Alpha Omega Alpha Honor Medical Society

2010 Research Abstract

Sulfonylurea Receptor 1—A Novel Therapeutic Target Germinal Matrix Hemorrhage

Investigator: David Kurland, University of Maryland School of Medicine
Mentor: J. Marc Simard, MD, PhD, University of Maryland School of Medicine

Background—Germinal Matrix Hemorrhage/Intraventricular Hemorrhage (GMH/IVH) is a common complication of prematurity, occurring in 15-45% of premature infants. Survivors exhibit persistent neurological sequelae, among which are cerebral palsy and behavioral/learning disabilities, leading to a lifetime cost to society of an estimated $11 billion. Episodes of hypoxia/ischemia are believed to play a role in the etiology of this disease. The SUR1-NCCa-ATP channel, extensively characterized for its pathological role in models of CNS injury in this lab, has been recently implicated as a mediator of endothelial cell dysfunction in the GM of premature infants. Block of this channel with non-hypoglycemic doses of the sulfonylurea glibenclamide (glyburide) has been shown to be highly neuroprotective in animal models of stroke, spinal cord injury and traumatic brain injury.

Objective—We developed a novel rodent model of GMH/IVH comprising tandem insults of in utero ischemia and postnatal venous hypertension (IUI+VH), and hypothesized that the SUR1-NCCaATP channel was a critical mediator of endothelial cell demise, the expression of which would predispose to deep brain hemorrhages. We hypothesized that block of the channel with glibenclamide would prevent hemorrhage and improve long-term vestibulomotor and neurobehavioral outcomes.

Methods—Time-pregnant Wistar rats underwent laparotomy under anesthesia on embryonic day 19 (E19). Intrauterine ischemia (IUI) was induced by clamping the uterine pedicle for 20 minutes. Natural birth occurred on E22. Six hours after birth, pups were subjected to an episode of venous hypertension (VH), induced by injecting 50% glycerol (13.5μL/g) IP. Treatment of glibenclamide was delivered over five days through a subcutaneous pump implanted in the mother, following surgery on E19. Pathological, histological and behavioral analyses were performed on pups up to postnatal (P) day 52.

Results—Compared to controls, pups subjected to IUI+VH exhibited significant increases in mortality and in deep brain hemorrhages, including choroid plexus and periventricular hemorrhages, significant reductions in brain weight and body weight, significant vestibulomotor abnormalities when tested at P1-P14 and P35-P52, and a significant abnormality in rapid spatial learning when tested at P35-P52. Perinatal treatment with glibenclamide significantly affected outcome in rats subjected to IUI+VH, reducing rates of mortality and hemorrhage and normalizing vestibulomotor and neurobehavioral function in survivors.

Conclusions—The SUR1-NCCaATP channel plays an important role in the pathogenesis of GMH/IVH. Briefly, perinatal exposure to non-hypoglycemic levels of glibenclamide significantly reduced acute and long-term morbidity in animals subjected to tandem insults of IUI+VH. We conclude that there is great potential for the use of glibenclamide to treat those known to be at risk for GMH/IVH.

Updated on June 16, 2011.

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