title: Heavy ethanol consumption aggravates the ischemic cerebral injury by inhibiting ALDH2.
abstract: BACKGROUND
  Heavy ethanol consumption is widely accepted as a risk for ischemic stroke. The molecular mechanisms of ethanol-induced brain injury have not been fully understood.
  
  
  OBJECTIVE
  This study aims to find out the mechanism of the ischemic cerebral injury.
  
  
  METHODS
  We used Sprague-Dawley rats with transient middle cerebral artery occlusion for acute experiment and stroke-prone spontaneously hypertensive rats for long-term experiment in vivo, and oxygen-glucose deprivation model in vitro to define a detrimental effect of different doses of ethanol on ischemic stroke injury. We also used mitochondrial aldehyde dehydrogenase 2 knockdown/overexpression or inhibitor/activator to investigate mechanism of the adverse effects of ethanol.
  
  
  RESULTS
  High-dose ethanol (36% of calorie derived from ethanol) significantly increased the infarct size in rats (P < 0·01) and decreased the survival time of stroke-prone spontaneously hypertensive rats by about 20%. Six-week treatment with high-dose ethanol changed a distribution of isoelectric point of aldehyde dehydrogenase 2 and inhibited aldehyde dehydrogenase 2 activity in brain. High dose of ethanol increased the cerebral acetaldehyde level, and increased 4-hydroxy-2-nonenal and malondialdehyde in serum of rats with middle cerebral artery occlusion. The activator of aldehyde dehydrogenase 2, Alda-1 abolished neuronal cells death and ischemic injury induced by ethanol and the inhibitor reversed the injurious effects. An overexpression of aldehyde dehydrogenase 2 completely abolished the increased infarct size and neurological deficit score by ethanol. Conversely, knockdown of aldehyde dehydrogenase 2 increased the infarct size and exaggerated the cerebral injury induced by ethanol.
  
  
  CONCLUSIONS
  High concentrations of ethanol aggravate cerebral injury by inhibiting of aldehyde dehydrogenase 2 and inducing excess accumulation of aldehydes.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.|Department of Pharmacy & Medical Appliances, Hangzhou Sanatorium of PLA, Hangzhou, Zhejiang, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.|Department of Pharmacology, Wuxi Higher Health Vocational Technology School, Wuxi, Jiangsu, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.|Department of Pharmacy, Jinan Military General Hospital, Jinan, Shandong, China.
authors.forename: Jin-Min
authors.initials: JM
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.|Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Yan-Qiong
authors.initials: YQ
authors.lastname: Cheng
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.|Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Qian
authors.affiliation: Division of Cardiology, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Ding-Feng
authors.initials: DF
authors.lastname: Su
authors.affiliation: School of Medicine, Shenzhen University, Shenzhen, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Luan
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Ai-Jun
authors.initials: AJ
authors.lastname: Liu
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002492:Central Nervous System Depressants / Q000633:toxicity*; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity*; D005947:Glucose / Q000172:deficiency; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D016716:PC12 Cells; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000201:enzymology* / Q000473:pathology
chemical_list: D002492:Central Nervous System Depressants; D024101:Mitochondrial Proteins; D000431:Ethanol; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D005947:Glucose
keywords: 4-HNE; ALDH2; acetaldehyde; heavy ethanol consumption; ischemic stroke; risk factor