Induction of the Wnt antagonist, Dickkopf-1, contributes to the development of neuronal death in models of brain focal ischemia

J Cereb Blood Flow Metab. 2009 Feb;29(2):264-76. doi: 10.1038/jcbfm.2008.111. Epub 2008 Oct 1.


Inhibition of the canonical Wnt pathway has been implicated in the pathophysiology of neuronal death. Here, we report that the secreted Wnt antagonist, Dickkopf-1 (Dkk-1) is rapidly induced in neurons after induction of focal brain ischemia. In rats undergoing transient focal ischemia in response to brain infusion of endothelin-1, Dkk-1 was induced in neurons of the ischemic core and the penumbra region. Induction of Dkk-1 was associated with a reduced expression of beta-catenin (a downstream signaling molecule of the canonical Wnt pathway), and was not observed in neurons expressing the protective protein, heat shock protein-70. Treatment with lithium ions, which, inter alia, rescue the canonical Wnt pathway, was highly protective against ischemic damage. Dkk-1 was also induced in cortical neurons of mice undergoing permanent middle cerebral artery (MCA) occlusion. This model allowed us to compare wild-type mice with doubleridge mice, which are characterized by a reduced expression of Dkk-1. Doubleridge mice showed an attenuated reduction of beta-catenin and a reduced infarct volume in response to MCA occlusion, providing a direct demonstration that Dkk-1 contributes to the pathophysiology of ischemic neuronal damage. These data rise the interesting possibility that Dkk-1 antagonists or drugs that rescue the Wnt pathway might be neuroprotective in stroke.

MeSH terms

  • Animals
  • Brain Ischemia / drug therapy
  • Brain Ischemia / genetics
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology*
  • Cell Death
  • Cerebral Arteries / drug effects
  • Disease Models, Animal
  • Endothelin-1 / administration & dosage
  • Endothelin-1 / therapeutic use
  • Infusions, Intra-Arterial
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Lithium Chloride / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Transgenic
  • Rats
  • Wnt Proteins / antagonists & inhibitors*
  • Wnt Proteins / metabolism
  • beta Catenin / metabolism


  • Dkk1 protein, mouse
  • Endothelin-1
  • Intercellular Signaling Peptides and Proteins
  • Wnt Proteins
  • beta Catenin
  • Lithium Chloride