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The Journal of Neuroscience, March 9, 2005, 25(10):2647-2657; doi:10.1523/JNEUROSCI.5230-04.2005

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Neurobiology of Disease
Induction of Dickkopf-1, a Negative Modulator of the Wnt Pathway, Is Required for the Development of Ischemic Neuronal Death

Irene Cappuccio,^1,2 * Agata Calderone,^2 * Carla L. Busceti,^3 * Francesca Biagioni,³ Fabrizio Pontarelli,³ Valeria Bruno,^1,3 Marianna Storto,³ Georg T. Terstappen,⁴ Giovanni Gaviraghi,⁴ Francesco Fornai,³ Giuseppe Battaglia,³ Daniela Melchiorri,¹ Suzanne Zukin,² Ferdinando Nicoletti,^1,3 and Andrea Caricasole⁴

¹Department of Human Physiology and Pharmacology, University of Rome "La Sapienza," 00185 Rome, Italy, ²Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10462, ³Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy, and ⁴Siena Biotech, 53100 Siena, Italy

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.

Key words: ischemia; neuron; hippocampus; necrosis; NMDA; lithium

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Received Aug 19, 2004; revised January 20, 2005; accepted January 20, 2005.

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