title: Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is required for the development of ischemic neuronal death.
abstract: Expression of Dickkopf-1 (Dkk-1), a secreted protein that negatively modulates the Wnt pathway, was induced in the hippocampus of gerbils and rats subjected to transient global cerebral ischemia as well as in cultured cortical neurons challenged with an excitotoxic pulse. In ischemic animals, the temporal and regional pattern of Dkk-1 expression correlated with the profile of neuronal death, as assessed by Nissl staining and Dkk-1 immunostaining in adjacent hippocampal sections. Treatment of ischemic animals with either Dkk-1 antisense oligonucleotides or lithium ions (which rescue the Wnt pathway acting downstream of the Dkk-1 blockade) protected vulnerable hippocampal neurons against ischemic damage. The same treatments protected cultured cortical neurons against NMDA toxicity. We conclude that induction of Dkk-1 with the ensuing inhibition of the canonical Wnt signaling pathway is required for the development of ischemic and excitotoxic neuronal death.
authors.affiliation: Department of Human Physiology and Pharmacology, University of Rome La Sapienza, 00185 Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Cappuccio
authors.forename: Agata
authors.initials: A
authors.lastname: Calderone
authors.forename: Carla L
authors.initials: CL
authors.lastname: Busceti
authors.forename: Francesca
authors.initials: F
authors.lastname: Biagioni
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pontarelli
authors.forename: Valeria
authors.initials: V
authors.lastname: Bruno
authors.forename: Marianna
authors.initials: M
authors.lastname: Storto
authors.forename: Georg T
authors.initials: GT
authors.lastname: Terstappen
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gaviraghi
authors.forename: Francesco
authors.initials: F
authors.lastname: Fornai
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.forename: Daniela
authors.initials: D
authors.lastname: Melchiorri
authors.forename: R Suzanne
authors.initials: RS
authors.lastname: Zukin
authors.forename: Suzanne
authors.initials: S
authors.lastname: Zukin
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Andrea
authors.initials: A
authors.lastname: Caricasole
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D018920:Coculture Techniques / Q000379:methods; D015536:Down-Regulation / Q000502:physiology*; D005849:Gerbillinae; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000502:physiology; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology
chemical_list: C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins