title: Cyclooxygenase 2 inhibitor celecoxib inhibits glutamate release by attenuating the PGE2/EP2 pathway in rat cerebral cortex endings.
abstract: 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 Ca(2+) ions and by the vesicular transporter inhibitor bafilomycin A1. Celecoxib inhibited a 4-AP-induced increase in cytosolic-free Ca(2+) 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 Ca(2+) entry through a signaling cascade involving EP2 and PKA.
authors.affiliation: Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei, Taiwan (T.-Y.L., C.-W.L., S.K.H.); Department of Mechanical Engineering, Yuan Ze University, Taoyuan, Taiwan (T.-Y.L., C.-W.L.); and Graduate Institute of Basic Medicine (S.-J.W.) and School of Medicine (C.-C.W., S.-J.W.), Fu Jen Catholic University, New Taipei, Taiwan.
authors.forename: Tzu-Yu
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei, Taiwan (T.-Y.L., C.-W.L., S.K.H.); Department of Mechanical Engineering, Yuan Ze University, Taoyuan, Taiwan (T.-Y.L., C.-W.L.); and Graduate Institute of Basic Medicine (S.-J.W.) and School of Medicine (C.-C.W., S.-J.W.), Fu Jen Catholic University, New Taipei, Taiwan.
authors.forename: Cheng-Wei
authors.initials: CW
authors.lastname: Lu
authors.affiliation: Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei, Taiwan (T.-Y.L., C.-W.L., S.K.H.); Department of Mechanical Engineering, Yuan Ze University, Taoyuan, Taiwan (T.-Y.L., C.-W.L.); and Graduate Institute of Basic Medicine (S.-J.W.) and School of Medicine (C.-C.W., S.-J.W.), Fu Jen Catholic University, New Taipei, Taiwan.
authors.forename: Chia-Chuan
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei, Taiwan (T.-Y.L., C.-W.L., S.K.H.); Department of Mechanical Engineering, Yuan Ze University, Taoyuan, Taiwan (T.-Y.L., C.-W.L.); and Graduate Institute of Basic Medicine (S.-J.W.) and School of Medicine (C.-C.W., S.-J.W.), Fu Jen Catholic University, New Taipei, Taiwan.
authors.forename: Shu Kuei
authors.initials: SK
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei, Taiwan (T.-Y.L., C.-W.L., S.K.H.); Department of Mechanical Engineering, Yuan Ze University, Taoyuan, Taiwan (T.-Y.L., C.-W.L.); and Graduate Institute of Basic Medicine (S.-J.W.) and School of Medicine (C.-C.W., S.-J.W.), Fu Jen Catholic University, New Taipei, Taiwan med0003@mail.fju.edu.tw.
authors.forename: Su-Jane
authors.initials: SJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D000068579:Celecoxib; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005089:Exocytosis; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D011458:Prostaglandins E / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D052246:Cyclooxygenase 2 Inhibitors; D026902:Potassium Channel Blockers; D011458:Prostaglandins E; D011720:Pyrazoles; D018078:Receptors, Prostaglandin E; D013449:Sulfonamides; D018698:Glutamic Acid; D012964:Sodium; D017868:Cyclic AMP-Dependent Protein Kinases; D000068579:Celecoxib; D011188:Potassium; D002118:Calcium