Dexamethasone-enhanced sensitivity of mouse hippocampal HT22 cells for oxidative stress is associated with the suppression of nuclear factor-kappaB.
Glucocorticoids (GCs) exacerbate various insults to the hippocampus but the exact molecular mechanisms of this GC activity is not known. GCs can suppress the activity of the redox-sensitive nuclear factor NF-kappaB, which potentially serves neuroprotective functions. Employing electrophoretic mobility shift assays and transfection assays using a NF-kappaB-dependent reporter plasmid, we demonstrate that the increased oxidative stress sensitivity of clonal mouse hippocampal HT22 cells caused by GCs is associated with the suppression of NF-kappaB. GCs increased the expression of IkappaBalpha, the physiological inhibitor of NF-kappaB. Downregulation of NF-kappaB activity after overexpression of a dominant-negative mutant form of IkappaBalpha results in an increased sensitivity to oxidative stress. We conclude that the suppression of the basal NF-kappaB activity contributes to the enhanced vulnerability of neuronal cells to oxidative stress caused by GCs.
Braun
S
S
Independent Research Group Neurodegeneration, Max Planck Institute of Psychiatry, 80804, Munich, Germany.
Liebetrau
W
W
Berning
B
B
Behl
C
C
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000633:toxicity*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014162:Transfection
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone