title: Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury.
abstract: Cyclooxygenase (COX) -1 and -2 metabolize arachidonic acid to prostanoids and reactive oxygen species, major players in the neuroinflammatory process. While most reports have focused on the inducible isoform, COX-2, the contribution of COX-1 to the inflammatory response is unclear. In the present study, the contribution of COX-1 in the neuroinflammatory response to intracerebroventricular lipopolysaccharide (LPS) was investigated using COX-1 deficient (COX-1(-/-)) mice or wild-type (COX-1(+/+)) mice pretreated with SC-560, a selective COX-1 inhibitor. Twenty-four hours after lipopolysaccharide (LPS) injection, COX-1(-/-) mice showed decreased protein oxidation and LPS-induced neuronal damage in the hippocampus compared with COX-1(+/+) mice. COX-1(-/-) mice showed a significant reduction of microglial activation, proinflammatory mediators, and expression of COX-2, inducible NOS, and NADPH oxidase. The transcriptional down-regulation of cytokines and other inflammatory markers in COX-1(-/-) mice was mediated by a reduced activation of NF-kappaB and signal transducer and activator of transcription 3. Administration of SC-560 prior to LPS injection also attenuated the neuroinflammatory response by decreasing brain levels of prostaglandin (PG)E(2), PGD(2), PGF(2alpha), and thromboxane B(2), as well as the expression of proinflammatory cytokines and chemokine. These findings suggest that COX-1 plays a previously unrecognized role in neuroinflammatory damage.
authors.affiliation: Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Choi
authors.forename: Robert
authors.initials: R
authors.lastname: Langenbach
authors.forename: Francesca
authors.initials: F
authors.lastname: Bosetti
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000172:deficiency*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004660:Encephalitis / Q000139:chemically induced / Q000503:physiopathology*; D008070:Lipopolysaccharides; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects; D009195:Peroxidase / Q000096:biosynthesis; D011720:Pyrazoles / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011720:Pyrazoles; C115461:SC 560; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051996:Transcription Factor RelA; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051545:Cyclooxygenase 1; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1