Glucocorticoids stimulate inflammatory 5-lipoxygenase gene expression and protein translocation in the brain

J Neurochem. 1999 Aug;73(2):693-9. doi: 10.1046/j.1471-4159.1999.0730693.x.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5-Lipoxygenase-Activating Proteins
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Arachidonate 5-Lipoxygenase / analysis
  • Arachidonate 5-Lipoxygenase / genetics*
  • Blotting, Western
  • Brain Chemistry / drug effects
  • Carrier Proteins / genetics
  • Cerebellum / enzymology*
  • Cerebellum / immunology
  • Corticosterone / pharmacology
  • Dexamethasone / pharmacology*
  • Encephalitis / chemically induced
  • Encephalitis / enzymology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / immunology
  • Glucocorticoids / pharmacology*
  • Hippocampus / enzymology*
  • Hippocampus / immunology
  • Male
  • Membrane Proteins / genetics
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • 5-Lipoxygenase-Activating Proteins
  • ALOX5AP protein, human
  • Anti-Inflammatory Agents
  • Carrier Proteins
  • Glucocorticoids
  • Membrane Proteins
  • RNA, Messenger
  • Dexamethasone
  • Arachidonate 5-Lipoxygenase
  • Corticosterone