Induction of the Wnt inhibitor, Dickkopf-1, is associated with neurodegeneration related to temporal lobe epilepsy.
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.
Busceti
Carla Letizia
CL
I.N.M. Neuromed, Pozzilli, Italy.
Biagioni
Francesca
F
Aronica
Eleonora
E
Riozzi
Barbara
B
Storto
Marianna
M
Battaglia
Giuseppe
G
Giorgi
Filippo S
FS
Gradini
Roberto
R
Fornai
Francesco
F
Caricasole
Andrea
A
Nicoletti
Ferdinando
F
Bruno
Valeria
V
D000818:Animals; D016923:Cell Death; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000473:pathology* / Q000503:physiopathology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000502:physiology*; D007608:Kainic Acid / Q000494:pharmacology; D018020:Lithium Compounds / Q000494:pharmacology; D008297:Male; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012598:Sclerosis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology
C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D018020:Lithium Compounds; D051153:Wnt Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D007608:Kainic Acid