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Implication of oxidative stress in glucocorticoid‐induced hippocampal damage
Author(s) -
You JungMan,
Park JiHo,
Lee Eunjoo H
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.lb125
Subject(s) - reactive oxygen species , glucocorticoid receptor , oxidative stress , hippocampal formation , nadph oxidase , chemistry , medicine , glucocorticoid , endocrinology , programmed cell death , glutathione , neurotoxicity , apoptosis , glutathione peroxidase , catalase , biology , biochemistry , enzyme , toxicity
Prolonged stress results in elevation of glucocorticoid (GC) hormone, which can have deleterious effects in the brain. The hippocampus, which has a high concentration of glucocorticoid receptor, is especially vulnerable to increasing levels of GC. GC has been suggested to endanger hippocampal neurons by exacerbating excitotoxic glutamatecalcium‐ 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 DCF 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 μM DEX. By contrast, other steroid hormones, progesterone and estradiol did not influence ROS production. Catalase and N‐acetyl‐L‐cystein 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 is mediated via GC receptor. Reverse transcriptase real‐time PCR analysis demonstrated that the levels of glutathione peroxidase and glutathione S transferase mRNAs were decreased while those of NADPH oxidase and bax mRNAs were significantly enhanced after DEX treatment. These findings suggest that excess GC causes hippocampal damage by regulating genes involved in ROS generation and apoptosis.