Differential effects of the mitochondrial uncoupling agent, 2,4-dinitrophenol, or the nitroxide antioxidant, Tempol, on synaptic or nonsynaptic mitochondria after spinal cord injury.
Differential effects of the mitochondrial uncoupling agent, 2,4-dinitrophenol, or the nitroxide antioxidant, Tempol, on synaptic or nonsynaptic mitochondria after spinal cord injury.
复制标题
DOI：
10.1002/jnr.21814
复制
发表时间：
2009-01
影响因子：
4.2
通讯作者：
Rabchevsky AG
中科院分区：
文献类型：
--
作者：
Patel SP;Sullivan PG;Pandya JD;Rabchevsky AG
我们最近记录了挫伤性脊髓损伤（SCI）后超过24小时线粒体功能障碍的进展性质，但其潜在机制尚未阐明。我们研究了针对两种不同的可能机制的线粒体功能障碍的影响，通过使用线粒体解偶联剂2，4-二硝基苯酚（2，4-DNP）或硝基氧抗氧化剂Tempol在大鼠挫伤后SCI。这项研究的一个新的方面是，所有的评估都在突触体（神经元）和非突触体（神经胶质和神经元索马）衍生的线粒体损伤后24小时。线粒体解偶联剂靶向损伤后线粒体中的Ca 2+循环和随后的活性氧产生。当2，4-DNP被注射15和30分钟后损伤，线粒体功能被保存在这两个群体相比，车辆治疗的大鼠，而1小时伤后治疗无效。相反，针对过氧亚硝酸盐与Tempol未能保持正常的生物能在突触线粒体，但在非突触线粒体损伤后15分钟给药时是有效的。当在损伤后15和30分钟给药时，增加的羟基壬烯醛、3-NT和蛋白质羰基水平被2，4-DNP显著降低，而Tempol在SCI后仅降低3-NT和蛋白质羰基。尽管有这样的抗氧化作用，但只有2，4-DNP能有效防止线粒体功能障碍，这表明线粒体Ca 2+超载可能是SCI后急性线粒体损伤的关键机制。总的来说，我们的观察表明线粒体功能障碍在SCI神经病理学中起着重要作用。此外，他们表明，针对不同线粒体群体的组合治疗方法在促进急性SCI后的神经保护方面具有巨大潜力。
We recently documented the progressive nature of mitochondrial dysfunction over 24 hr after contusion spinal cord injury (SCI), but the underlying mechanism has not been elucidated. We investigated the effects of targeting two distinct possible mechanisms of mitochondrial dysfunction by using the mitochondrial uncoupler 2,4-dinitrophenol (2,4-DNP) or the nitroxide antioxidant Tempol after contusion SCI in rats. A novel aspect of this study was that all assessments were made in both synaptosomal (neuronal)- and nonsynaptosomal (glial and neuronal soma)-derived mitochondria 24 hr after injury. Mitochondrial uncouplers target Ca2+ cycling and subsequent reactive oxygen species production in mitochondria after injury. When 2,4-DNP was injected 15 and 30 min after injury, mitochondrial function was preserved in both populations compared with vehicle-treated rats, whereas 1 hr postinjury treatment was ineffective. Conversely, targeting peroxynitrite with Tempol failed to maintain normal bioenergetics in synaptic mitochondria, but was effective in nonsynaptic mitochondria when administered 15 min after injury. When administered at 15 and 30 min after injury, increased hydroxynonenal, 3-NT, and protein carbonyl levels were significantly reduced by 2,4-DNP, whereas Tempol only reduced 3-NT and protein carbonyls after SCI. Despite such antioxidant effects, only 2,4-DNP was effective in preventing mitochondrial dysfunction, indicating that mitochondrial Ca2+ overload may be the key mechanism involved in acute mitochondrial damage after SCI. Collectively, our observations demonstrate the significant role that mitochondrial dysfunction plays in SCI neuropathology. Moreover, they indicate that combinatorial therapeutic approaches targeting different populations of mitochondria holds great potential in fostering neuroprotection after acute SCI.