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 K_ATP [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 NC_Ca-ATP channel) and, in some cases, via brain K_ATP 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.

We studied a model of hemorrhagic encephalopathy of prematurity (EP) that closely recapitulates findings in humans with hemorrhagic EP. This model involves tandem insults of 20 min intrauterine ischemia (IUI) plus an episode of elevated venous pressure induced by intraperitoneal glycerol on post-natal day (P) 0. We examined Sur1 expression, which is upregulated after focal ischemia but has not been studied after brief global ischemia including IUI. We found that 20 min IUI resulted in robust upregulation of Sur1 in periventricular microvessels and tissues. We studied tandem insult pups from untreated or vehicle-treated dams (TI-CTR), and tandem insult pups from dams administered a low-dose, non-hypoglycemogenic infusion of the Sur1 blocker, glibenclamide, for 1 week after IUI (TI-GLIB). Compared to pups from the TI-CTR group, pups from the TI-GLIB group had significantly fewer and less severe hemorrhages on P1, performed significantly better on the beam walk and accelerating Rotarod on P35 and in tests of thigmotaxis and rapid learning on P35–49, and had significantly greater body and brain weights at P52. We conclude that low-dose glibenclamide administered to the mother at the end of pregnancy protects pups subjected to IUI from post-natal events of elevated venous pressure and its consequences.

Three risk factors are associated with hemorrhagic forms of encephalopathy of prematurity (EP): (i) prematurity, (ii) in utero ischemia (IUI) or perinatal ischemia, and (iii) mechanical ventilation. We hypothesized that IUI would induce an angiogenic response marked by activation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9), the latter degrading vascular basement membrane and increasing vulnerability to raised intravenous pressure during positive pressure mechanical ventilation. We studied a rat model of hemorrhagic-EP characterized by periventricular hemorrhages in which a 20-min episode of IUI is induced at E19, pups are born naturally at E21-22, and on P0, are subjected to a 20-min episode of positive pressure mechanical ventilation. Tissues were studied by H&E staining, immunolabeling, immunoblot, and zymography. Mechanical ventilation of rat pups 2–3 d after 20-min IUI caused widespread hemorrhages in periventricular tissues. IUI resulted in upregulation of VEGF and MMP-9. Zymography confirmed significantly elevated gelatinase activity. MMP-9 activation was accompanied by severe loss of MMP-9 substrates, collagen IV and laminin, in microvessels in periventricular areas. Our findings are consistent with the hypothesis that positive pressure mechanical ventilation of the newborn in the context of recent prenatal ischemia/hypoxia can predispose to periventricular hemorrhages.