Binge ethanol exposure increases the Krüppel-like factor 11-monoamine oxidase (MAO) pathway in rats: Examining the use of MAO inhibitors to prevent ethanol-induced brain injury. (June 2016)

• Record Type: Journal Article
• Authors: Duncan, Jeremy W.; Zhang, Xiao; Wang, Niping; Johnson, Shakevia; Harris, Sharonda; Udemgba, Chinelo; Ou, Xiao-Ming; Youdim, Moussa B.; Stockmeier, Craig A.; Wang, Jun Ming
• Is Part Of: Neuropharmacology. Volume 105(2016)
• Page Start: 329
• Page End: 340
• Publication Date: 2016-06
• Subjects: Binge ethanol -- Rats -- Kruppel-like factor 11 (KLF11) -- Transcription factor -- Monoamine oxidase (MAO) -- Neurotoxicity -- Protein oxidation -- BDNF -- Caspase-3; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2016.01.024
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Binge drinking induces several neurotoxic consequences including oxidative stress and neurodegeneration. Because of these effects, drugs which prevent ethanol-induced damage to the brain may be clinically beneficial. In this study, we investigated the ethanol-mediated KLF11-MAO cell death cascade in the frontal cortex of Sprague–Dawley rats exposed to a modified Majchowicz 4-day binge ethanol model and control rats. Moreover, MAO inhibitors (MAOIs) were investigated for neuroprotective activity against binge ethanol. Binge ethanol-treated rats demonstrated a significant increase in KLF11, both MAO isoforms, protein oxidation and caspase-3, as well as a reduction in BDNF expression in the frontal cortex compared to control rats. MAOIs prevented these binge ethanol-induced changes, suggesting a neuroprotective benefit. Neither binge ethanol nor MAOI treatment significantly affected protein expression levels of the oxidative stress enzymes, SOD2 or catalase. Furthermore, ethanol-induced antinociception was enhanced following exposure to the 4-day ethanol binge. These results demonstrate that the KLF11-MAO pathway is activated by binge ethanol exposure and MAOIs are neuroprotective by preventing the binge ethanol-induced changes associated with this cell death cascade. This study supports KLF11-MAO as a mechanism of ethanol-induced neurotoxicity and cell death that could be targeted with MAOI drug therapy to alleviate alcohol-related brain injury. Further examination of MAOIs to reduce alcohol use disorder-related brain injury could provide pivotal insight to future pharmacotherapeutic opportunities. Highlights: The Krüppel-like factor 11-monoamine oxidase (KLF11-MAO) pathway is activated by binge ethanol exposure. Monoamine oxidase inhibitors (MAOIs) demonstrate neuroprotection by preventing binge ethanol-induced changes. Binge ethanol enhances markers of cell death/dysfunction such as caspase-3 and protein oxidation.