title: Celecoxib Inhibits Prion Protein 90-231-Mediated Pro-inflammatory Responses in Microglial Cells.
abstract: Activation of microglia is a central event in the atypical inflammatory response occurring during prion encephalopathies. We report that the prion protein fragment encompassing amino acids 90-231 (PrP90-231), a model of the neurotoxic activity of the pathogenic prion protein (PrP(Sc)), causes activation of both primary microglia cultures and N9 microglial cells in vitro. This effect was characterized by cell proliferation arrest and induction of a secretory phenotype, releasing prostaglandin E2 (PGE2) and nitric oxide (NO). Conditioned medium from PrP90-231-treated microglia induced in vitro cytotoxicity of A1 mesencephalic neurons, supporting the notion that soluble mediators released by activated microglia contributes to the neurodegeneration during prion diseases. The neuroinflammatory role of COX activity, and its potential targeting for anti-prion therapies, was tested measuring the effects of ketoprofen and celecoxib (preferential inhibitors of COX1 and COX2, respectively) on PrP90-231-induced microglial activation. Celecoxib, but not ketoprofen significantly reverted the growth arrest as well as NO and PGE2 secretion induced by PrP90-231, indicating that PrP90-231 pro-inflammatory response in microglia is mainly dependent on COX2 activation. Taken together, these data outline the importance of microglia in the neurotoxicity occurring during prion diseases and highlight the potentiality of COX2-selective inhibitors to revert microglia as adjunctive pharmacological approach to contrast the neuroinflammation-dependent neurotoxicity.
authors.affiliation: Laboratory of Pharmacology, Dept. of Internal Medicine, and Center of Excellence for Biomedical Research (CEBR), University of Genova, 16132, Genoa, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Villa
authors.affiliation: Laboratory of Pharmacology, Dept. of Internal Medicine, and Center of Excellence for Biomedical Research (CEBR), University of Genova, 16132, Genoa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Thellung
authors.affiliation: Laboratory of Pharmacology, Dept. of Internal Medicine, and Center of Excellence for Biomedical Research (CEBR), University of Genova, 16132, Genoa, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corsaro
authors.affiliation: Department of Pharmacy, University of Genova, 16132, Genoa, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Novelli
authors.affiliation: Department of Pharmacy, University of Genova, 16132, Genoa, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Tasso
authors.affiliation: Laboratory of Experimental Neuropathology, Department of Environmental, Biological and Pharmaceutical Science and Technologies, Second University of Napoli, 81100, Caserta, Italy.|Centro Interuniversitario per la Ricerca in Neuroscienze (CIRN), Second University of Napoli, 81100, Caserta, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Colucci-D'Amato
authors.affiliation: Department of Physics, University of Genova, 16132, Genoa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Gatta
authors.affiliation: Department of Pharmacy, University of Genova, 16132, Genoa, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Tonelli
authors.affiliation: Laboratory of Pharmacology, Dept. of Internal Medicine, and Center of Excellence for Biomedical Research (CEBR), University of Genova, 16132, Genoa, Italy. tullio.florio@unige.it.|Department of Internal Medicine, University of Genova, Viale Benedetto XV, 2, Genoa, 16132, Italy. tullio.florio@unige.it.
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
mesh_terms: D000818:Animals; D000068579:Celecoxib / Q000494:pharmacology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D017096:Prion Diseases / Q000188:drug therapy / Q000378:metabolism; D011328:Prions / Q000378:metabolism; D017207:Rats, Sprague-Dawley
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D008070:Lipopolysaccharides; D011328:Prions; D009569:Nitric Oxide; D000068579:Celecoxib
keywords: Celecoxib; Cyclooxygenase; Microglia; Nitric oxide synthase; PrP90-231; Prion diseases