ABSTRACT
Title
Molecular mechanisms underlying melanocortin-induced neurogenesis following ischemic stroke
Authors
L. Spaccapelo1, M. Galantucci1, A. Ottani1, M. Contri2, F. Cavallini1, D. Zaffe3, D. Giuliani1 and S. Guarini1.
Dept. of Biomedical Sciences, Section of Pharmacology1, Section of General Pathology2 and Section of Human Morphology3, University of Modena and Reggio Emilia, Italy
Dept. of Biomedical Sciences, Section of Pharmacology1, Section of General Pathology2 and Section of Human Morphology3, University of Modena and Reggio Emilia, Italy
Abstract
Melanocortins induce neuroprotection and stimulate neurogenesis in ischemic stroke, with subsequent long-lasting functional recovery (Giuliani et al., 2006a,b,2007,2009, 2011; Ottani et al., 2009), through a melanocortin MC4 receptor-dependent mechanism. Here we investigated the molecular mechanisms underlying melanocortin-induced neurogenesis following ischemic stroke. Gerbils were subjected to transient global cerebral ischemia by occluding both common carotid arteries for a 10-min period, then they were treated every 12 h and until sacrifice with the melanocortin analog [Nle4,D-Phe7]α-melanocyte-stimulating hormone (NDP-α-MSH) or saline. A group of animals was pretreated (before each administration of NDP-α-MSH) with the MC4 receptor antagonist HS024. The expressions of Wnt-3A, Sonic hedgehog (Shh), β-catenin, Zif268, interleukin-10 (IL-10) and doublecortin (DCX) by fluorescence immunohistochemistry, as well as morphological damage, were detected in the hippocampus dentate girus (DG). Immunohistochemical examination of the DG at days 3, 6 and 10 after stroke showed that NDP-α-MSH favourably affected Wnt-3A/β-catenin and Shh signaling pathways, as well as Zif268, IL-10 and DCX expressions.Histological analysis at day 10 showed that NDP-α-MSH-also reduced neuronal loss. Pharmacological blockade of MC4 receptors prevented all effects of NDP-α-MSH. These data indicate that neurogenesis amplification induced by treatment of stroke animals with melanocortins acting at MC4 receptors involves signaling pathways, such as Wnt-3A/β-catenin and Shh, that play an important role in regulating neural stem/progenitor cell proliferation. Activation of these pathways leads to up-regulation of the repair factor Zif268, and of the neurogenesis facilitating factor IL-10, thus addressing towards a neuronal fate, as indicated by the increase in DCX positive cells.