TY - JOUR T1 - Cyclooxygenase 2 Inhibitor Celecoxib Inhibits Glutamate Release by Attenuating the PGE<sub>2</sub>/EP2 Pathway in Rat Cerebral Cortex Endings JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 134 LP - 145 DO - 10.1124/jpet.114.217372 VL - 351 IS - 1 AU - Tzu-Yu Lin AU - Cheng-Wei Lu AU - Chia-Chuan Wang AU - Shu Kuei Huang AU - Su-Jane Wang Y1 - 2014/10/01 UR - http://jpet.aspetjournals.org/content/351/1/134.abstract N2 - The excitotoxicity caused by excessive glutamate is a critical element in the neuropathology of acute and chronic brain disorders. Therefore, inhibition of glutamate release is a potentially valuable therapeutic strategy for treating these diseases. In this study, we investigated the effect of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor that reduces the level of prostaglandin E2 (PGE2), on endogenous glutamate release in rat cerebral cortex nerve terminals (synaptosomes). Celecoxib substantially inhibited the release of glutamate induced by the K+ channel blocker 4-aminopyridine (4-AP), and this phenomenon was prevented by chelating the extracellular Ca2+ ions and by the vesicular transporter inhibitor bafilomycin A1. Celecoxib inhibited a 4-AP–induced increase in cytosolic-free Ca2+ concentration, and the celecoxib-mediated inhibition of glutamate release was prevented by the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel blocker ω-conotoxin MVIIC. However, celecoxib did not alter 4-AP–mediated depolarization and Na+ influx. In addition, this glutamate release–inhibiting effect of celecoxib was mediated through the PGE2 subtype 2 receptor (EP2) because it was not observed in the presence of butaprost (an EP2 agonist) or PF04418948 [1-(4-fluorobenzoyl)-3-[[6-methoxy-2-naphthalenyl)methyl]-3-azetidinecarboxylic acid; an EP2 antagonist]. The celecoxib effect on 4-AP–induced glutamate release was prevented by the inhibition or activation of protein kinase A (PKA), and celecoxib decreased the 4-AP–induced phosphorylation of PKA. We also determined that COX-2 and the EP2 receptor are present in presynaptic terminals because they are colocalized with synaptophysin, a presynaptic marker. These results collectively indicate that celecoxib inhibits glutamate release from nerve terminals by reducing voltage-dependent Ca2+ entry through a signaling cascade involving EP2 and PKA. ER -