Pretreatment with the ALDH2 agonist Alda-1 reduces intestinal injury induced by ischaemia and reperfusion in mice

Clin Sci (Lond). 2017 Jun 1;131(11):1123-1136. doi: 10.1042/CS20170074. Epub 2017 Mar 21.

Abstract

Many studies demonstrate that activation of aldehyde dehydrogenase 2 (ALDH2) protects against oxidative stress via detoxification of cytotoxic aldehydes, and could attenuate cardiac, cerebral, lung and renal ischaemia-reperfusion (I/R) injuries. However, the effect of ALDH2 in intestinal I/R is unknown. The present study was set up to determine whether an ALDH2 agonist, Alda-1, could alleviate intestinal injury after gut I/R. In a mouse model of intestinal I/R injury, histological grading, proinflammatory cytokines, oxidative stress, cellular apoptosis, chemokine contents, ALDH2 activity, 4-hydroxy-trans-2-nonenal (4-HNE) and malondialdehyde (MDA) were evaluated. The results indicated that I/R treatment conferred elevation in pathological scores, proinflammatory cytokines, oxidative stress, cellular apoptosis and chemokine levels, accompanied by accumulated 4-HNE and MDA. No significant changes in ALDH2 activity were observed after I/R. However, Alda-1 pretreatment significantly decreased these injurious indicators, concomitant with up-regulated ALDH2 activity, and lessened 4-HNE and MDA accumulation. Taken together, our results implicate activation of ALDH2 by Alda-1 in the significant abatement intestinal I/R injury.

Keywords: 4-hydroxy-trans-2-nonenal; ALDH2; Alda-1; intestine; ischaemia–reperfusion injury; multiple organ dysfunction syndrome.

MeSH terms

  • Aldehyde Dehydrogenase, Mitochondrial / metabolism*
  • Aldehydes / metabolism
  • Animals
  • Apoptosis / drug effects
  • Benzamides / pharmacology
  • Benzamides / therapeutic use*
  • Benzodioxoles / pharmacology
  • Benzodioxoles / therapeutic use*
  • Chemokines / metabolism
  • Cytokines / metabolism
  • Drug Evaluation, Preclinical / methods
  • Enzyme Activation / drug effects
  • Inflammation Mediators / metabolism
  • Intestinal Diseases / metabolism
  • Intestinal Diseases / pathology
  • Intestinal Diseases / prevention & control*
  • Lung Diseases / metabolism
  • Lung Diseases / pathology
  • Lung Diseases / prevention & control
  • Male
  • Mice, Inbred C57BL
  • Oxidative Stress / drug effects
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control*
  • Toll-Like Receptor 4 / metabolism

Substances

  • Aldehydes
  • Benzamides
  • Benzodioxoles
  • Chemokines
  • Cytokines
  • Inflammation Mediators
  • N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • ALDH2 protein, mouse
  • Aldehyde Dehydrogenase, Mitochondrial