http://www.sciencedirect.com/science/article/pii/S0014299913002203
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 [Nle4,D-Phe7]α-melanocyte-stimulating
hormone (NDP-α-MSH) or saline. NDP-α-MSH increased hippocampus dentate
gyrus (DG) expression of Wnt-3 A, 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-3 A/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-3 A/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 towards a neuronal fate, as indicated by the increase in
DCX positive cells.
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