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

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 [Nle4,D-Phe7]-melanocyte-stimulating hormone (NDP--MSH) or saline. NDP--MSH increased hippocampus dentate gyrus (DG) expression of Wnt-3A, -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/-catenin and Shh pathways, as well as of melanocortin MC4 receptors, prevented all effects of NDP--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/-catenin and Shh signaling pathways. Activation of these pathways is associated with upregulation of the repair factor Zif268 and the neurogenesis facilitating factor IL-10, and it seems to address mainly towards a neuronal fate, as indicated by the increase in DCX positive cells.