Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids

J Clin Invest. 2002 Dec;110(11):1729-38. doi: 10.1172/JCI15481.


Many cellular responses to corticosteroids involve the transcriptional modulation of target genes by the glucocorticoid receptor (GR). A rapid, non-nuclear effect of GR was found to mediate neuroprotection. High-dose corticosteroids (20 mg/kg intraperitoneally), given within 2 hours of transient cerebral ischemia, acutely increased endothelial nitric oxide synthase (eNOS) activity, augmented regional cerebral blood flow (CBF) by 40% to 50%, and reduced cerebral infarct size by 32%. These neuroprotective effects of corticosteroids were abolished by the GR antagonist RU486 and by inhibition of phosphatidylinositol 3-kinase (PI3K), and were absent in eNOS(-/-) mice. To determine the mechanism by which GR activated eNOS, we measured the effect of corticosteroids on PI3K and the protein kinase Akt. In a ligand-dependent manner, GR activated PI3K and Akt in vitro and in vivo caused NO-dependent vasodilation, which was blocked by cotreatment with RU486 or the PI3K inhibitor LY294002 but not by transcriptional inhibitors. Indeed, a mutant GR, which cannot dimerize and bind to DNA, still activated PI3K and Akt in response to corticosteroids. These findings indicate that non-nuclear GR rapidly activates eNOS through the PI3K/Akt pathway and suggest that this mechanism mediates the acute neuroprotective effects of corticosteroids through augmentation of CBF.

Publication types

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

MeSH terms

  • Adrenal Cortex Hormones / therapeutic use*
  • Animals
  • Base Sequence
  • COS Cells
  • Cattle
  • Cells, Cultured
  • Cerebral Infarction / prevention & control*
  • Cerebrovascular Circulation / physiology*
  • Chlorocebus aethiops
  • DNA Primers
  • Endothelium, Vascular / physiology
  • Gene Expression Regulation, Enzymologic*
  • Genes, Reporter
  • Humans
  • Ischemic Attack, Transient / enzymology
  • Ischemic Attack, Transient / physiopathology
  • Mice
  • Mice, Inbred Strains
  • Neuroprotective Agents
  • Nitric Oxide Synthase / genetics*
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Phosphatidylinositol 3-Kinases / metabolism
  • Polymerase Chain Reaction
  • Receptors, Glucocorticoid / physiology
  • Recombinant Proteins / metabolism
  • Stroke / prevention & control*
  • Transfection


  • Adrenal Cortex Hormones
  • DNA Primers
  • Neuroprotective Agents
  • Receptors, Glucocorticoid
  • Recombinant Proteins
  • NOS3 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse