The Endothelin ET_B Receptor Antagonist BQ788 Protects against Brain Edema after Fluid Percussion Injury by Decreasing Vascular Endothelial Growth Factor-A Expression in Mice

Abstract

Brain edema is a severe morbid complication of brain injury, characterized by excessive ‰uid accumulation and an elevation of intracranial pressure. However, eŠective anti-brain edema drugs are lacking. One of the causes of brain edema is disruption of blood-brain barrier (BBB) function, which results in extravasation of intravascular ‰uid. After brain damage, astrocytes are activated, and astrocyte-derived vascular endothelial growth factor-A (VEGF-A) is known to induce BBB dysfunction. Therefore maintaining BBB integrity by regulating astrocyte function is a potentially eŠec-tive strategy for treating brain edema. In this review, we focus on the endothelin ET B receptor and its role in regulation of astrocyte functions. In mice, brain damage was induced by ‰uid percussion injury (FPI), and the resulting BBB disruption and brain edema were observed in the mouse cerebrum. BQ788, a selective ET B receptor antagonist, attenuated the FPI-induced BBB disruption and brain edema. Levels of brain VEGF-A increased after FPI, mainly in reactive astrocytes. BQ788 suppressed the FPI-induced increase in VEGF-A expression in reactive astrocytes. Moreover, intraventricular administration of VEGF neutralizing antibody also attenuated FPI-induced BBB disruption and brain edema. Claudin-5 is an endothelial tight junction protein essential for normal BBB structure and function. Levels of claudin-5 protein were reduced by FPI. Furthermore, VEGF neutralizing antibody blocked FPI-induced decrease in claudin-5. These results suggest that the ET B receptor antagonist BQ788 protects against brain edema by inhibiting VEGF-Amediated decrease in claudin-5.

Drug Discovery Research for Traumatic Brain Injury Focused on Functional Molecules in Astrocytes

“…34) Repeated intracerebroventricular (i.c.v.) administration of an MMP-9 inhibitor or VEGF-neutralizing antibody alleviates BBB disruption in experimental TBI model mice, 1,31) and astrocyte-derived MMP-9 and VEGF-A promote TBI-induced BBB disruption.…”

“…1,[17][18][19][20] The vascular protective factors include angiopoietin-1 (Ang-1) and sonic hedgehog (Shh), which decrease BBB permeability and alleviate BBB disruption. 16,[21][22][23][24][25][26] In contrast, vascular permeability-accelerating factors decrease the expression levels of endothelial tight junction proteins, including claudin-5 and occludin, which are essential components for the barrier function of the BBB, [27][28][29][30][31] whereas vascular protective factors increase these expression levels. 16,22,23,32,33) After FPI, the number of GFAP-positive reactive astrocytes increases in injured mouse cerebrum (Figs.…”