Inhibition of Transient Receptor Potential Vanilloid 1 Attenuates Blood-Brain Barrier Disruption after Traumatic Brain Injury in Mice
Inhibition of Transient Receptor Potential Vanilloid 1 Attenuates Blood-Brain Barrier Disruption after Traumatic Brain Injury in Mice
复制标题
抑制瞬时受体电位香草酸 1 可减轻小鼠脑外伤后血脑屏障的破坏
DOI：
10.1089/neu.2018.5942
复制
发表时间：
2018-12-04
影响因子：
4.2
通讯作者：
Tian, Heng-li
中科院分区：
文献类型：
--
作者：
Yang, Dian-xu;Jing, Yao;Tian, Heng-li
瞬时受体电位香草样蛋白1 （TRPV1）在中枢神经系统中广泛表达，可被各种刺激激活。抑制TRPV1对脑缺血有神经保护作用。然而，抑制TRPV1在创伤性脑损伤（TBI）后维持血脑屏障（BBB）完整性中的作用尚不清楚。因此，我们研究了capsazepin介导的TRPV1抑制对脑外伤小鼠模型血脑屏障的影响。成年雄性C57BL/6小鼠控制性皮质撞击损伤，给予1 μ mol/kg体重的卡萨平，每天2次，腹腔注射，直至牺牲。此外，培养小鼠脑微血管内皮细胞（bEnd.3）并进行双轴拉伸损伤，以研究辣椒平保护作用的机制。TRPV1在脑外伤后眶周表达上调，在24 h达到峰值。capsazepine处理的小鼠在TBI后表现出脑水肿（p = 0.010）、Evans Blue外渗（p = 0.001）、组织血红蛋白水平（p = 0.002）和紧密连接蛋白（p = 0.016 ZO-1表达；p = 0.013 occludin表达）的减少。Capsazepine通过降低JNK、P38、caspase-3的活化，显著缓解早期凋亡，对bEnd组织ZO-1水平有保护作用。拉伸损伤后3个细胞。我们得出结论，TRPV1的表达在脑外伤后上调，抑制TRPV1减轻脑外伤小鼠模型血脑屏障的破坏，至少部分是通过其对脑内皮细胞的抗凋亡作用。阻断TRPV1可能是一种有希望的药物治疗干预措施，以防止脑外伤后血脑屏障中断。
Transient receptor potential vanilloid 1 (TRPV1) is expressed widely in the central nervous system and is activated by various stimuli. Inhibiting TRPV1 has neuroprotective effects in cerebral ischemia. The role of inhibiting TRPV1 to maintain blood-brain barrier (BBB) integrity after traumatic brain injury (TBI) remains unclear, however. Therefore, we investigated the effects of capsazepine-mediated TRPV1 inhibition on the BBB in a mouse model of TBI. Adult male C57BL/6 mice underwent controlled cortical impact injury and received capsazepine (1 mu mol/kg body weight, twice daily, intraperitoneally) until sacrifice. Further, mouse brain microvascular endothelial (bEnd.3) cells were cultured and underwent biaxial stretch injury to investigate the mechanisms underlying the protective effects of capsazepine. The TRPV1 expression was upregulated in the pericontusional area after TBI, peaking at 24 h post-TBI. Capsazepine-treated mice demonstrated decreased brain edema (p = 0.010), Evans Blue extravasation (p = 0.001), tissue hemoglobin levels (p = 0.002), and loss of tight junction proteins (p = 0.016 ZO-1 expression; p = 0.013 occludin expression) after TBI compared with the vehicle-treated group. Capsazepine significantly alleviated early-stage apoptosis by attenuating activation of JNK, P38, and caspase-3, resulting in a protective effect on the level of ZO-1 in bEnd.3 cells after stretch injury. We conclude that the expression of TRPV1 is upregulated after TBI, and inhibition of TRPV1 attenuated disruption of the BBB in a mouse model of TBI, at least partly, through its antiapoptotic effects on brain endothelial cells. Blocking TRPV1 may be a promising pharmacotherapeutic intervention to protect against BBB disruption after TBI.