Prostacyclin mediates endothelial COX-2-dependent neuroprotective effects during excitotoxic brain injury

In a previous study, we found that intracerebral administration of excitotoxin (RS)-(tetrazole-5yl) glycine caused increased neural damage in the brain in an endothelial COX-2 deleted mouse line (Tie2Cre COX-2(flox/flox)). In this study, we investigated whether prostacyclin might mediate this endothelial COX-2-dependent neuroprotection. Administration of excitotoxin into the striatum induced the production of prostacyclin (PGI(2)) in wild type, but not in endothelial COX-2 deleted mice. Inhibition of PGI(2) synthase exacerbated brain lesions induced by the excitotoxin in wild type, but not in endothelial COX-2 deleted mice. Administration of a PGI(2) agonist reduced neural damage in both wild type and endothelial COX-2 deleted mice. Increased PGI(2) synthase expression was found in infiltrating neutrophils. In an ex vivo assay, PGI(2) reduced the excitotoxin-induced calcium influx into neurons, suggesting a cellular mechanism for PGI(2) mediated neuroprotection. These results reveal that PGI(2) mediates endothelial COX-2 dependent neuroprotection.