Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury Sang-Ho Choi * , Robert Langenbach † and Francesca Bosetti * ,1 * Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA, and † Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA 1 Correspondence: Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. E-mail: frances@mail.nih.gov 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)E 2 , PGD 2 , PGF 2α , 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.—Choi, S-H., Langenbach, R., Bosetti, F. Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury. Key Words: microglia • astrocytes • prostaglandin • NADPH oxidase • oxidative stress
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Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury
Choi, Sang-Ho; Langenbach, Robert; Bosetti, Francesca
Follow The FASEB Journal
, Volume 22 (5): 1491
Fed of American Socs for Experimental Biology – May 1, 2008
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