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 μM)-increased 5LOX mRNA and protein contents were already observed at 3 h of treatment, and they persisted for at least 24 h. Dexamethasone also ! imulatory 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.