title: Gadolinium-induced oxidative stress triggers endoplasmic reticulum stress in rat cortical neurons.
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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs and Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China. xqing@bjmu.edu.cn
authors.forename: Qing
authors.initials: Q
authors.lastname: Xia
authors.forename: Xudong
authors.initials: X
authors.lastname: Feng
authors.forename: Haifeng
authors.initials: H
authors.lastname: Huang
authors.forename: Lingyan
authors.initials: L
authors.lastname: Du
authors.forename: Xiaoda
authors.initials: X
authors.lastname: Yang
authors.forename: Kui
authors.initials: K
authors.lastname: Wang
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005682:Gadolinium / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D005682:Gadolinium