The melanocortin receptor system has been shown to provide neuro-protection and anti-inflammatory actions in a number of disease models, however the relative contribution of the receptors that mediate these effects (MC1, MC3 and MC4) have yet to be determined. This study aims to evaluate the anti-inflammatory potential of the MRS in the brain following stroke.
In a murine model of global stroke, intravital microscopy revealed significant recruitment of neutrophils to the brain within 40 min of reperfusion. This neutrophil recruitment was found to be enhanced in MC1 mutant (recessive yellow) mice at 40 min but not in MC3 null. In WT mice treatment with the pan receptor agonist α-MSH reduced leukocyte recruitment. Antagonism of MC3 and MC4 with SHU-9119 failed to abrogate the anti-inflammatory effects of α-MSH by 40 min of reperfusion, but was able to blunt these effects at 2 h. Furthermore selective pharmacological activation of MC1 with BMS-470,539 was found to provide potent inhibition of leukocyte recruitment to the brain only at 40 min and not at 2 h. The inflammatory phenotype of the MC1 mutant mouse was also found to be transient and was not detected at 2 h post stroke. On the other hand MC3 targeted compounds were highly effective at this later time point. These investigations reveal an important role for MC1 immediately following cerebral ischemia with a later shift toward MC3 mediated processes. qRT-PCR revealed no changes in receptor mRNA expression in both blood and brain across these time points, however by 2 h α-MSH treatment was found to reduce NF-κβ related gene expression. It is thus possible that the apparent shift in receptor importance is due to the activation of distinct signalling pathways.