Glibenclamide for the Treatment of Acute CNS Injury

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.

Cerebral Vascular Injury in Traumatic Brain Injury

“…Other FDA-approved medications have proven beneficial in preclinical trials potentially through angiogenesis promotion after TCVI, including atorvastatin (Wang et al, 2012) and glibenclamide (Kurland et al, 2013). Both drugs have multiple modes of action.…”

“…Both drugs have multiple modes of action. Glibenclamide has several protective effects in the CNS, including its action on cerebral microvessels to reduce edema formation and secondary hemorrhage, inhibition of cellular necrosis, potent anti-inflammatory effects and neurogenesis promotion (Kurland et al, 2013). In a rat model of CCI, glibenclamide administered shortly after injury, reduces the spatial and temporal "blossoming" of hemorrhagic contusion (Simard et al, 2009).…”

Injectable Hydrogels for Spinal Cord Repair: A Focus on Swelling and Intraspinal Pressure

“…Hence, as we develop new therapies using injectable biomaterials for implantation into the spinal cord, swelling of these materials in vivo is an important consideration. Edema -abnormalities in the location and amount of water -is associated with many pathological conditions of the CNS, including traumatic SCI, TBI, and stroke [Simard et al, 2012;Kurland et al, 2013]. Edema leads to an increase in local pressure, potentially causing tissue isch- Local intraspinal pressures increase significantly after injury to the spinal cord.…”

“…emia and eventually cell death [Simard et al, 2012;Kurland et al, 2013]. Aquaporins (AQPs), a family of transmembrane proteins that serve as channels for water, are expressed throughout the brain and spinal cord [Manley et al, 2004;Bradl and Lassmann, 2008;Benfenati and Ferroni, 2010;Hinson et al, 2010;MacAulay and Zeuthen, 2010;Saadoun and Papadopoulos, 2010;Verkman et al, 2011;Brosnan and Raine, 2013;Delgado et al, 2014;Freitas and Guimaraes, 2015].…”

NADPH oxidase- and mitochondria-derived reactive oxygen species in proinflammatory microglial activation: a bipartisan affair?

“…NLRP3 knockdown by siRNA reduced brain edema and improved neurological functions at 24-72 hours after intracerebral hemorrhage [142], suggesting a deleterious role for the NLRP3 inflammasome following acute brain injury. Interestingly, glibenclamide (also known as glyburide), a diabetes drug proposed as a novel treatment for acute brain injury due to its ability to inhibit the Sur1-Trpm4 channel involved in brain edema [143], was also shown to inhibit the NLRP3 inflammasome [144]. Similar to NLRP3 knockdown, glibenclamide reduced neuroinflammation and cognitive impairment following subarachnoid brain hemorrhage [145].…”