Induction of the Wnt antagonist, Dickkopf-1, contributes to the development of neuronal death in models of brain focal ischemia.
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.
Mastroiacovo
Federica
F
Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy.
Busceti
Carla L
CL
Biagioni
Francesca
F
Moyanova
Slavianka G
SG
Meisler
Miriam H
MH
Battaglia
Giuseppe
G
Caricasole
Andrea
A
Bruno
Valeria
V
Nicoletti
Ferdinando
F
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death; D002536:Cerebral Arteries / Q000187:drug effects; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000008:administration & dosage / Q000627:therapeutic use; D007261:Infusions, Intra-Arterial; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D018021:Lithium Chloride / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D051381:Rats; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
C501127:Dkk1 protein, mouse; D019332:Endothelin-1; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D018021:Lithium Chloride