Michinaga Shotaro
Department of Pharmacodynamics, Meiji Pharmaceutical University.
Biol Pharm Bull. 2024;47(2):350-360. doi: 10.1248/bpb.b23-00731.
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 ET receptor, histamine H receptor, and transient receptor potential vanilloid 4 (TRPV4) were predominantly expressed in reactive astrocytes. We also showed that repeated administration of an ET receptor antagonist, H 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 ET receptor, H receptor, and TRPV4 are molecules that regulate astrocyte function, and might be attractive candidates for the development of therapeutic drugs for TBI.
创伤性脑损伤（TBI）是由交通事故、跌倒和运动导致的头部严重损伤。由于TBI引起的血脑屏障（BBB）破坏会导致脑水肿和神经炎症，而这是死亡或严重残疾的主要原因，因此保护和恢复BBB功能可能是TBI有益的治疗策略。星形胶质细胞是BBB完整性的关键组成部分，星形胶质细胞衍生的生物活性因子在TBI中促进和抑制BBB破坏。因此，调节星形胶质细胞功能对于保护BBB至关重要。在TBI模型小鼠的受损大脑中，我们发现内皮素ET受体、组胺H受体和瞬时受体电位香草酸亚型4（TRPV4）主要在反应性星形胶质细胞中表达。我们还表明，在TBI小鼠模型中反复给予ET受体拮抗剂、H受体激动剂和TRPV4拮抗剂可减轻BBB破坏和脑水肿。此外，这些药物降低了TBI后受损大脑中促进BBB破坏的星形胶质细胞衍生因子的表达水平，并增加了星形胶质细胞衍生的保护因子的表达水平。这些结果表明，ET受体、H受体和TRPV4是调节星形胶质细胞功能的分子，可能是开发TBI治疗药物的有吸引力的候选分子。
