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

Authors An Y, Belevych N, Wang Y, Zhang H, Nasse J, Herschman H, Chen Q, Tarr A, Liu X, Quan N

Received 27 February 2014

Accepted for publication 2 April 2014

Published 21 May 2014 Volume 2014:7 Pages 57—67

DOI https://doi.org/10.2147/JIR.S63205

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 4

Ying An,1,2 Natalya Belevych,1,2 Yufen Wang,1,2 Hao Zhang,1 Jason S Nasse,3 Harvey Herschman,4 Qun Chen,1,2 Andrew Tarr,1,2 Xiaoyu Liu,1,2 Ning Quan1,2

1Institute for Behavior Medicine Research, 2Department of Oral Biology, College of Dentistry, 3Neuroscience Graduate Studies Program, The Ohio State University, Columbus, OH, USA; 4Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA

Abstract: 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-2flox/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 (PGI2) in wild type, but not in endothelial COX-2 deleted mice. Inhibition of PGI2 synthase exacerbated brain lesions induced by the excitotoxin in wild type, but not in endothelial COX-2 deleted mice. Administration of a PGI2 agonist reduced neural damage in both wild type and endothelial COX-2 deleted mice. Increased PGI2 synthase expression was found in infiltrating neutrophils. In an ex vivo assay, PGI2 reduced the excitotoxin-induced calcium influx into neurons, suggesting a cellular mechanism for PGI2 mediated neuroprotection. These results reveal that PGI2 mediates endothelial COX-2 dependent neuroprotection.

Keywords: neural injury, prostaglandins, neutrophil, conditional COX-2 deletion, PGI2

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