Pathway Analysis Reveals Common Pro-Survival Mechanisms of Metyrapone and Carbenoxolone after Traumatic Brain Injury
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.
World Neurosurgery 09/2013; DOI:10.1016/j.wneu.2013.09.009 · 2.42 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Traumatic encephalopathy has emerged as a significant public health problem. It is believed that traumatic encephalopathy is caused by exposure to repetitive brain trauma prior to the initial symptoms of neurodegenerative disease. Therefore, prevention is important for the disease. The PI3K/AKT/PTEN (phosphoinositide-3 kinase/AKT/phosphatase and tensin homologue deleted on chromosome 10) pathway has been shown to play a pivotal role in neuroprotection, enhancing cell survival by stimulating cell proliferation and inhibiting apoptosis. PTEN negatively regulates the PI3K/AKT pathways through its lipid phosphatase activity. Although PTEN has been discovered as a tumor suppressor, PTEN is also involved in several other diseases, including diabetes and Alzheimer's disease. Dietary fish oil rich in polyunsaturated fatty acids may induce the PTEN expression by activation of peroxisome proliferator-activated receptor. Supplementation of these natural compounds may provide a new therapeutic approach to the brain disorder. We review recent studies on the features of several diets and the signaling pathways involved in traumatic encephalopathy.Alzheimer's Research and Therapy 09/2013; 5(5):42. DOI:10.1186/alzrt208 · 3.50 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: High mobility group box 1 (HMGB1) is an evolutionarily conserved protein, and is constitutively expressed in virtually all types of cells. Infection and injury converge on common inflammatory responses that are mediated by HMGB1 secreted from immunologically activated immune cells or passively released from pathologically damaged cells. Herein we review the emerging molecular mechanisms underlying the regulation of pathogen-associated molecular patterns (PAMPs)-induced HMGB1 secretion, and summarize many HMGB1-targeting therapeutic strategies for the treatment of infection- and injury-elicited inflammatory diseases. It may well be possible to develop strategies that specifically attenuate damage-associated molecular patterns (DAMPs)-mediated inflammatory responses without compromising the PAMPs-mediated innate immunity for the clinical management of infection- and injury-elicited inflammatory diseases.Expert Review of Clinical Immunology 04/2014; DOI:10.1586/1744666X.2014.909730 · 3.34 Impact Factor