Neurovascular protection by post‐ischemic intravenous injections of the lipoxin A4 receptor agonist, BML‐111, in a rat model of ischemic stroke

Resolution of inflammation is an emerging new strategy to reduce damage following ischemic stroke. Lipoxin A4 (LXA4) is an anti‐inflammatory, pro‐resolution lipid mediator with high affinity binding to ALX, the lipoxin A4 receptor. Since LXA4 is rapidly inactivated, potent analogs have been created, including the ALX agonist BML‐111. We hypothesized that post‐ischemic intravenous administration of BML‐111 would provide protection to the neurovascular unit and reduce neuroinflammation in a rat stroke model. Animals were subjected to 90 min of middle cerebral artery occlusion (MCAO) and BML‐111 was injected 100 min and 24 h after stroke onset and animals euthanized at 48 h. Post‐ischemic treatment with BML‐111 significantly reduced infarct size, decreased vasogenic edema, protected against blood–brain barrier disruption, and reduced hemorrhagic transformation. Matrix metalloproteinase‐9 and matrix metalloproteinase‐3 were significantly reduced following BML‐111 treatment. Administration of BML‐111 dramatically decreased microglial activation, as seen with CD68, and neutrophil infiltration and recruitment, as assessed by levels of myeloperoxidase and intracellular adhesion molecule‐1. The tight junction protein zona occludens‐1 was protected from degradation following treatment with BML‐111. These results indicate that post‐ischemic activation of ALX has pro‐resolution effects that limit the inflammatory damage in the cerebral cortex and helps maintain blood–brain barrier integrity after ischemic stroke. Lipoxin A4 (LXA4) is a potent anti‐inflammatory, pro‐resolution mediator. Post‐ischemic injections of BML‐111, a LXA4 receptor agonist, significantly reduced infarct size, matrix metalloproteinases, microglial activation, and neutrophil infiltration, while providing protection to the blood–brain barrier at 48 h following middle cerebral artery occlusion in rats. This suggests that activation and enhancement of the LXA4 resolution pathway may be a new target for therapeutics aimed at reducing neuroinflammation following ischemic stroke. Lipoxin A4 (LXA4) is a potent anti‐inflammatory, pro‐resolution mediator. Post‐ischemic injections of BML‐111, a LXA4 receptor agonist, significantly reduced infarct size, matrix metalloproteinases, microglial activation, and neutrophil infiltration, while providing protection to the blood–brain barrier at 48 h following middle cerebral artery occlusion in rats. This suggests that activation and enhancement of the LXA4 resoluti