Xu Zhi-Ming, Yuan Fang, Liu Ying-Liang, Ding Jun, Tian Heng-Li
Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, China .
J Neurotrauma. 2017 Feb 15;34(4):925-933. doi: 10.1089/neu.2016.4491. Epub 2016 Jul 8.
Glibenclamide is a hypoglycemic drug that is widely used for the treatment of diabetes mellitus type 2 (DM II), but it also plays a protective role following injury to the central nervous system (CNS). However, the precise mechanisms underlying its neuroprotective actions remain to be elucidated. Therefore, the present study evaluated the effects of glibenclamide on the blood-brain barrier (BBB) in a mouse model of traumatic brain injury (TBI). In the present study, 86 adult male C57BL/6 mice were exposed to a controlled cortical impact (CCI) injury and then received glibenclamide (10 μg) for 3 days. Tight junction (TJ) protein levels, BBB permeability, and tissue hemoglobin levels were evaluated following the CCI injury. Additionally, a biaxial stretch injury was applied to cell cultures of bEnd.3 cells using the Cell Injury Controller II system to explore the mechanisms by which glibenclamide inhibits apoptosis-signaling pathways. Compared with the control group, glibenclamide-treated mice exhibited decreases in brain water content (p < 0.05), tissue hemoglobin levels (p < 0.05), and Evans Blue extravasation (p < 0.01) after the CCI injury. Glibenclamide primarily attenuated apoptosis via the JNK/c-jun signaling pathway and resulted in an elevation of stretch injury-induced ZO-1 expression in bEnd.3 cells (p < 0.01).Glibenclamide downregulated the activity of the JNK/c-jun apoptosis-signaling pathway which, in turn, decreased apoptosis in endothelial cells (ECs). This may have prevented the disruption of the BBB in a mouse model of TBI.
格列本脲是一种降糖药物，广泛用于治疗2型糖尿病（DM II），但它在中枢神经系统（CNS）损伤后也发挥保护作用。然而，其神经保护作用的精确机制仍有待阐明。因此，本研究评估了格列本脲对创伤性脑损伤（TBI）小鼠模型血脑屏障（BBB）的影响。在本研究中，86只成年雄性C57BL/6小鼠遭受控制性皮质撞击（CCI）损伤，然后接受格列本脲（10μg）治疗3天。在CCI损伤后评估紧密连接（TJ）蛋白水平、BBB通透性和组织血红蛋白水平。此外，使用细胞损伤控制器II系统对bEnd.3细胞培养物施加双轴拉伸损伤，以探索格列本脲抑制凋亡信号通路的机制。与对照组相比，CCI损伤后，格列本脲治疗的小鼠脑含水量（p<0.05）、组织血红蛋白水平（p<0.05）和伊文思蓝外渗（p<0.01）均降低。格列本脲主要通过JNK/c-jun信号通路减轻细胞凋亡，并导致bEnd.3细胞中拉伸损伤诱导的ZO-1表达升高（p<0.01）。格列本脲下调JNK/c-jun凋亡信号通路的活性，进而减少内皮细胞（ECs）的凋亡。这可能预防了TBI小鼠模型中BBB的破坏。
