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

Abstract

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.

• Authors: Kimberly E Hawkins, Kelly M DeMars, Jonathan Singh, Changjun Yang, Henry S Cho, Jan C Frankowski, Sylvain Doré, Eduardo Candelario-Jalil
• Journal: Journal of neurochemistry (J Neurochem) Vol. 129 Issue 1 Pg. 130-42 (Apr 2014) ISSN: 1471-4159 [Electronic] England
• PMID: 24225006 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of The International Society for Neurochemistry.

Chemical References

• 5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester
• Heptanoic Acids
• Neuroprotective Agents
• Receptors, Lipoxin
• lipoxin A(4) receptor, rat

Topics

• Animals
• Brain Ischemia (pathology, prevention & control)
• Cell Line, Tumor
• Disease Models, Animal
• Heptanoic Acids (administration & dosage)
• Humans
• Injections, Intravenous
• Male
• Neuroprotective Agents (administration & dosage)
• Rats
• Rats, Wistar
• Receptors, Lipoxin (agonists)
• Stroke (pathology, prevention & control)
• Time Factors