Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America.
PLoS One. 2013;8(1):e53230. doi: 10.1371/journal.pone.0053230. Epub 2013 Jan 9.
Developing new pharmacotherapies for traumatic brain injury (TBI) requires elucidation of the neuroprotective mechanisms of many structurally and functionally diverse compounds. To test our hypothesis that diverse neuroprotective drugs similarly affect common gene targets after TBI, we compared the effects of two drugs, metyrapone (MT) and carbenoxolone (CB), which, though used clinically for noncognitive conditions, improved learning and memory in rats and humans. Although structurally different, both MT and CB inhibit a common molecular target, 11β hydroxysteroid dehydrogenase type 1, which converts inactive cortisone to cortisol, thereby effectively reducing glucocorticoid levels. We examined injury-induced signaling pathways to determine how the effects of these two compounds correlate with pro-survival effects in surviving neurons of the injured rat hippocampus. We found that treatment of TBI rats with MT or CB acutely induced in hippocampal neurons transcriptional profiles that were remarkably similar (i.e., a coordinated attenuation of gene expression across multiple injury-induced cell signaling networks). We also found, to a lesser extent, a coordinated increase in cell survival signals. Analysis of injury-induced gene expression altered by MT and CB provided additional insight into the protective effects of each. Both drugs attenuated expression of genes in the apoptosis, death receptor and stress signaling pathways, as well as multiple genes in the oxidative phosphorylation pathway such as subunits of NADH dehydrogenase (Complex1), cytochrome c oxidase (Complex IV) and ATP synthase (Complex V). This suggests an overall inhibition of mitochondrial function. Complex 1 is the primary source of reactive oxygen species in the mitochondrial oxidative phosphorylation pathway, thus linking the protective effects of these drugs to a reduction in oxidative stress. The net effect of the drug-induced transcriptional changes observed here indicates that suppressing expression of potentially harmful genes, and also, surprisingly, reduced expression of pro-survival genes may be a hallmark of neuroprotective therapeutic effects.
开发治疗创伤性脑损伤（TBI）的新药物疗法需要阐明许多结构和功能不同的化合物的神经保护机制。为了验证我们的假说，即多种神经保护药物在 TBI 后同样影响共同的基因靶点，我们比较了两种药物（美替拉酮（MT）和卡波氯铵（CB））的作用，尽管它们在临床上用于非认知疾病，但能改善大鼠和人类的学习和记忆。尽管结构不同，但 MT 和 CB 都抑制了一种共同的分子靶点，即 11β羟类固醇脱氢酶 1 型，它将无活性的皮质酮转化为皮质醇，从而有效降低糖皮质激素水平。我们研究了损伤诱导的信号通路，以确定这两种化合物的作用如何与受伤大鼠海马体中存活神经元的促生存作用相关。我们发现，用 MT 或 CB 治疗 TBI 大鼠会在海马神经元中急性诱导转录谱，这些转录谱非常相似（即，多个损伤诱导的细胞信号网络中的基因表达协调衰减）。我们还发现，存活信号的协调增加程度较小。对 MT 和 CB 改变的损伤诱导基因表达的分析提供了对每种药物保护作用的更多了解。两种药物都减弱了凋亡、死亡受体和应激信号通路中的基因表达，以及氧化磷酸化途径中的多个基因，如 NADH 脱氢酶（复合物 1）、细胞色素 c 氧化酶（复合物 4）和 ATP 合酶（复合物 5）的亚基。这表明线粒体功能总体受到抑制。复合物 1 是线粒体氧化磷酸化途径中活性氧的主要来源，因此将这些药物的保护作用与氧化应激的减少联系起来。这里观察到的药物诱导的转录变化的净效应表明，抑制潜在有害基因的表达，以及令人惊讶的是，促生存基因的表达减少，可能是神经保护治疗效果的标志。
