Mechanism of glucocorticoid-induced oxidative stress in rat hippocampal slice cultures
- 1 June 2009
- journal article
- Published by Canadian Science Publishing in Canadian Journal of Physiology and Pharmacology
- Vol. 87 (6), 440-447
- https://doi.org/10.1139/y09-027
Abstract
Prolonged stress results in elevation of glucocorticoid (GC) hormones, which can have deleterious effects in the brain. The hippocampus, which has a high concentration of glucocorticoid receptors, is especially vulnerable to increasing levels of GCs. GCs have been suggested to endanger hippocampal neurons by exacerbating the excitotoxic glutamate–calcium–reactive oxygen species (ROS) cascade. In an effort to reveal the mechanisms underlying GC-mediated hippocampal neurotoxicity, we aimed to clarify the molecular pathway of GC-induced ROS increase by using organotypic hippocampal slice cultures. Assays for ROS, using 2′,7′-dichlorodihydrofluorescein diacetate fluorescence, showed that treatment of synthetic GC, dexamethasone (DEX) significantly enhanced ROS levels. Time course and dose response analyses indicated that peak amount of ROS was generated at 4 h after treatment with 50 µmol/L DEX. By contrast, other steroid hormones, progesterone and estradiol did not influence ROS production. N-acetyl-l-cysteine completely suppressed ROS produced by DEX. Propidium iodide staining exhibited prominent cell death in the hippocampal layer after 96 h of DEX treatment. RU486, a GC receptor antagonist, almost completely blocked the effect of DEX on ROS production and cell death, indicating that DEX-induced ROS overproduction and hippocampal death are mediated via GC receptors. Real-time reverse transcriptase PCR analysis demonstrated that after DEX treatment the level of glutathione peroxidase mRNA was decreased whereas that of NADPH oxidase mRNA was significantly enhanced. These findings suggest that excess GCs cause hippocampal damage by regulating genes involved in ROS generation.Keywords
This publication has 29 references indexed in Scilit:
- N‐Acetylcysteine Attenuates Arsenite‐Induced Oxidative Injury in Dorsal Root Ganglion ExplantsAnnals of the New York Academy of Sciences, 2007
- A protective role of 27-kDa heat shock protein in glucocorticoid-evoked apoptotic cell death of hippocampal progenitor cellsBiochemical and Biophysical Research Communications, 2005
- Restructuring the neuronal stress response with anti-glucocorticoid gene deliveryNature Neuroscience, 2004
- Glutamate up-regulates P-glycoprotein expression in rat brain microvessel endothelial cells by an NMDA receptor-mediated mechanismLife Sciences, 2004
- Reduction but not cleavage of poly(ADP-ribose) polymerase during stress-mediated cell death in the rat hippocampusNeuroReport, 2003
- Relative expression software tool (REST(C)) for group-wise comparison and statistical analysis of relative expression results in real-time PCRNucleic Acids Research, 2002
- How Do Glucocorticoids Influence Stress Responses? Integrating Permissive, Suppressive, Stimulatory, and Preparative ActionsEndocrine Reviews, 2000
- Brain Corticosteroid Receptor Balance in Health and DiseaseEndocrine Reviews, 1998
- Oxidative Stress in Neurodegenerative DiseasesAnnual Review of Pharmacology and Toxicology, 1996
- Stress induces neuronal death in the hippocampus of castrated ratsNeuroscience Letters, 1992