PMID- 30114398
OWN - NLM
STAT- MEDLINE
DCOM- 20190321
LR  - 20211204
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 356
DP  - 2018 Oct 1
TI  - Binge ethanol exposure induces endoplasmic reticulum stress in the brain of adult 
      mice.
PG  - 172-181
LID - S0041-008X(18)30373-9 [pii]
LID - 10.1016/j.taap.2018.08.006 [doi]
AB  - Alcohol abuse causes brain damage and cognitive dysfunction. However, the 
      underlying mechanisms remain elusive. Endoplasmic reticulum (ER) acts as 
      machinery to ensure the proper folding of newly synthesized proteins. The 
      perturbation of ER, i.e., ER stress, plays a pivotal role in some neurological 
      disorders. Mammalian target of rapamycin (mTOR), a serine/threonine kinase, is 
      involved in the regulation of ER stress. The current study sought to determine 
      whether binge ethanol exposure induces ER stress in adult mouse brain and the 
      role mTOR signaling during this process. Adult C57BL6 mice received binge ethanol 
      exposure by daily gavage (5 g/kg, 25% ethanol w/v) for 1, 5 or 10 days. Binge 
      ethanol exposure caused neurodegeneration and neuroinflammation after 5 days of 
      exposure, and a concomitant increase of ER stress and inhibition of mTOR. 
      However, ethanol exposure did not significantly alter spatial learning and 
      memory, and spontaneous locomotor activity. Ethanol treatment induced ER stress 
      and the death of cultured neuronal cells. Cotreatment with an ER stress 
      inhibitor, sodium 4-phenylbutyrate (4-PBA) significantly diminished 
      ethanol-induced ER stress and neuronal apoptosis, suggesting that ER stress 
      contributes to ethanol-induced neurodegeneration. Furthermore, the blockage of 
      mTOR activity by rapamycin increased ER stress in cultured neuronal cells; 
      whereas the activation or inhibition of ER stress by tunicamycin or 4-PBA 
      respectively had little effects on mTOR signaling. These results suggested that 
      mTOR signaling is upstream of ER stress and may thereby mediate ethanol-induced 
      ER stress.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Wang, Yongchao
AU  - Wang Y
AD  - Department of Pharmacology and Nutritional Sciences, University of Kentucky 
      College of Medicine, Lexington, KY 40536, United States.
FAU - Wang, Xin
AU  - Wang X
AD  - Department of Pharmacology and Nutritional Sciences, University of Kentucky 
      College of Medicine, Lexington, KY 40536, United States; Center for Health 
      Services Research, University of Kentucky College of Medicine, Lexington, KY 
      40536, United States.
FAU - Li, Hui
AU  - Li H
AD  - Department of Pharmacology and Nutritional Sciences, University of Kentucky 
      College of Medicine, Lexington, KY 40536, United States.
FAU - Xu, Mei
AU  - Xu M
AD  - Department of Pharmacology and Nutritional Sciences, University of Kentucky 
      College of Medicine, Lexington, KY 40536, United States.
FAU - Frank, Jacqueline
AU  - Frank J
AD  - Department of Pharmacology and Nutritional Sciences, University of Kentucky 
      College of Medicine, Lexington, KY 40536, United States.
FAU - Luo, Jia
AU  - Luo J
AD  - Department of Pharmacology and Nutritional Sciences, University of Kentucky 
      College of Medicine, Lexington, KY 40536, United States. Electronic address: 
      jialuo888@uky.edu.
LA  - eng
GR  - I01 BX001721/BX/BLRD VA/United States
GR  - R01 AA015407/AA/NIAAA NIH HHS/United States
GR  - R01 AA017226/AA/NIAAA NIH HHS/United States
GR  - T32 DK007778/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20180813
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Central Nervous System Depressants)
RN  - 3K9958V90M (Ethanol)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Behavior, Animal/drug effects
MH  - Binge Drinking/*pathology/psychology
MH  - Brain/drug effects/*pathology
MH  - Central Nervous System Depressants/toxicity
MH  - Endoplasmic Reticulum Stress/*drug effects
MH  - Ethanol/toxicity
MH  - Male
MH  - Maze Learning/drug effects
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neurodegenerative Diseases/chemically induced/pathology
MH  - Psychomotor Performance/drug effects
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/biosynthesis/drug effects
PMC - PMC6258015
MID - NIHMS1510962
OTO - NOTNLM
OT  - Alcohol use isorder
OT  - Brain damage
OT  - Endoplasmic reticulum tress
OT  - Neurodegeneration
OT  - Oxidative stress
OT  - mTOR signaling
COIS- All authors have read and approved the manuscript. We do not have conflict of 
      interest. This manuscript has not been and will not be submitted or published in 
      other scientific journals in whole or in part while it is under the consideration 
      of Toxicol Appl Pharmacol
EDAT- 2018/08/17 06:00
MHDA- 2019/03/22 06:00
PMCR- 2019/10/01
CRDT- 2018/08/17 06:00
PHST- 2018/04/19 00:00 [received]
PHST- 2018/08/02 00:00 [revised]
PHST- 2018/08/11 00:00 [accepted]
PHST- 2018/08/17 06:00 [pubmed]
PHST- 2019/03/22 06:00 [medline]
PHST- 2018/08/17 06:00 [entrez]
PHST- 2019/10/01 00:00 [pmc-release]
AID - S0041-008X(18)30373-9 [pii]
AID - 10.1016/j.taap.2018.08.006 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2018 Oct 1;356:172-181. doi: 10.1016/j.taap.2018.08.006. 
      Epub 2018 Aug 13.