Induction of the Wnt Inhibitor, Dickkopf‐1, Is Associated with Neurodegeneration Related to Temporal Lobe Epilepsy

Abstract

Summary: Inhibition of the Wnt pathway by the secreted glycoprotein, Dickkopf‐1 (Dkk‐1) has been related to processes of excitotoxic and ischemic neuronal death. We now report that Dkk‐1 is induced in neurons of the rat olfactory cortex and hippocampus degenerating in response to seizures produced by systemic injection of kainate (12 mg/kg, i.p.). There was a tight correlation between Dkk‐1 expression and neuronal death in both regions, as shown by the different expression profiles in animals classified as “high” and “low” responders to kainate. For example, no induction of Dkk‐1 was detected in the hippocampus of low responder rats, in which seizures did not cause neuronal loss. Induction of Dkk‐1 always anticipated neuronal death and was associated with a reduction in nuclear levels of β‐catenin, which reflects an ongoing inhibition of the canonical Wnt pathway. Intracerebroventricular injections of Dkk‐1 antisense oligonucleotides (12 nmol/2 μL) substantially reduced kainate‐induced neuronal damage, as did a pretreatment with lithium ions (1 mEq/kg, i.p.), which rescue the Wnt pathway by acting downstream of the Dkk‐1 blockade. Taken collectively, these data suggest that an early inhibition of the Wnt pathway by Dkk‐1 contributes to neuronal damage associated with temporal lobe epilepsy. We also examined Dkk‐1 expression in the hippocampus of epileptic patients and their controls. A strong Dkk‐1 immunolabeling was found in six bioptic samples and in one autoptic sample from patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis. Dkk‐1 expression was undetectable or very low in autoptic samples from nonepileptic patients or in bioptic samples from patients with complex partial seizures without neuronal loss and/or reactive gliosis in the hippocampus. Our data raise the attractive possibility that drugs able to rescue the canonical Wnt pathway, such as Dkk‐1 antagonists or inhibitors of glycogen synthase kinase‐3β, reduce the development of hippocampal sclerosis in patients with temporal lobe epilepsy.

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.…”

Lithium delays progression of amyotrophic lateral sclerosis

“…Lithium is a compound used as a mood stabilizer, which is neuroprotective in a variety of disease models (12,13), such as brain ischemia (14) and kainate toxicity (15). The ability of lithium to promote autophagy, through the inhibition of the inositol-monophosphatase 1 (16)(17)(18), together with the protective effects of autophagy in neurodegeneration (19 -22), prompted us to test the neuroprotective effects of lithium in the G93A ALS mouse model.…”

Induction of the Wnt Antagonist, Dickkopf-1, Contributes to the Development of Neuronal Death in Models of Brain Focal Ischemia

“…A growing body of evidence shows that inhibition of the canonical Wnt pathway contributes to the pathophysiology of neuronal damage in model of acute and chronic neurodegenerative disorders (De Ferrari and Inestrosa, 2000;Garrido et al, 2002;Inestrosa et al, 2002;Caricasole et al, 2003Caricasole et al, , 2004De Ferrari et al, 2003;Cappuccio et al, 2005;Scali et al, 2006;Busceti et al, 2007). Wnts are members of a family of secreted glycoproteins that regulate neuronal homeostasis during development, as well as in the adult life (Dale, 1998).…”