• The Protective Effect of Glibenclamide in a Novel Model of Hemorrhagic Encephalopathy of Prematurity

      Tosun, Cigdem; Simard, J. Marc (2014)
      Encephalopathy of prematurity (EP) is common in preterm, low-birth weight infants who require mechanical ventilation. The worst forms of EP include choroid plexus and germinal matrix hemorrhages, which often extend intraventricularly. Survivors suffer life-long cognitive, behavioral and motor (cerebral palsy) abnormalities. A clinically relevant model was developed in the rat that featured tandem insults of transient intra-uterine ischemia (IUI) plus transient postnatal venous hypertension. In utero ischemia upregulates SUR1/Trpm4 channels in endothelial cells, similar to channel upregulation in veins of infants with germinal matrix hemorrhage. When the channels are opened by ATP depletion, endothelial cells undergo cytotoxic edema and injury. This weakens the veins, making them susceptible to rupture during later episodes of venous hypertension. This model incorporates hemorrhages in the choroid plexus and periventricular areas that inciteoxidative and inflammatory responses that cause secondary injury to the surrounding white matter. Aside from the developmental abnormalities in infants with hemorrhagic EP secondary to reduced brain mass, there are associated vestibulomotor abnormalities and cognitive dysfunction. Blockade of the SUR1/Trpm4 channel following in utero ischemia with the selective, potent SUR1 inhibitor, glibenclamide, reduces hemorrhage, inflammation, mortality and loss in brain mass, and improve vestibulomotor and cognitive abnormalities in this model. Treatment with glibenclamide 3-day prior to delivery in pregnant rats that were subjected to IUI may act as effective prophylaxis against periventricular hemorrhage, reduce the severity of developmental delay and, most strikingly, reduce loss of tissue mass associated with hemorrhagic EP.