Glucocorticoids stimulate inflammatory 5-lipoxygenase gene expression and protein translocation in the brain

In the brain, the expression of 5-lipoxygenase (5-LO), the enzyme responsib le for the synthesis of inflammatory leukotrienes, increases during aging. Antiinflammatory drugs are currently being evaluated for the treatment of a ging-associated neurodegenerative diseases such as Alzheimer's disease. Alt hough generally considered antiinflammatory, glucocorticoids, whose product ion also increases during aging, are not particularly effective in this dis ease. In human monocytes, 5-LO mRNA content increases on exposure to the sy nthetic glucocorticoid dexamethasone, which prompted us to hypothesize that glucocorticoids might increase 5-LO expression in the brain as well, We tr eated 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 foun d increased levels of 5-LO mRNA and protein in hippocampus and cerebellum o f glucocorticoid-treated rats; 5-LO-activating protein (FLAP) mRNA content was not affected. Using western immunobloting, we also observed the concurr ent translocation of 5-LO protein from cytosol to membrane, an indication o f its activation. Thus, glucocorticoid-mediated up-regulation of the neuron al 5-LO pathway may contribute to rendering an aging brain vulnerable to de generation.