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.
Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA.
Kimberly E
KE
Hawkins
Kelly M
KM
DeMars
Jonathan
J
Singh
Changjun
C
Yang
Henry S
HS
Cho
Jan C
JC
Frankowski
Sylvain
S
Doré
Eduardo
E
Candelario-Jalil
D000818:Animals; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D044067:Receptors, Lipoxin / Q000819:agonists*; D020521:Stroke / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors
C530770:5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester; D006538:Heptanoic Acids; D018696:Neuroprotective Agents; D044067:Receptors, Lipoxin; C482540:lipoxin A(4) receptor, rat
blood-brain barrier; hemorrhagic transformation; matrix metalloproteinases; neuroinflammation; neutrophil recruitment; vasogenic edema