Up-Regulation of PKR Signaling Pathway by Ethanol Displays an Age of Onset-Dependent Relationship

Jeremy W Duncan; Shakevia Johnson; Xiao Zhang; Baoying Zheng; Jia Luo; Xiao-Ming Ou; Craig A Stockmeier; Jun Ming Wang

doi:10.1111/acer.13209

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Up-Regulation of PKR Signaling Pathway by Ethanol Displays an Age of Onset-Dependent Relationship

Journal article

Open access

Peer reviewed

Up-Regulation of PKR Signaling Pathway by Ethanol Displays an Age of Onset-Dependent Relationship

Jeremy W Duncan, Shakevia Johnson, Xiao Zhang, Baoying Zheng, Jia Luo, Xiao-Ming Ou, Craig A Stockmeier and Jun Ming Wang

Alcoholism, clinical and experimental research, Vol.40(11), pp.2320-2328

11/2016

DOI: 10.1111/acer.13209

PMCID: PMC5446081

PMID: 27647657

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https://www.ncbi.nlm.nih.gov/pmc/articles/5446081View

Open Access

Abstract

Ethanol (EtOH) neurotoxicity can result in devastating effects on brain and behavior by disrupting homeostatic signaling cascades and inducing cell death. One such mechanism involves double-stranded RNA activated protein kinase (PKR), a primary regulator of protein translation and cell viability in the presence of a virus or other external stimuli. EtOH-mediated up-regulation of interferon-gamma (IFN-γ; the oxidative stress-inducible regulator of PKR), PKR, and its target, p53, are still being fully elucidated. Using Western blot analysis, immunofluorescence, and linear regression analyses, changes in the IFN-γ-PKR-p53 pathway following chronic EtOH treatment in the frontal cortex of rodents were examined. The role of PKR on cell viability was also assessed in EtOH-treated cells using PKR overexpression vector and PKR inhibitor (PKRI). In rats chronically fed EtOH, PKR, phosphorylated PKR (p-PKR), IFN-γ, and p53 were significantly increased following chronic EtOH exposure. Linear regression revealed a significant correlation between IFN-γ and p-PKR protein levels, as well as p-PKR expression and age of EtOH exposure. Overexpression of PKR resulted in greater cell death, while use of PKRI enhanced cell viability in EtOH-treated cells. Chronic EtOH exposure activates the IFN-γ-PKR-p53 pathway in the frontal cortex of rodents. p-PKR expression is greater in brains of rodents exposed to EtOH at earlier ages compared to later life, suggesting a mechanism by which young brains could be more susceptible to EtOH-related brain injury. PKR and p-PKR were also colocalized in neurons and astrocytes of rats. This study provides additional insight into biochemical mechanisms underlying alcohol use disorder related neuropathology and warrants further investigation of PKR as a potential pharmacotherapeutic target to combat EtOH-related neurotoxicity, loss of protein translation and brain injury.

Age of Onset

Animals

Cell Death - drug effects

Cell Line, Tumor

Central Nervous System Depressants - pharmacology

eIF-2 Kinase - metabolism

Ethanol - pharmacology

Humans

Interferon-gamma - metabolism

Male

Prefrontal Cortex - drug effects

Prefrontal Cortex - metabolism

Random Allocation

Rats, Wistar

Signal Transduction - drug effects

Tumor Suppressor Protein p53 - metabolism

Up-Regulation - drug effects

Details

Title: Subtitle: Up-Regulation of PKR Signaling Pathway by Ethanol Displays an Age of Onset-Dependent Relationship
Creators: Jeremy W Duncan - University of Mississippi Medical Center
Shakevia Johnson - University of Mississippi Medical Center
Xiao Zhang - University of Mississippi Medical Center
Baoying Zheng - University of Mississippi Medical Center
Jia Luo - University of Kentucky
Xiao-Ming Ou - University of Mississippi Medical Center
Craig A Stockmeier - University of Mississippi Medical Center
Jun Ming Wang - University of Mississippi Medical Center
Resource Type: Journal article
Publication Details: Alcoholism, clinical and experimental research, Vol.40(11), pp.2320-2328
DOI: 10.1111/acer.13209
PMID: 27647657
PMCID: PMC5446081
NLM abbreviation: Alcohol Clin Exp Res
ISSN: 0145-6008
eISSN: 1530-0277
Publisher: Wiley
Grant note: R01 AA020103 / NIAAA NIH HHS R24 AA015512 / NIAAA NIH HHS P30 GM103328 / NIGMS NIH HHS U24 AA015512 / NIAAA NIH HHS
Language: English
Date published: 11/2016
Academic Unit: Pathology
Record Identifier: 9984201246302771

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