4 and KATP channels, glibenclamide protects microvascular endothelium to reduce the formation of edema and secondary hemorrhage, it inhibits neuronal cell death, it exerts potent anti-inflammatory effects and it promotes neurogenesis
Summary
Glibenclamide (US adopted name, glyburide) is a member of the sulfonylurea class of drugs and has been in clinical use as an oral hypoglycemic agent since the 1960s [1]. Phase II clinical trials have begun to evaluate an intravenous formulation of glibenclamide in patients with traumatic brain injury [30] and stroke [31,32,33]. We begin with an overview of the preclinical studies of glibenclamide therapy for specific CNS insults, and conclude with a discussion of the available data from clinical investigations
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