Glucocorticoids stimulate inflammatory 5-lipoxygenase gene expression and protein translocation in the brain.
In the brain, the expression of 5-lipoxygenase (5-LO), the enzyme responsible for the synthesis of inflammatory leukotrienes, increases during aging. Antiinflammatory drugs are currently being evaluated for the treatment of aging-associated neurodegenerative diseases such as Alzheimer's disease. Although generally considered antiinflammatory, glucocorticoids, whose production also increases during aging, are not particularly effective in this disease. In human monocytes, 5-LO mRNA content increases on exposure to the synthetic glucocorticoid dexamethasone, which prompted us to hypothesize that glucocorticoids might increase 5-LO expression in the brain as well. We treated rats for 10 days either with corticosterone (implanted subcutaneously) or with dexamethasone (injected daily); they were killed on day 10 after pellet implantation or 24 h after the 10th dexamethasone injection. We found increased levels of 5-LO mRNA and protein in hippocampus and cerebellum of glucocorticoid-treated rats; 5-LO-activating protein (FLAP) mRNA content was not affected. Using western immunobloting, we also observed the concurrent translocation of 5-LO protein from cytosol to membrane, an indication of its activation. Thus, glucocorticoid-mediated up-regulation of the neuronal 5-LO pathway may contribute to rendering an aging brain vulnerable to degeneration.
Uz
T
T
Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, 60612, USA.
Dwivedi
Y
Y
Savani
P D
PD
Impagnatiello
F
F
Pandey
G
G
Manev
H
H
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000032:analysis / Q000235:genetics*; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics; D002531:Cerebellum / Q000201:enzymology* / Q000276:immunology; D003345:Corticosterone / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004660:Encephalitis / Q000139:chemically induced / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D005938:Glucocorticoids / Q000494:pharmacology*; D006624:Hippocampus / Q000201:enzymology* / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D000893:Anti-Inflammatory Agents; D002352:Carrier Proteins; D005938:Glucocorticoids; D008565:Membrane Proteins; D012333:RNA, Messenger; D003907:Dexamethasone; D001094:Arachidonate 5-Lipoxygenase; D003345:Corticosterone