Time course of post-traumatic mitochondrial oxidative damage and dysfunction in a mouse model of focal traumatic brain injury: implications for neuroprotective therapy
Time course of post-traumatic mitochondrial oxidative damage and dysfunction in a mouse model of focal traumatic brain injury: implications for neuroprotective therapy
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DOI：
10.1038/sj.jcbfm.9600297
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发表时间：
2006-11-01
影响因子：
6.3
通讯作者：
Hall, Edward D.
中科院分区：
文献类型：
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作者：
Singh, Indrapal N.;Sullivan, Patrick G.;Hall, Edward D.
在本研究中，我们调查的假设，线粒体氧化损伤和功能障碍之前的神经元损失后，控制皮质撞击创伤性脑损伤（TBI）小鼠的发病。因此，我们评估了严重TBI后30分钟、1、3、6、12、24、48和72小时损伤皮层和海马中创伤后线粒体功能障碍的时间过程。损伤后30 min观察到电子传递系统与氧化磷酸化的偶联显著减少，随后在损伤后1 h恢复至基线。在3 h时观察到呼吸控制率的统计学显著（P < 0.0001）下降，在皮层和海马线粒体损伤后72 h的所有后续时间点均持续下降。在纯化的皮质线粒体中观察到的结构损伤包括严重肿胀的线粒体、嵴破坏和外膜破裂，表明线粒体渗透性转变。与这一发现相一致，皮层线粒体钙缓冲能力严重受损3小时后，损伤，并伴随着线粒体蛋白质氧化和脂质过氧化反应的显着增加。一个可能的致病作用，活性氮物种的快速增加，皮层线粒体3-硝基酪氨酸水平显示，早在30分钟后损伤。这些研究结果表明，创伤后氧化脂质和蛋白质损伤，介导的过氧亚硝酸盐的一部分，发生在线粒体伴随超微结构损伤和线粒体生物能量学的损害。数据还表明，特异性抑制过氧亚硝酸根（ONOO-）或ONOO-衍生自由基（例如ONOO-+ H+ -> ONOOH ->（NO2）-N-中心点+（OH）-O-中心点）的化合物对于治疗TBI可能特别有效，尽管这种神经保护方法的治疗窗口可能仅为3小时。
In the present study, we investigate the hypothesis that mitochondrial oxidative damage and dysfunction precede the onset of neuronal loss after controlled cortical impact traumatic brain injury (TBI) in mice. Accordingly, we evaluated the time course of post-traumatic mitochondrial dysfunction in the injured cortex and hippocampus at 30 mins, 1, 3, 6, 12, 24, 48, and 72 h after severe TBI. A significant decrease in the coupling of the electron transport system with oxidative phosphorylation was observed as early as 30 mins after injury, followed by a recovery to baseline at 1 h after injury. A statistically significant (P < 0.0001) decline in the respiratory control ratio was noted at 3 h, which persisted at all subsequent time-points up to 72 h after injury in both cortical and hippocampal mitochondria. Structural damage seen in purified cortical mitochondria included severely swollen mitochondria, a disruption of the cristae and rupture of outer membranes, indicative of mitochondrial permeability transition. Consistent with this finding, cortical mitochondrial calcium-buffering capacity was severely compromised by 3 h after injury, and accompanied by significant increases in mitochondrial protein oxidation and lipid peroxidation. A possible causative role for reactive nitrogen species was suggested by the rapid increase in cortical mitochondrial 3-nitrotyrosine levels shown as early as 30 mins after injury. These findings indicate that post-traumatic oxidative lipid and protein damage, mediated in part by peroxynitrite, occurs in mitochondria with concomitant ultrastructural damage and impairment of mitochondrial bioenergetics. The data also indicate that compounds which specifically scavenge peroxynitrite (ONOO-) or ONOO--derived radicals (e.g. ONOO-+ H+ -> ONOOH -> (NO2)-N-center dot + (OH)-O-center dot) may be particularly effective for the treatment of TBI, although the therapeutic window for this neuroprotective approach might only be 3 h.