Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is required for the development of ischemic neuronal death

Irene Cappuccio, Agata Calderone, Carla L. Busceti, Francesca Biagioni, Fabrizio Pontarelli, Valeria Bruno, Marianna Storto, Georg T. Terstappen, Giovanni Gaviraghi, Francesco Fornai, Giuseppe Battaglia, Daniela Melchiorri, Suzanne Zukin, Ferdinando Nicoletti, Andrea Caricasole

Research output: Contribution to journalArticle

105 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2647-2657
Number of pages11
JournalJournal of Neuroscience
Volume25
Issue number10
DOIs
StatePublished - Mar 9 2005

Keywords

  • Hippocampus
  • Ischemia
  • Lithium
  • NMDA
  • Necrosis
  • Neuron

ASJC Scopus subject areas

  • Neuroscience(all)

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    Cappuccio, I., Calderone, A., Busceti, C. L., Biagioni, F., Pontarelli, F., Bruno, V., Storto, M., Terstappen, G. T., Gaviraghi, G., Fornai, F., Battaglia, G., Melchiorri, D., Zukin, S., Nicoletti, F., & Caricasole, A. (2005). Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is required for the development of ischemic neuronal death. Journal of Neuroscience, 25(10), 2647-2657. https://doi.org/10.1523/JNEUROSCI.5230-04.2005