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.