The sigma-1 receptor-zinc finger protein 179 pathway protects against hydrogen peroxide-induced cell injury

Neuropharmacology. 2016 Jun:105:1-9. doi: 10.1016/j.neuropharm.2016.01.015. Epub 2016 Jan 11.

Abstract

The accumulation of reactive oxygen species (ROS) have implicated the pathogenesis of several human diseases including neurodegenerative disorders, stroke, and traumatic brain injury, hence protecting neurons against ROS is very important. In this study, we focused on sigma-1 receptor (Sig-1R), a chaperone at endoplasmic reticulum, and investigated its protective functions. Using hydrogen peroxide (H2O2)-induced ROS accumulation model, we verified that apoptosis-signaling pathways were elicited by H2O2 treatment. However, the Sig-1R agonists, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS), reduced the activation of apoptotic pathways significantly. By performing protein-protein interaction assays and shRNA knockdown of Sig-1R, we identified the brain Zinc finger protein 179 (Znf179) as a downstream target of Sig-1R regulation. The neuroprotective effect of Znf179 overexpression was similar to that of DHEAS treatment, and likely mediated by affecting the levels of antioxidant enzymes. We also quantified the levels of peroxiredoxin 3 (Prx3) and superoxide dismutase 2 (SOD2) in the hippocampi of wild-type and Znf179 knockout mice, and found both enzymes to be reduced in the knockout versus the wild-type mice. In summary, these results reveal that Znf179 plays a novel role in neuroprotection, and Sig-1R agonists may be therapeutic candidates to prevent ROS-induced damage in neurodegenerative and neurotraumatic diseases.

Keywords: DHEA/DHEAS; Hydrogen peroxide; Reactive oxygen species; Sig-1R; Znf179.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / pathology
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dehydroepiandrosterone / administration & dosage
  • Dehydroepiandrosterone Sulfate / administration & dosage
  • Gene Knockdown Techniques
  • Hydrogen Peroxide
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuroprotective Agents / administration & dosage
  • Reactive Oxygen Species / metabolism*
  • Receptors, sigma / agonists
  • Receptors, sigma / genetics
  • Receptors, sigma / metabolism*
  • Sigma-1 Receptor

Substances

  • DNA-Binding Proteins
  • Neuroprotective Agents
  • Reactive Oxygen Species
  • Receptors, sigma
  • ZNF179 protein, mouse
  • Dehydroepiandrosterone
  • Dehydroepiandrosterone Sulfate
  • Hydrogen Peroxide