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Pathway Analysis Reveals Common Pro-Survival Mechanisms of Metyrapone and Carbenoxolone after Traumatic Brain Injury

Overview of attention for article published in PLOS ONE, January 2013
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Title
Pathway Analysis Reveals Common Pro-Survival Mechanisms of Metyrapone and Carbenoxolone after Traumatic Brain Injury
Published in
PLOS ONE, January 2013
DOI 10.1371/journal.pone.0053230
Pubmed ID
Authors

Helen L. Hellmich, Daniel R. Rojo, Maria-Adelaide Micci, Stacy L. Sell, Deborah R. Boone, Jeanna M. Crookshanks, Douglas S. DeWitt, Brent E. Masel, Donald S. Prough

Abstract

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.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 37 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 3%
United States 1 3%
Belgium 1 3%
Unknown 34 92%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 8 22%
Student > Master 4 11%
Student > Doctoral Student 3 8%
Student > Bachelor 3 8%
Professor > Associate Professor 3 8%
Other 7 19%
Unknown 9 24%
Readers by discipline Count As %
Neuroscience 8 22%
Medicine and Dentistry 5 14%
Biochemistry, Genetics and Molecular Biology 3 8%
Agricultural and Biological Sciences 3 8%
Psychology 3 8%
Other 3 8%
Unknown 12 32%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 06 December 2013.
All research outputs
#18,325,190
of 22,691,736 outputs
Outputs from PLOS ONE
#153,972
of 193,720 outputs
Outputs of similar age
#219,295
of 282,271 outputs
Outputs of similar age from PLOS ONE
#3,599
of 4,894 outputs
Altmetric has tracked 22,691,736 research outputs across all sources so far. This one is in the 11th percentile – i.e., 11% of other outputs scored the same or lower than it.
So far Altmetric has tracked 193,720 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 15.0. This one is in the 10th percentile – i.e., 10% of its peers scored the same or lower than it.
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