Induction of the Wnt inhibitor, Dickkopf-1, is associated with neurodegeneration related to temporal lobe epilepsy.

Abstract

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 beta-catenin, which reflects an ongoing inhibition of the canonical Wnt pathway. Intracerebroventricular injections of Dkk-1 antisense oligonucleotides (12 nmol/2 microL) 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-3beta, reduce the development of hippocampal sclerosis in patients with temporal lobe epilepsy.

• Authors: Carla Letizia Busceti, Francesca Biagioni, Eleonora Aronica, Barbara Riozzi, Marianna Storto, Giuseppe Battaglia, Filippo S Giorgi, Roberto Gradini, Francesco Fornai, Andrea Caricasole, Ferdinando Nicoletti, Valeria Bruno
• Journal: Epilepsia (Epilepsia) Vol. 48 Issue 4 Pg. 694-705 (Apr 2007) ISSN: 0013-9580 [Print] United States
• PMID: 17437412 (Publication Type: Journal Article)

Chemical References

• DKK1 protein, human
• Intercellular Signaling Peptides and Proteins
• Lithium Compounds
• Wnt Proteins
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Glycogen Synthase Kinase 3
• Kainic Acid

Topics

• Animals
• Cell Death
• Disease Models, Animal
• Epilepsy, Temporal Lobe (pathology, physiopathology)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• Glycogen Synthase Kinase 3 beta
• Hippocampus (drug effects, metabolism, pathology)
• Immunohistochemistry
• Intercellular Signaling Peptides and Proteins (biosynthesis, physiology)
• Kainic Acid (pharmacology)
• Lithium Compounds (pharmacology)
• Male
• Nerve Degeneration (metabolism, physiopathology, prevention & control)
• Neurons (drug effects, metabolism, pathology)
• Rats
• Rats, Sprague-Dawley
• Sclerosis (metabolism, physiopathology, prevention & control)
• Wnt Proteins (antagonists & inhibitors, physiology)