title: Novel selective COX-1 inhibitors suppress neuroinflammatory mediators in LPS-stimulated N13 microglial cells.
abstract: COX-1 plays a previously unrecognized part in the neuroinflammation. Genetic ablation or pharmacological inhibition of COX-1 activity attenuates the inflammatory response and neuronal loss. In this context, the effects of selective COX-1 inhibitors (P6, P10, SC-560, aspirin) and coxibs (celecoxib and etoricoxib) on LPS-stimulated microglial cell function (a worldwide accepted neuroinflammation model) were investigated, and the effects on COX-1/COX-2, cPGES mRNA and iNOS expression, PGE(2) and NO production and NF-κB activation by IκBα phosphorylation were evaluated. The total suppression of the expression of both COX-1 and COX-2 by their respective selective inhibitors occurred. NF-κB remained almost completely inactive in the presence of coxibs, as expected, and totally inactive in the presence of P6. P6 also markedly counteracted LPS enhancing cPGES mRNA expression and PGE(2) production. Since COX-1 is predominantly localized in microglia, its high selective inhibition rather than COX-2 (by coxibs) is more likely to reduce neuroinflammation and has been further investigated as a potential therapeutic approach and prevention in neurodegenerative diseases with a marked inflammatory component.
authors: Dipartimento Farmaco-Biologico, Università degli Studi di Bari A. Moro, Via E.Orabona 4, 70125 Bari, Italy.
authors: Rosa
authors: R
authors: Calvello
authors: Maria Antonietta
authors: MA
authors: Panaro
authors: Maria Luigia
authors: ML
authors: Carbone
authors: Antonia
authors: A
authors: Cianciulli
authors: Maria Grazia
authors: MG
authors: Perrone
authors: Paola
authors: P
authors: Vitale
authors: Paola
authors: P
authors: Malerba
authors: Antonio
authors: A
authors: Scilimati
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D000068579:Celecoxib; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D000077613:Etoricoxib; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation; D000071876:Prostaglandin-E Synthases; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; C115461:SC 560; D013449:Sulfonamides; D013450:Sulfones; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D000068579:Celecoxib; D015232:Dinoprostone; D001241:Aspirin; D000077613:Etoricoxib