Xiong Ye, Chopp Michael, Lee Chuan-Pu
Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, USA.
Neurol Res. 2009 Jun;31(5):496-502. doi: 10.1179/174313208X353703. Epub 2008 Dec 18.
Mitochondria play a central role in cellular energetics, calcium homeostasis and apoptosis. Our previous study demonstrates traumatic brain injury induces brain mitochondrial dysfunction after injury. Preservation and/or restoration of mitochondrial function may be one of the strategies for neuroprotection. Erythropoietin, a hormone for erythropoiesis, also provides tissue protection against traumatic brain injury and stroke. The present study was undertaken to evaluate the effect of erythropoietin on traumatic brain injury-induced brain mitochondrial dysfunction. Traumatic brain injury decreased rates of respiration at the active state (state 3), increased that at the resting state (state 4) and consequently decreased respiratory control index (state 3/state 4 ratio) and the efficiency of ATP synthesis (the amount of ADP phosphorylated by inorganic phosphate divided by the amount of oxygen consumed during state 3 respiration). Erythropoietin administered intraperitoneally 30 minutes post-injury at 1000 U/kg partially improved mitochondrial function at day 1 post-injury. However, erythropoietin-induced improvement was not sustained at day 7 post-injury. Erythropoietin at 2000 or 5000 U/kg restored states 3 and 4 examined at day 1 post-injury to the sham levels. Consequently, the energy coupling capacities, such as respiratory control index and/or the efficiency of ATP synthesis, were also improved. The beneficial effect of erythropoietin at these doses persisted for at least 7 days post-injury. The beneficial effect of erythropoietin on brain mitochondrial function was observed with a wide therapeutic window from 5 minutes to 6 hours post-injury. Our data, for the first time, demonstrate that erythropoietin treatment restores brain mitochondrial function after traumatic brain injury, which will enhance cellular energy generation and reduce oxidative stress, strongly supporting erythropoietin as a promising agent for the therapeutic treatment of traumatic brain injury.
线粒体在细胞能量代谢、钙稳态和细胞凋亡中起着核心作用。我们之前的研究表明，创伤性脑损伤会导致损伤后脑线粒体功能障碍。保留和/或恢复线粒体功能可能是神经保护的策略之一。促红细胞生成素是一种促进红细胞生成的激素，也能为创伤性脑损伤和中风提供组织保护。本研究旨在评估促红细胞生成素对创伤性脑损伤诱导的脑线粒体功能障碍的影响。创伤性脑损伤降低了活跃状态（状态3）下的呼吸速率，增加了静止状态（状态4）下的呼吸速率，从而降低了呼吸控制指数（状态3/状态4比值）和ATP合成效率（无机磷酸磷酸化的ADP量除以状态3呼吸期间消耗的氧量）。损伤后30分钟腹腔注射1000 U/kg的促红细胞生成素可在损伤后第1天部分改善线粒体功能。然而，促红细胞生成素诱导的改善在损伤后第7天未持续。2000或5000 U/kg的促红细胞生成素将损伤后第1天检测的状态3和状态4恢复到假手术水平。因此，诸如呼吸控制指数和/或ATP合成效率等能量偶联能力也得到了改善。这些剂量的促红细胞生成素的有益作用在损伤后至少持续7天。在损伤后5分钟至6小时的宽治疗窗内观察到促红细胞生成素对脑线粒体功能的有益作用。我们的数据首次证明，促红细胞生成素治疗可恢复创伤性脑损伤后的脑线粒体功能，这将增强细胞能量生成并减少氧化应激，有力地支持促红细胞生成素作为创伤性脑损伤治疗的有前景的药物。
