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Neurovascular protection by post‐ischemic intravenous injections of the lipoxin A 4 receptor agonist, BML ‐111, in a rat model of ischemic stroke
Author(s) -
Hawkins Kimberly E.,
DeMars Kelly M.,
Singh Jonathan,
Yang Changjun,
Cho Henry S.,
Frankowski Jan C.,
Doré Sylvain,
CandelarioJalil Eduardo
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12607
Subject(s) - neuroinflammation , agonist , blood–brain barrier , medicine , stroke (engine) , ischemia , inflammation , pharmacology , anesthesia , lipoxin , receptor , central nervous system , mechanical engineering , engineering
Resolution of inflammation is an emerging new strategy to reduce damage following ischemic stroke. Lipoxin A 4 ( LXA 4 ) is an anti‐inflammatory, pro‐resolution lipid mediator with high affinity binding to ALX, the lipoxin A 4 receptor. Since LXA 4 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 CD 68, 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 A 4 (LXA 4 ) is a potent anti‐inflammatory, pro‐resolution mediator. Post‐ischemic injections of BML‐111, a LXA 4 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 LXA 4 resolution pathway may be a new target for therapeutics aimed at reducing neuroinflammation following ischemic stroke.