Gadolinium-induced Oxidative Stress Triggers Endoplasmic Reticulum Stress in Rat Cortical Neurons

J Neurochem. 2011 Apr;117(1):38-47. doi: 10.1111/j.1471-4159.2010.07162.x. Epub 2011 Feb 11.

Abstract

Introduction of Gadolinium (Gd) to the nervous system is linked to the development of neurotoxicity involving both oxidative and endoplasmic reticulum (ER) stress. Gd levels (0.2-20 μm) in the form of gadolinium trichloride (GdCl(3)) cause neurotoxicity in vitro. We investigated the signaling pathways in primary cultured rat cortical neurons and tested whether GdCl(3) induced oxidative and ER stress. Results showed that Gd-induced neural cell death followed a rapid accumulation of intracellular reactive oxygen species. In addition, Gd exposure resulted in spliced X-box binding protein 1 mRNA and increased expression of binding immunoglobulin protein, thus activating transcription factor 4 (ATF4), ATF6, and C/EBP homologous protein mRNA. Up-regulated expression of binding immunoglobulin protein is a hallmark of ER stress and C/EBP homologous protein is an ER stress-related pro-apoptotic transcription factor. Activation of ER stress downstream substrates, inositol-requiring kinase 1 and ATF6, was also observed in Gd-treated cells. The neurotoxic effects of Gd were blocked by the antioxidant N-acetylcysteine. Results demonstrated that Gd-induced cytotoxicity in neurons occurs via oxidative injury and ER stress-related signal transduction, thus offering new insight into the neurotoxicology of gadolinium.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism*
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Gadolinium / toxicity*
  • Neurons / drug effects
  • Neurons / metabolism*
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism

Substances

  • Reactive Oxygen Species
  • Gadolinium