Glucocorticoid receptors are required for up-regulation of neuronal 5-lipoxygenase (5LOX) expression by dexamethasone

5- lipoxygenase (5LOX) is the key enzyme in the synthesis of leukotrienes from arachidonic acid. Hyperglucocorticoidemia, dexamethasone, and aging up-regulate 5LOX in the brain, including the cerebellum in vivo. We studied the mechanisms of dexamethasone-triggered 5LOX upregulation in primary cultures of rat cerebellar granule neurons (CGN). We measured 5LOX mRNA and protein contents, and the formation of cysteinyl leukotrienes (LTC4, LTD4, and LTE4). The dexamethasone (0.1 muM or 1 muM)-increased 5LOX mRNA and protein contents were already observed at 3 h of treatment, and they persisted for at least 24 h. Dexamethasone also increased the content of cysteinyl leukotrienes, assayed in the presence of 2 muM calcium ionophore A23187 and 10 muM arachidonic acid. The stimulatory effect of dexamethasone on 5LOX expression was inhibited by the glucocorticoid receptor (GR) antagonist RU486 and by reducing the CGN content of GR receptor protein with a GR-specific antisense oligonucleotide. The 5LOX mRNA half-life was longer in dexamethasone than in vehicle-treated CGNs. Our results indicate that dexamethasone increases 5LOX expression in CGNs in a GR-dependent manner and that it also increases the stability of 5LOX mRNA. Further studies are warranted to elucidate the physiologic/pathologic significance of glucocorticoid-regulated expression of 5LOX in the central nervous system.