title: Induction of the Wnt antagonist, Dickkopf-1, contributes to the development of neuronal death in models of brain focal ischemia.
abstract: 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.
authors.affiliation: Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Mastroiacovo
authors.forename: Carla L
authors.initials: CL
authors.lastname: Busceti
authors.forename: Francesca
authors.initials: F
authors.lastname: Biagioni
authors.forename: Slavianka G
authors.initials: SG
authors.lastname: Moyanova
authors.forename: Miriam H
authors.initials: MH
authors.lastname: Meisler
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.forename: Andrea
authors.initials: A
authors.lastname: Caricasole
authors.forename: Valeria
authors.initials: V
authors.lastname: Bruno
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: 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
chemical_list: C501127:Dkk1 protein, mouse; D019332:Endothelin-1; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D018021:Lithium Chloride