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 f rom arachidonic acid. Hyperglucocorticoidemia, dexamethasone, and aging up- regulate 5LOX in the brain, including the cerebellum in vivo. We studied th e mechanisms of dexamethasone-triggered 5LOX upregulation in primary cultur es of rat cerebellar granule neurons (CGN). We measured 5LOX mRNA and prote in contents, and the formation of cysteinyl leukotrienes (LTC4, LTD4, and L TE4). 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 leukot rienes, assayed in the presence of 2 muM calcium ionophore A23187 and 10 mu M arachidonic acid. The stimulatory effect of dexamethasone on 5LOX express ion was inhibited by the glucocorticoid receptor (GR) antagonist RU486 and by reducing the CGN content of GR receptor protein with a GR-specific antis ense oligonucleotide. The 5LOX mRNA half-life was longer in dexamethasone t han in vehicle-treated CGNs. Our results indicate that dexamethasone increa ses 5LOX expression in CGNs in a GR-dependent manner and that it also incre ases the stability of 5LOX mRNA. Further studies are warranted to elucidate the physiologic/pathologic significance of glucocorticoid-regulated expres sion of 5LOX in the central nervous system.