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The Journal of Neuroscience, April 5, 2006, 26(14):3813-3820; doi:10.1523/JNEUROSCI.4398-05.2006

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Cellular/Molecular
Chronic Unpredictable Stress Exacerbates Lipopolysaccharide-Induced Activation of Nuclear Factor-B in the Frontal Cortex and Hippocampus via Glucocorticoid Secretion

Carolina Demarchi Munhoz,¹ Lucilia B. Lepsch,¹ Elisa Mitiko Kawamoto,¹ Marília Brinati Malta,¹ Larissa de Sá Lima,¹ Maria Christina Werneck Avellar,² Robert M. Sapolsky,³ and Cristoforo Scavone¹

¹Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil 05508-900, ²Section of Experimental Endocrinology, Department of Pharmacology, Federal University of São Paulo–Escola Paulista de Medicina, São Paulo, Brazil 04044-020, and ³Department of Biological Sciences, Stanford University, Stanford, California 94305-5020

Correspondence should be addressed to Cristoforo Scavone, Department of Pharmacology, Institute of Biomedical Science-ICB-1, Avenida Professor Lineu Prestes, 1524, University of São Paulo, São Paulo, Brazil 05508-900. Email: cscavone{at}icb.usp.br

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-B (NF-B), 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-B 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-B 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-B activation when compared with the effect of each treatment alone. Our results indicate that stress, via GC secretion, can increase LPS-induced NF-B activation in the frontal cortex and hippocampus, agreeing with a growing literature demonstrating proinflammatory effects of GCs.

Key words: glucocorticoids; chronic stress; NF-B; LPS; NMDA; brain

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Received Sept. 10, 2004; revised Feb. 7, 2006; accepted Feb. 8, 2006.

Correspondence should be addressed to Cristoforo Scavone, Department of Pharmacology, Institute of Biomedical Science-ICB-1, Avenida Professor Lineu Prestes, 1524, University of São Paulo, São Paulo, Brazil 05508-900. Email: cscavone{at}icb.usp.br

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