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Genetic deletion or pharmacological inhibition of cyclooxygenase‐1 attenuate lipopolysaccharide‐ induced inflammatory response and brain injury
Author(s) -
Choi SangHo,
Langenbach Robert,
Bosetti Francesca
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-9411com
Subject(s) - proinflammatory cytokine , lipopolysaccharide , cyclooxygenase , neuroinflammation , pharmacology , chemistry , microglia , arachidonic acid , inflammation , chemokine , medicine , endocrinology , immunology , biochemistry , enzyme
Cyclooxygenase (COX) ‐1 and ‐2 metabolize arachidonic acid to prostanoids and reactive oxygen species, major μlayers 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‐ κ B 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 2h , and thromboxane B 2 , as well as the expression of proinflammatory cytokines and chemokine. These findings suggest that COX‐1 μlays 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. FASEB J . 22, 1491–1501 (2008)