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.
Highlights
To date, all pharmacotherapeutic agents in clinical trials for treatment of traumatic brain injury (TBI) have failed to show efficacy, suggesting a need for more effective pre-clinical screening of novel therapeutic compounds [1]
We found that the effects of both drugs at 24 h, with some exceptions, were more divergent, i.e., fewer common gene targets were affected by both drugs at this later time point, which prompted us to focus on common drug effects at 4 h
The overall effect of both drugs was to prevent the injury-induced upregulation of multiple genes in the oxidative phosphorylation (OxPhos) pathway; both drugs attenuated expression of separate genes associated with subunits of cytochrome c oxidase (Complex IV) and ATP synthase (Complex V), suggesting an overall inhibition of mitochondrial function. This is the first molecular comparison of the potential mechanisms underlying the neuroprotective effects of MT and CB, and of the molecular targets and associated cell signaling pathways that mediate their protective effects on hippocampal neurons after TBI
Summary
All pharmacotherapeutic agents in clinical trials for treatment of traumatic brain injury (TBI) have failed to show efficacy, suggesting a need for more effective pre-clinical screening of novel therapeutic compounds [1]. Our screening efforts focused on compounds that provide neuroprotection in the hippocampus [2]. The large group of compounds that have been shown to reduce neuronal damage in animal models of hippocampal injury are structurally and functionally diverse and target multiple cell signaling pathways [3], their common neuroprotective effects suggest a common mechanism of action. Comparing common changes in cell signaling pathways generated by otherwise diverse neuroprotective compounds could provide useful mechanistic insights into the essential elements of neuroprotection
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