Zweckberger K, Hackenberg K, Jung C S, Hertle D N, Kiening K L, Unterberg A W, Sakowitz O W
Department of Neurosurgery, University Heidelberg, Germany.
Department of Neurosurgery, University Heidelberg, Germany.
Neuroscience. 2014 Jul 11;272:199-206. doi: 10.1016/j.neuroscience.2014.04.040. Epub 2014 Apr 30.
Following traumatic brain injury (TBI) SUR1-regulated NCCa-ATP (SUR1/TRPM4) channels are transcriptionally up-regulated in ischemic astrocytes, neurons, and capillaries. ATP depletion results in depolarization and opening of the channel leading to cytotoxic edema. Glibenclamide is an inhibitor of SUR-1 and, thus, might prevent cytotoxic edema and secondary brain damage following TBI. Anesthetized adult Sprague-Dawley rats underwent parietal craniotomy and were subjected to controlled cortical impact injury (CCI). Glibenclamide was administered as a bolus injection 15min after CCI injury and continuously via osmotic pumps throughout 7days. In an acute trial (180min) mean arterial blood pressure, heart rate, intracranial pressure, encephalographic activity, and cerebral metabolism were monitored. Brain water content was assessed gravimetrically 24h after CCI injury and contusion volumes were measured by MRI scanning technique at 8h, 24h, 72h, and 7d post injury. Throughout the entire time of observation neurological function was quantified using the "beam-walking" test. Glibenclamide-treated animals showed a significant reduction in the development of brain tissue water content(80.47%±0.37% (glibenclamide) vs. 80.83%±0.44% (control); p<0.05; n=14). Contusion sizes increased continuously within 72h following CCI injury, but glibenclamide-treated animals had significantly smaller volumes at any time-points, like 172.53±38.74mm(3) (glibenclamide) vs. 299.20±64.02mm(3) (control) (p<0.01; n=10; 24h) or 211.10±41.03mm(3) (glibenclamide) vs. 309.76±19.45mm(3) (control) (p<0.05; n=10; 72h), respectively. An effect on acute parameters, however, could not be detected, most likely because of the up-regulation of the channel within 3-6h after injury. Furthermore, there was no significant effect on motor function assessed by the beam-walking test throughout 7days. In accordance to these results and the available literature, glibenclamide seems to have promising potency in the treatment of TBI.
创伤性脑损伤（TBI）后，SUR1调节的NCCa-ATP（SUR1/TRPM4）通道在缺血性星形胶质细胞、神经元和毛细血管中转录上调。ATP耗竭导致通道去极化并开放，进而引发细胞毒性水肿。格列本脲是SUR-1的抑制剂，因此可能预防TBI后的细胞毒性水肿和继发性脑损伤。对成年Sprague-Dawley大鼠进行麻醉后行顶骨开颅术，并施加控制性皮质撞击伤（CCI）。CCI损伤15分钟后，以推注方式注射格列本脲，并通过渗透泵持续给药7天。在急性试验（180分钟）中，监测平均动脉血压、心率、颅内压、脑电图活动和脑代谢。CCI损伤24小时后，通过重量法评估脑含水量，并在损伤后8小时、24小时、72小时和7天通过MRI扫描技术测量挫伤体积。在整个观察期间，使用“走杆”试验对神经功能进行量化。格列本脲治疗的动物脑组织含水量的增加显著减少（格列本脲组为80.47%±0.37%，对照组为80.83%±0.44%；p<0.05；n=14）。CCI损伤后72小时内挫伤大小持续增加，但格列本脲治疗的动物在任何时间点的体积均显著较小，如24小时时，格列本脲组为172.53±38.74mm³，对照组为299.20±64.02mm³（p<0.01；n=10）；72小时时，格列本脲组为211.10±41.03mm³，对照组为309.76±19.45mm³（p<0.05；n=IO）。然而，未检测到对急性参数的影响，最可能的原因是损伤后3-6小时内通道上调。此外，在7天内通过走杆试验评估的运动功能方面，未发现显著影响。根据这些结果和现有文献，格列本脲在TBI治疗中似乎具有可观的潜力。
