Acute Brain Injury Research Laboratory, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Pharm Res. 2011 Nov;28(11):2945-53. doi: 10.1007/s11095-011-0463-0. Epub 2011 May 17.
To investigate the possible impact of reduction of mitochondrial membrane permeabilization by modulation of the 18 kDa translocator protein mediated by Ro5-4864 over post-traumatic cerebral edema and metabolic crisis.
Cerebral microdialysis and intracranial pressure (ICP) monitoring were performed in Sprague-Dawley rats treated by intraperitoneal injection of either dimethylsulfoxide (vehicle) or Ro5-4864 following cortical contusion and further correlated with quantitative assessment of mitochondrial damage, water content in the injured tissue, modified neurological severity score, and lesion size.
Ro5-4864 resulted in a profound decrease in ICP that correlated with improved cerebral metabolism characterized by significantly higher glucose and pyruvate and lower lactate concentrations in the pericontusional area in comparison with vehicle-treated animals. Reduced ICP correlated with reduced water content in the injured tissue; improved metabolism was associated with reduced mitochondrial damage evidenced by electron microscopy. Both effects were associated with a profound and significant reduction in glycerol release and lesion size, and correlated with improved neurological recovery.
The present study shows that Ro5-4864 has a favorable effect on the fate of injured brain, presumably mediated by improvement of metabolism. It further suggests that improvement of metabolism may contribute to ICP relief.
通过调节 18 kDa 转位蛋白介导的线粒体膜通透性降低，研究 Ro5-4864 对创伤后脑水肿和代谢危机的可能影响。
对 Sprague-Dawley 大鼠进行皮质挫伤后腹腔注射二甲基亚砜（载体）或 Ro5-4864 ，进行脑微透析和颅内压（ICP）监测，并与线粒体损伤的定量评估、损伤组织的水含量、改良神经严重程度评分和病变大小进行相关性分析。
Ro5-4864 可显著降低 ICP，与改善的脑代谢相关，表现为伤侧区域葡萄糖和丙酮酸浓度显著升高，乳酸浓度降低。降低的 ICP 与损伤组织中降低的水含量相关；改善的代谢与电子显微镜下减少的线粒体损伤相关。这两种作用均与甘油释放和病变体积的显著减少以及神经功能的显著恢复相关。
本研究表明，Ro5-4864 对损伤大脑的预后有良好影响，可能通过改善代谢来介导。进一步提示改善代谢可能有助于缓解 ICP。
