PMID- 29581524
OWN - NLM
STAT- MEDLINE
DCOM- 20191025
LR  - 20240326
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 8
IP  - 1
DP  - 2018 Mar 26
TI  - Exercise Mitigates Alcohol Induced Endoplasmic Reticulum Stress Mediated 
      Cognitive Impairment through ATF6-Herp Signaling.
PG  - 5158
LID - 10.1038/s41598-018-23568-z [doi]
LID - 5158
AB  - Chronic ethanol/alcohol (AL) dosing causes an elevation in homocysteine (Hcy) 
      levels, which leads to the condition known as Hyperhomocysteinemia (HHcy). HHcy 
      enhances oxidative stress and blood-brain-barrier (BBB) disruption through 
      modulation of endoplasmic reticulum (ER) stress; in part by epigenetic 
      alternation, leading to cognitive impairment. Clinicians have recommended 
      exercise as a therapy; however, its protective effect on cognitive functions has 
      not been fully explored. The present study was designed to observe the protective 
      effects of exercise (EX) against alcohol-induced epigenetic and molecular 
      alterations leading to cerebrovascular dysfunction. Wild-type mice were subjected 
      to AL administration (1.5 g/kg-bw) and subsequent treadmill EX for 12 weeks 
      (5 day/week@7-11 m/min). AL affected mouse brain through increases in oxidative 
      and ER stress markers, SAHH and DNMTs alternation, while decreases in CBS, CSE, 
      MTHFR, tight-junction proteins and cellular H(2)S levels. Mechanistic study 
      revealed that AL increased epigenetic DNA hypomethylation of Herp promoter. BBB 
      dysfunction and cognitive impairment were observed in the AL treated mice. AL 
      mediated transcriptional changes were abolished by administration of ER stress 
      inhibitor DTT. In conclusion, exercise restored Hcy and H(2)S to basal levels 
      while ameliorating AL-induced ER stress, diminishing BBB dysfunction and 
      improving cognitive function via ATF6-Herp-signaling. EX showed its protective 
      efficacy against AL-induced neurotoxicity.
FAU - George, Akash K
AU  - George AK
AD  - Department of Physiology, University of Louisville School of medicine, 
      Louisville, KY, 40202, USA.
FAU - Behera, Jyotirmaya
AU  - Behera J
AD  - Department of Physiology, University of Louisville School of medicine, 
      Louisville, KY, 40202, USA.
FAU - Kelly, Kimberly E
AU  - Kelly KE
AD  - Department of Physiology, University of Louisville School of medicine, 
      Louisville, KY, 40202, USA.
FAU - Mondal, Nandan K
AU  - Mondal NK
AD  - Department of Physiology, University of Louisville School of medicine, 
      Louisville, KY, 40202, USA.
FAU - Richardson, Kennedy P
AU  - Richardson KP
AD  - Department of Physiology, University of Louisville School of medicine, 
      Louisville, KY, 40202, USA.
FAU - Tyagi, Neetu
AU  - Tyagi N
AD  - Department of Physiology, University of Louisville School of medicine, 
      Louisville, KY, 40202, USA. n0tyag01@louisville.edu.
LA  - eng
GR  - R01 AR067667/AR/NIAMS NIH HHS/United States
GR  - R01 HL107640/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180326
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Activating Transcription Factor 6)
RN  - 0 (Atf6 protein, mouse)
RN  - 0 (Herpud1 protein, mouse)
RN  - 0 (Membrane Proteins)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 3K9958V90M (Ethanol)
SB  - IM
MH  - Activating Transcription Factor 6/*metabolism
MH  - Analysis of Variance
MH  - Animals
MH  - Behavior, Animal
MH  - Blood Pressure/physiology
MH  - Blood-Brain Barrier/physiopathology
MH  - Capillary Permeability/physiology
MH  - Cerebrovascular Circulation/physiology
MH  - Cognitive Dysfunction/*metabolism
MH  - Endoplasmic Reticulum Stress/*physiology
MH  - Epigenesis, Genetic/physiology
MH  - Ethanol/administration & dosage/adverse effects/*metabolism
MH  - Exercise Test
MH  - Exercise Therapy
MH  - Homocysteine/metabolism
MH  - Hyperhomocysteinemia/chemically induced/therapy
MH  - Male
MH  - Membrane Proteins/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Models, Animal
MH  - Normal Distribution
MH  - Oxidative Stress/physiology
MH  - Physical Conditioning, Animal/*physiology
PMC - PMC5980102
COIS- The authors declare no competing interests.
EDAT- 2018/03/28 06:00
MHDA- 2019/10/28 06:00
PMCR- 2018/03/26
CRDT- 2018/03/28 06:00
PHST- 2018/01/30 00:00 [received]
PHST- 2018/03/13 00:00 [accepted]
PHST- 2018/03/28 06:00 [entrez]
PHST- 2018/03/28 06:00 [pubmed]
PHST- 2019/10/28 06:00 [medline]
PHST- 2018/03/26 00:00 [pmc-release]
AID - 10.1038/s41598-018-23568-z [pii]
AID - 23568 [pii]
AID - 10.1038/s41598-018-23568-z [doi]
PST - epublish
SO  - Sci Rep. 2018 Mar 26;8(1):5158. doi: 10.1038/s41598-018-23568-z.