Department of Pharmacodynamics, Meiji Pharmaceutical University.
Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University.
Biol Pharm Bull. 2021;44(11):1759-1766. doi: 10.1248/bpb.b21-00512.
Vasogenic edema results from blood-brain barrier (BBB) disruption after traumatic brain injury (TBI), and although it can be fatal, no promising therapeutic drugs have been developed as yet. Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable channel that is sensitive to temperature and osmotic pressure. As TRPV4 is known to be responsible for various pathological conditions following brain injury, we investigated the effects of pharmacological TRPV4 antagonists on TBI-induced vasogenic edema in this study. A TBI model was established by inflicting fluid percussion injury (FPI) in the mouse cerebrum and cultured astrocytes. Vasogenic brain edema and BBB disruption were assessed based on brain water content and Evans blue (EB) extravasation into brain tissue, respectively. After FPI, brain water content and EB extravasation increased. Repeated intracerebroventricular administration of the specific TRPV4 antagonists HC-067047 and RN-1734 dose-dependently reduced brain water content and alleviated EB extravasation in FPI mice. Additionally, real-time PCR analysis indicated that administration of HC-067047 and RN-1734 reversed the FPI-induced increase in mRNA levels of endogenous causal factors for BBB disruption, including matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor-A (VEGF-A), and endothelin-1 (ET-1). In astrocytes, TRPV4 level was observed to be higher than that in brain microvascular endothelial cells. Treatment with HC-067047 and RN-1734 inhibited the increase in mRNA levels of MMP-9, VEGF-A, and ET-1 in cultured astrocytes subjected to in vitro FPI. These results suggest that pharmacological inhibition of TRPV4 is expected to be a promising therapeutic strategy for treating TBI-induced vasogenic edema.
血管源性水肿是由创伤性脑损伤 (TBI) 后血脑屏障 (BBB) 破坏引起的，尽管它可能是致命的，但迄今为止尚未开发出有前途的治疗药物。瞬时受体电位香草酸 4 (TRPV4) 是一种对温度和渗透压敏感的钙通透性通道。由于 TRPV4 已知在脑损伤后与各种病理状况有关，因此我们在本研究中研究了药理学 TRPV4 拮抗剂对 TBI 引起的血管源性水肿的影响。通过在小鼠大脑中施加液压冲击伤 (FPI) 建立 TBI 模型，并培养星形胶质细胞。分别基于脑水含量和 Evans 蓝 (EB) 向脑组织中的渗出来评估血管源性脑水肿和 BBB 破坏。在 FPI 后，脑水含量和 EB 渗出增加。重复脑室内给予特异性 TRPV4 拮抗剂 HC-067047 和 RN-1734 剂量依赖性地降低脑水含量并减轻 FPI 小鼠的 EB 渗出。此外，实时 PCR 分析表明，给予 HC-067047 和 RN-1734 逆转了 FPI 诱导的 BBB 破坏的内源性因果因子 mRNA 水平的增加，包括基质金属蛋白酶-9 (MMP-9)、血管内皮生长因子-A (VEGF-A) 和内皮素-1 (ET-1)。在星形胶质细胞中，TRPV4 水平高于脑微血管内皮细胞。用 HC-067047 和 RN-1734 处理可抑制体外 FPI 处理的培养星形胶质细胞中 MMP-9、VEGF-A 和 ET-1 的 mRNA 水平升高。这些结果表明，药理学抑制 TRPV4 有望成为治疗 TBI 引起的血管源性水肿的有前途的治疗策略。
