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 b-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 b-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.

β-Catenin, a Transcription Factor Activated by Canonical Wnt Signaling, Is Expressed in Sensory Neurons of Calves Latently Infected with Bovine Herpesvirus 1

“…Chronic stress or increased corticosteroids are known to induce DKK-1 expression and neuronal damage in the hippocampus (81), which is required for ischemic neuronal death (82). DKK-1 also mediates glucocorticoid-induced changes in human neuronal progenitor cell growth and differentiation (83), adding support to the finding that DEX stimulates DKK-1 gene expression in TG.…”

The Secreted Wnt Antagonist Dickkopf-1 Is Required for Amyloid β-Mediated Synaptic Loss

“…In our system, Dkk1 reversibly affects the number of synapses without affecting programmed cell death. Interestingly, previous studies have indicated that increased Dkk1 levels contribute to cell death in cerebral ischemia (Cappuccio et al, 2005;Mastroiacovo et al, 2009), epilepsy (Busceti et al, 2007) and neurodegenerative diseases (Scali et al, 2006;Rosi et al, 2010). This apparent discrepancy could be explained by the low level and short-term treatment with Dkk1 used in our system.…”

Protective Role for Type 4 Metabotropic Glutamate Receptors against Ischemic Brain Damage

“…The drug PHCCC (10 mg/kg) was administered subcutaneously 20 minutes after Et-1 infusion, and ischemic damage was assessed 3 days later (Moyanova et al, 2007;Mastroiacovo et al, 2009). The drug reduced the infarct volume by 35% to 40% as compared with control animals; this reduction was prominent in subcortical regions ( Figures 3A and 3B).…”