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

Traumatic brain injury (TBI) is severe damage to the head caused by traffic accidents, falls, and sports. Because TBI-induced disruption of the blood-brain barrier (BBB) causes brain edema and neuroinflammation, which are major causes of death or serious disabilities, protection and recovery of BBB function may be beneficial therapeutic strategies for TBI. Astrocytes are key components of BBB integrity, and astrocyte-derived bioactive factors promote and suppress BBB disruption in TBI. Therefore, the regulation of astrocyte function is essential for BBB protection. In the injured cerebrum of TBI model mice, we found that the endothelin ETB receptor, histamine H2 receptor, and transient receptor potential vanilloid 4 (TRPV4) were predominantly expressed in reactive astrocytes. We also showed that repeated administration of an ETB receptor antagonist, H2 receptor agonist, and TRPV4 antagonist alleviated BBB disruption and brain edema in a TBI mouse model. Furthermore, these drugs decreased the expression levels of astrocyte-derived factors promoting BBB disruption and increased the expression levels of astrocyte-derived protective factors in the injured cerebrum after TBI. These results suggest that the ETB receptor, H2 receptor, and TRPV4 are molecules that regulate astrocyte function, and might be attractive candidates for the development of therapeutic drugs for TBI.

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

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 ETB 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 ETB 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 ETB receptor antagonist BQ788 protects against brain edema by inhibiting VEGF-A-mediated decrease in claudin-5.