title: 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.
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.
authors.affiliation: Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Duncan
authors.affiliation: Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Niping
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Shakevia
authors.initials: S
authors.lastname: Johnson
authors.affiliation: Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Sharonda
authors.initials: S
authors.lastname: Harris
authors.affiliation: Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Chinelo
authors.initials: C
authors.lastname: Udemgba
authors.affiliation: Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Ou
authors.affiliation: Technion-Rappaport Family Faculty of Medicine, Eve Topf Center of Excellence, For Neurodegenerative Diseases Research, Haifa, 31096, Israel.
authors.forename: Moussa B
authors.initials: MB
authors.lastname: Youdim
authors.affiliation: Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Stockmeier
authors.affiliation: Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA; Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA. Electronic address: jwang@umc.edu.
authors.forename: Jun Ming
authors.initials: JM
authors.lastname: Wang
mesh_terms: D000818:Animals; D063425:Binge Drinking / Q000201:enzymology*; D001927:Brain Diseases / Q000139:chemically induced / Q000517:prevention & control*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000431:Ethanol / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008297:Male; D008995:Monoamine Oxidase / Q000235:genetics*; D008996:Monoamine Oxidase Inhibitors / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000494:pharmacology; D020258:Neurotoxicity Syndromes / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000187:drug effects* / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002492:Central Nervous System Depressants; C569356:KLF11 protein, rat; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D015534:Trans-Activators; D000431:Ethanol; D008995:Monoamine Oxidase; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: BDNF; Binge ethanol; Caspase-3; Kruppel-like factor 11 (KLF11); Monoamine oxidase (MAO); Neurotoxicity; Protein oxidation; Rats; Transcription factor