Neuregulin-1 Effects on Endothelial and Blood-Brain Barrier Permeability After Experimental Injury

Blood brain barrier (BBB) disruption occurs with a high incidence after traumatic brain injury, and is an important contributor to many pathological processes, including brain edema, inflammation, and neuronal cell death. Therefore, BBB integrity is an important potential therapeutic target in the treatment of the acute phase of brain trauma. In this short communication, we report our data showing that neuregulin-1 (NRG1), a growth factor with diverse functions in the central nervous system (CNS), ameliorates pathological increases in endothelial permeability and in BBB permeability in experimental models of injury. For in vitro studies, rat brain endothelial cells were incubated with the inflammatory cytokine IL-1 beta, which caused an increase in permeability of the cell layer. Co-incubation with NRG1 ameliorated this permeability increase. For in vivo studies, C57B1/6 mice were subjected to controlled cortical impact (CCI) under anesthesia, and BBB permeability was assessed by measuring the amount of Evans blue dye extravasation at 2 h. NRG1 administered by tail-vein injection 10 min after CCI resulted in a decrease in Evans blue dye extravasation by 35 %. Since Evans blue extravasation may result from an increase in BBB permeability or from bleeding due to trauma, hemoglobin ELISA was also performed at the same time point. There was a trend toward lower levels of hemoglobin extravasation in the NRG1 group, but the results did not reach statistical significance. MMP-9 activity was not different between groups at 2 h. These data suggest that NRG1 has beneficial effects on endothelial permeability and BBB permeability following experimental trauma, and may have neuroprotective potential during CNS injury.