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

Helen Hellmich, Daniel R. Rojo, Maria Micci, Stacy Sell, Deborah R. Boone, Jeanna M. Crookshanks, Douglas Dewitt, Brent E. Masel, Donald Prough

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere53230
JournalPLoS One
Volume8
Issue number1
DOIs
StatePublished - Jan 9 2013

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metyrapone
Carbenoxolone
Metyrapone
Brain
Genes
brain
drugs
Survival
Oxidative Phosphorylation
Neuroprotective Agents
Rats
Gene Expression
oxidative phosphorylation
Gene expression
Pharmaceutical Preparations
gene expression
Neurons
protective effect
11-beta-Hydroxysteroid Dehydrogenases
rats

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Pathway Analysis Reveals Common Pro-Survival Mechanisms of Metyrapone and Carbenoxolone after Traumatic Brain Injury. / Hellmich, Helen; Rojo, Daniel R.; Micci, Maria; Sell, Stacy; Boone, Deborah R.; Crookshanks, Jeanna M.; Dewitt, Douglas; Masel, Brent E.; Prough, Donald.

In: PLoS One, Vol. 8, No. 1, e53230, 09.01.2013.

Research output: Contribution to journalArticle

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