1 research outputs found
Glucocorticoid receptors are required for upâregulation of neuronal 5âlipoxygenase (5LOX) expression by dexamethasone
5âlipoxygenase (5LOX) is the key enzyme in the synthesis of leukotrienes from arachidonic acid. Hyperglucocorticoidemia, dexamethasone, and aging upâregulate 5LOX in the brain, including the cerebellum in vivo. We studied the mechanisms of dexamethasoneâtriggered 5LOX upâregulation 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 ÎŒM or 1 ÎŒM)âincreased 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 ÎŒM calcium ionophore A23187 and 10 ÎŒM 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 GRâspecific antisense oligonucleotide. The 5LOX mRNA halfâlife was longer in dexamethasone than in vehicleâtreated CGNs. Our results indicate that dexamethasone increases 5LOX expression in CGNs in a GRâdependent manner and that it also increases the stability of 5LOX mRNA. Further studies are warranted to elucidate the physiologic/pathologic significance of glucocorticoidâregulated expression of 5LOX in the central nervous system.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154349/1/fsb2fj000836fje-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154349/2/fsb2fj000836fje.pd