Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury
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 st...
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Published in | The FASEB journal Vol. 22; no. 5; pp. 1491 - 1501 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
United States
The Federation of American Societies for Experimental Biology
01.05.2008
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Subjects | |
Online Access | Get more information |
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Summary: | 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-κB 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)E₂, PGD₂, PGF₂α, and thromboxane B₂, as well as the expression of proinflammatory cytokines and chemokine. These findings suggest that COX-1 plays a previously unrecognized role in neuroinflammatory damage.--Choi, S-H., Langenbach, R., Bosetti, F. Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury. |
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ISSN: | 0892-6638 1530-6860 |
DOI: | 10.1096/fj.07-9411com |