Both MC1 and MC3 Receptors Provide Protection From Cerebral Ischemia-Reperfusion-Induced Neutrophil Recruitment.

Objective Neutrophil recruitment is a key process in the pathogenesis of stroke, and may provide a valuable therapeutic target. Targeting the melanocortin receptors (MC) has previously shown to inhibit leukocyte recruitment in peripheral inflammation, however it is not known whether treatments are effective in the unique cerebral microvascular environment. Here, we provide novel research highlighting the effects of the melanocortin peptides on cerebral neutrophil recruitment, demonstrating important yet discrete roles for both MC1 and MC3. Approach and Results Using intravital microscopy, in two distinct murine models of cerebral ischemia-reperfusion (I/R) injury we have investigated melanocortin control over neutrophil recruitment. Following global I/R, pharmacological treatments suppressed pathological neutrophil recruitment. MC1 selective treatment rapidly inhibited neutrophil recruitment while a non-selective MC agonist provided protection even when co-administered with an MC3/4 antagonist, suggesting the importance of early MC1 signaling. However by 2h reperfusion, MC1 mediated effects were reduced, and MC3 anti-inflammatory circuits predominated. Mice bearing a non-functional MC1 displayed a transient exacerbation of neutrophil recruitment following global I/R, which diminished by 2h. However importantly, enhanced inflammatory responses in both MC1 mutant and MC3 -/- mice resulted in increased infarct size and poor functional outcome following focal I/R. Furthermore we utilized an in vitro model of leukocyte recruitment to demonstrate these anti-inflammatory actions are also effective in human cells. Conclusions These studies reveal for the first time melanocortin control over neutrophil recruitment in the unique pathophysiological context of cerebral I/R, whilst also demonstrating the potential therapeutic value of targeting multiple MCs in developing effective therapeutics