流体衝撃による脳傷害後のマウス脳浮腫に対するエンドセリンETB受容体遮断薬の効果 —血管透過性亢進因子VEGF-Aの関与—

摘要

Brain edema is a severe morbid complication of brain injury, characterized by excessive fluid accumulation and an elevation of intracranial pressure. However, effective 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 fluid. 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 effective 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 fluid 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-A-mediated decrease in claudin-5.