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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

¹Correspondence: Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. E-mail: frances{at}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-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)E₂, PGD₂, PGF₂, 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.

Key Words: microglia • astrocytes • prostaglandin • NADPH oxidase • oxidative stress