Up-regulation of the canonical Wnt-3A and Sonic hedgehog signaling underlies melanocortin-induced neurogenesis after cerebral ischemia.

Abstract

In experimental cerebral ischemia, melanocortin MC4 receptor agonists induce neuroprotection and neurogenesis with subsequent long-lasting functional recovery. Here we investigated the molecular mechanisms underlying melanocortin-induced neurogenesis. Gerbils were subjected to transient global cerebral ischemia, then they were treated every 12 h, and until sacrifice, with 5-bromo-2'-deoxyuridine (BrdU; to label proliferating cells), and the melanocortin analog [Nle(4),d-Phe(7)]α-melanocyte-stimulating hormone (NDP-α-MSH) or saline. NDP-α-MSH increased hippocampus dentate gyrus (DG) expression of Wnt-3A, β-catenin, Sonic hedgehog (Shh), Zif268, interleukin-10 (IL-10) and doublecortin (DCX), as detected at days 3, 6 and 10 after the ischemic insult. Further, an elevated number of BrdU immunoreactive cells was found at days 3 and 10, and an improved histological picture with reduced neuronal loss at day 10, associated with learning and memory recovery. Pharmacological blockade of the Wnt-3A/β-catenin and Shh pathways, as well as of melanocortin MC4 receptors, prevented all effects of NDP-α-MSH. These data indicate that, in experimental brain ischemia, treatment with melanocortins acting at MC4 receptors induces neural stem/progenitor cell proliferation in the DG by promptly and effectively triggering the canonical Wnt-3A/β-catenin and Shh signaling pathways. Activation of these pathways is associated with up-regulation of the repair factor Zif268 and the neurogenesis facilitating factor IL-10, and it seems to address mainly toward a neuronal fate, as indicated by the increase in DCX positive cells.

• Authors: Luca Spaccapelo, Maria Galantucci, Laura Neri, Miranda Contri, Roberto Pizzala, Roberto D'Amico, Alessandra Ottani, Maurizio Sandrini, Davide Zaffe, Daniela Giuliani, Salvatore Guarini
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 707 Issue 1-3 Pg. 78-86 (May 05 2013) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 23535605 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Doublecortin Domain Proteins
• Hedgehog Proteins
• Microtubule-Associated Proteins
• Neuropeptides
• Receptor, Melanocortin, Type 4
• Wnt3A Protein
• alpha-MSH
• MSH, 4-Nle-7-Phe-alpha-

Topics

• Animals
• Brain Ischemia (drug therapy, pathology)
• Cell Proliferation (drug effects)
• Dentate Gyrus (drug effects, pathology)
• Disease Models, Animal
• Doublecortin Domain Proteins
• Gerbillinae
• Hedgehog Proteins (metabolism)
• Male
• Microtubule-Associated Proteins (metabolism)
• Neural Stem Cells (drug effects, metabolism)
• Neurogenesis (drug effects)
• Neurons (drug effects, metabolism)
• Neuropeptides (metabolism)
• Receptor, Melanocortin, Type 4 (agonists)
• Signal Transduction (drug effects)
• Time Factors
• Up-Regulation (drug effects)
• Wnt Signaling Pathway (drug effects)
• Wnt3A Protein (metabolism)
• alpha-MSH (analogs & derivatives, pharmacology)