Oxidative stress and neuronal apoptosis play crucial roles in secondary
brain injury (SBI) after
intracerebral hemorrhage (ICH). Recently, Nle4-D-Phe7-α-melanocyte-stimulating
hormone (
NDP-MSH), a synthetic agonist of the
melanocortin-1 receptor (Mc1r), has been proved to inhibit neuroinflammatory in several diseases. This study is aimed at exploring if
NDP-MSH could reduce oxidative stress and neuronal apoptosis following ICH, as well as the potential mechanism. A mouse ICH model was induced by autologous blood injection.
NDP-MSH was intraperitoneally injected at 1 h after ICH. Mc1r
siRNA and PI3K inhibitor
LY294002 were administrated to inhibit the expression of Mc1r and phosphorylation of PI3K, respectively. Neurological test, brain water content,
enzyme-linked
immunosorbent assay (ELISA),
terminal deoxynucleotidyl transferase-mediated dUTP-
biotin nick end labeling (TUNEL), immunofluorescence, and Western blot analysis were utilized in this study. The results exhibited that Mc1r was mainly expressed in neurons, and its level in the ipsilateral hemisphere was significantly elevated after ICH.
NDP-MSH treatment significantly attenuated the neurological deficits and brain water content 24 hours after ICH, which was accompanied by the inhibition of oxidative stress and neuronal apoptosis. The administration of
NDP-MSH after ICH significantly promoted the expression of Mc1r, p-PI3K, p-Akt, and p-Nrf2, followed by an increase of Bcl-2 and reduction of cleaved
caspase-3. Conversely, downregulating the expression of Mc1r and phosphorylation of PI3K aggravated the neurological deficits and
brain edema at 24 hours after ICH, meanwhile, the effect of
NDP-MSH on the expression of Mc1r, p-PI3K, p-Akt, p-Nrf2, Bcl-2, and cleaved
caspase 3 was also abolished. In conclusion, our data suggest that the activation of Mc1r by
NDP-MSH ameliorates oxidative stress and neuronal apoptosis through the PI3K/Akt/Nrf2 signaling pathway after ICH in mice.