Chronic unpredictable stress exacerbates lipopolysaccharide-induced activation of nuclear factor-kappaB in the frontal cortex and hippocampus via glucocorticoid secretion.
Although the anti-inflammatory actions of glucocorticoids (GCs) are well established in the periphery, these stress hormones can increase inflammation under some circumstances in the brain. The transcription factor nuclear factor-kappaB (NF-kappaB), which is inhibited by GCs, regulates numerous genes central to inflammation. In this study, the effects of stress, GCs, and NMDA receptors on lipopolysaccharide (LPS)-induced activation of NF-kappaB in the brain were investigated. One day after chronic unpredictable stress (CUS), nonstressed and CUS rats were treated with saline or LPS and killed 2 h later. CUS potentiated the increase in LPS-induced activation of NF-kappaB in frontal cortex and hippocampus but not in the hypothalamus. This stress effect was blocked by pretreatment of rats with RU-486, an antagonist of the GC receptor. MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate], an NMDA receptor antagonist, also reduced the effect of LPS in all three brain regions. However, the combined antagonism of both GC and NMDA receptors produced no further reduction in NF-kappaB activation when compared with the effect of each treatment alone. Our results indicate that stress, via GC secretion, can increase LPS-induced NF-kappaB activation in the frontal cortex and hippocampus, agreeing with a growing literature demonstrating proinflammatory effects of GCs.
Munhoz
Carolina Demarchi
CD
Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, 05508-900, Brazil.
Lepsch
Lucilia B
LB
Kawamoto
Elisa Mitiko
EM
Malta
Marília Brinati
MB
Lima
Larissa de Sá
Lde S
Avellar
Maria Christina Werneck
MC
Sapolsky
Robert M
RM
Scavone
Cristoforo
C
D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism*; D005625:Frontal Lobe / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013315:Stress, Psychological / Q000150:complications* / Q000378:metabolism*; D014018:Tissue Distribution
D005938:Glucocorticoids; D008070:Lipopolysaccharides; D016328:NF-kappa B