DUOX2, a common modulator in preventive effects of monoamine-based antidepressants on water immersion restraint stress- and indomethacin- induced gastric mucosal damage

Eur J Pharmacol. 2020 Jun 5;876:173058. doi: 10.1016/j.ejphar.2020.173058. Epub 2020 Mar 1.


Multiple kinds of monoamine-based antidepressants have been shown prophylactic effects in experimentally induced gastric ulcer. The loss of redox homeostasis plays a principle role in the development of peptic mucosal damage. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are one of the most important sources of reactive oxygen species within the gastrointestinal tract. It is unclear whether there are some common NADPH oxidases modulated by monoamine-based antidepressants in different gastric mucosal damage models. We explored the effects of selective serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine on the reactive oxygen species production and antioxidant capacity in the gastric mucosa of water immersion restraint (WIRS) or indomethacin treated rats, and examined the role of NADPH oxidases in the protective effects. Pretreated duloxetine prevented the increase of gastric mucosal NADPH oxidase activity and NADPH oxidase inhibitor apocynin dose-dependently protected gastric mucosa from damage by the two factors. Furthermore, dual oxidase 2 (DUOX2) and NADPH oxidase4 (NOX4) are involved in the protective effects of duloxetine in both models. We then examined NADPH oxidases expression modulated by the other monoamine-based antidepressants including selective serotonin reuptake inhibitor (SSRIs) fluoxetine, tricyclic agent (TCAs) amitriptyline and monoamine oxidase inhibitor (MAOs) moclobemide in the two models, and all the three antidepressants reduced the DUOX2 expression in the gastric mucosa. So DUOX2 was a common modulator in the preventive effects of all the monoamine-based antidepressants on WIRS- and indomethacin-induced gastric lesion. Our work provided a peripheral joint molecular target for monoamine modulatory antidepressants, which may be helpful to reveal the mechanisms of this kind of drugs more than monoamine regulation.

Keywords: DUOX2; Duloxetine; Gastric mucosal damage; Indomethacin; Monoamine-based antidepressant; NADPH oxidases; Oxidative stress; Water immersion restraint stress.

MeSH terms

  • Animals
  • Antidepressive Agents / therapeutic use*
  • Disease Models, Animal
  • Dual Oxidases / metabolism*
  • Duloxetine Hydrochloride / therapeutic use*
  • Gastric Mucosa / drug effects*
  • Immersion / adverse effects
  • Indomethacin / toxicity*
  • Male
  • NADPH Oxidases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Restraint, Physical / psychology
  • Serotonin and Noradrenaline Reuptake Inhibitors / toxicity*
  • Stomach Ulcer / chemically induced
  • Stomach Ulcer / enzymology
  • Stomach Ulcer / prevention & control*
  • Stomach Ulcer / psychology
  • Stress, Psychological / complications*


  • Antidepressive Agents
  • Serotonin and Noradrenaline Reuptake Inhibitors
  • Duloxetine Hydrochloride
  • Dual Oxidases
  • NADPH Oxidases
  • Duox2 protein, rat
  • Indomethacin