title: Dexamethasone enhances oxidative stress-induced cell death in murine neural stem cells.
abstract: Glucocorticoids (GCs) are essential for normal brain development; however, there is consistent evidence that prenatal exposure of the fetal brain to excess GCs permanently modifies the phenotype of neuronal cells. In this paper, the murine-derived multipotent stem cell line C17.2 was used, as an in vitro model, to investigate the impact of GCs on neural stem cell survival. Our results indicate that dexamethasone (Dex) increases the sensitivity of murine neural stem cells (NSCs) to 2,3-methoxy-1,4-naphthoquinone-induced apoptosis, and this effect could be blocked by the glucocorticoid-receptor (GR) antagonist mifepristone, strongly suggesting the involvement of the GR. Furthermore, our results show that Dex decreases cell number and induces a G1-arrest. We hypothesized that the mitochondria are the main target of Dex. Interestingly, after treatment with Dex, 72% of the investigated genes involved in the mitochondrial respiratory chain are down-regulated, as well as 29% of the genes encoding for antioxidant enzymes. In conclusion, using the C17.2 cell line as a model to study developmental neurotoxicity in vitro, we have shown that GCs can increase cellular sensitivity to oxidative stress and alter the phenotype of NCSs.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, P.O. Box 210, 171177 Stockholm, Sweden. r.mutsaers@pharmtox.umcn.nl
authors.forename: Henricus A M
authors.initials: HA
authors.lastname: Mutsaers
authors.forename: Roshan
authors.initials: R
authors.lastname: Tofighi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000037:antagonists & inhibitors / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004579:Electron Transport / Q000187:drug effects; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D009285:Naphthoquinones / Q000633:toxicity; D058953:Neural Stem Cells / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000187:drug effects; D014343:Trypan Blue
chemical_list: D000893:Anti-Inflammatory Agents; D009285:Naphthoquinones; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; C063002:2,3-dimethoxy-1,4-naphthoquinone; D003907:Dexamethasone; D053148:Caspase 3; D014343:Trypan Blue