Glucocorticoids Stimulate Inflammatory 5-Lipoxygenase Gene Expression and Protein Translocation in the Brain

Authors


  • Abbreviations used : cyc, cyclophilin ; FLAP, 5-lipoxygenase-activating protein ; 5-LO, 5-lipoxygenase ; TBST buffer, 10 mM Tris base, 0.15 M NaCl, and 0.05% Tween 20.

Address correspondence and reprint requests to Dr. H. Manev at Psychiatric Institute, University of Illinois at Chicago, 1601 West Taylor Street, MC 912, Chicago, IL 60612, U.S.A.

Abstract

Abstract : In the brain, the expression of 5-lipoxygenase (5-LO), the enzyme responsible for the synthesis of inflammatory leukotrienes, increases during aging. Antiinflammatory drugs are currently being evaluated for the treatment of aging-associated neurodegenerative diseases such as Alzheimer's disease. Although generally considered antiinflammatory, glucocorticoids, whose production also increases during aging, are not particularly effective in this disease. In human monocytes, 5-LO mRNA content increases on exposure to the synthetic glucocorticoid dexamethasone, which prompted us to hypothesize that glucocorticoids might increase 5-LO expression in the brain as well. We treated rats for 10 days either with corticosterone (implanted subcutaneously) or with dexamethasone (injected daily) ; they were killed on day 10 after pellet implantation or 24 h after the 10th dexamethasone injection. We found increased levels of 5-LO mRNA and protein in hippocampus and cerebellum of glucocorticoid-treated rats ; 5-LO-activating protein (FLAP) mRNA content was not affected. Using western immunobloting, we also observed the concurrent translocation of 5-LO protein from cytosol to membrane, an indication of its activation. Thus, glucocorticoid-mediated up-regulation of the neuronal 5-LO pathway may contribute to rendering an aging brain vulnerable to degeneration.

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