Abstract
5-lipoxygenase (5-LOX), the enzyme responsible for the synthesis of inflammatory leukotrienes, is expressed in the brain, including in neurons. The presence of hormone response elements for several hormones, among them, melatonin, glucocorticoids, estrogens, and thyroid hormone, in the promoter of the 5-LOX gene suggests possible regulation of this gene by the above-mentioned hormones. Hormonal changes that occur during aging might participate in the aging-associated up-regulation of 5-LOX mRNA and protein in the brain, which we observed in our previous work. In human monocytes, 5-LOX mRNA content increases on exposure to the synthetic glucocorticoid dexamethasone, which prompted us to hypothesize that glucocorticoids (which are up-regulated during aging) might increase 5-LOX expression in the brain as well. After treatment of rats for 10 days either with corticosterone (implanted subcutaneously) or with dexamethasone (injected daily) we found increased levels of 5-LOX mRNA and protein in hippocampus and cerebellum. To understand better whether the stimulatory effect of glucocorticoids on 5-LOX mRNA/protein requires the involvement of glucocorticoid receptors, we studied 5-LOX expression in primary cultures of rat cerebellar granule cells. The cultures were grown in serum-free chemically defined medium (B-27) and treated for 24 hours either with corticosterone or with dexamethasone in the presence or absence of the glucocorticoid receptor antagonist mifepristone (RU486). Corticosterone and dexamethasone both increased 5-LOX mRNA and protein levels; RU486 decreased the dexamethasonestimulated 5-LOX expression, which suggests that the effect of glucocorticoids is achieved via a receptor-mediated mechanism. Thus, increased glucocorticoid levels, which occur during aging and/or in stress, may up-regulate the neuronal 5-LOX pathway and thereby contribute to the development of neurodegenerative pathologies.
Published Version
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