Delayed Administration of BQ788, an ET B Antagonist, after Experimental Traumatic Brain Injury Promotes Recovery of Blood–Brain Barrier Function and a Reduction of Cerebral Edema in Mice

Traumatic brain injury (TBI) is induced by immediate physical disruption of brain tissue, and causes death and disability. Studies on experimental TBI animal models show that disruption of the blood–brain barrier (BBB) underlies brain edema and neuroinflammation during the delayed phase of TBI. In neurological disorders, endothelin-1 (ET-1) is involved in BBB dysfunction and brain edema. In this study, the effect of ET antagonists on BBB dysfunction and brain edema were examined in a mouse focal TBI model using lateral fluid percussion injury (FPI). ET-1 and ETB receptors were increased at 2–7 days after FPI, which was accompanied by extravasation of Evans blue (EB) and brain edema. Repeated intracerebroventricular administration of BQ788 (15 nmol/day), an ETB antagonist, from 2 days after FPI promoted recovery of EB extravasation and brain edema, while FR 139317, an ETA antagonist, had no effect. Delayed intravenous administration of BQ788 also promoted recovery from FPI-induced EB extravasation and brain edema. While FPI caused decreases in claudin-5, occludin, and zonula occludens-1 proteins, BQ788 reversed FPI-induced reductions of them. Immunohistochemical observation of the cerebrum after FPI showed that ETB receptors are predominantly expressed in glial fibrillary acidic protein (GFAP)-positive astrocytes. BQ788 reduced FPI-induced increases in GFAP-positive astrocytes. GFAP-positive astrocytes produced vascular endothelial growth factor-A (VEGF-A) and matrix metalloproteinase-9 (MMP9). FPI-induced increases in VEGF-A and MMP-9 production were reversed by BQ788. These results suggest that ETB receptor antagonism during the delayed phase of focal TBI promotes recovery of BBB function and reduction of brain edema.