Pathway Analysis Reveals Common Pro-Survival Mechanisms of Metyrapone and Carbenoxolone after Traumatic Brain Injury
Pathway Analysis Reveals Common Pro-Survival Mechanisms of Metyrapone and Carbenoxolone after Traumatic Brain Injury
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DOI：
10.1371/journal.pone.0053230
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发表时间：
2013-01-09
期刊：
影响因子：
3.7
通讯作者：
Prough, Donald S.
中科院分区：
文献类型：
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作者：
Hellmich, Helen L.;Rojo, Daniel R.;Prough, Donald S.
开发新的药物治疗创伤性脑损伤（TBI）需要阐明许多结构和功能不同的化合物的神经保护机制。为了验证我们的假设，即不同的神经保护药物在TBI后同样影响共同的基因靶点，我们比较了两种药物的作用，甲吡酮（MT）和甘珀酸（CB），虽然临床上用于非认知条件，但改善了大鼠和人类的学习和记忆。虽然在结构上不同，MT和CB都抑制一个共同的分子靶点，11 β羟类固醇脱氢酶1型，它将非活性可的松转化为皮质醇，从而有效地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损伤大鼠海马存活神经元的促存活作用相关。我们发现用MT或CB治疗TBI大鼠急性诱导海马神经元转录谱非常相似（即，在多个损伤诱导的细胞信号传导网络中基因表达的协调衰减）。我们还发现，在较小程度上，细胞存活信号的协调增加。MT和CB改变损伤诱导的基因表达的分析提供了对各自保护作用的额外见解。两种药物均减弱了细胞凋亡、死亡受体和应激信号传导途径中的基因以及氧化磷酸化途径中的多个基因的表达，如NADH脱氢酶（复合物1）、细胞色素c氧化酶（复合物IV）和ATP合酶（复合物V）的亚基。这表明线粒体功能的总体抑制。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，减少促存活基因的表达可能是神经保护性治疗效果的标志。
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, 11 beta 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.