Abstract
BackgroundCyclooxygenases (COX) -1 and -2 are key mediators of the inflammatory response in the central nervous system. Since COX-2 is inducible by inflammatory stimuli, it has been traditionally considered as the most appropriate target for anti-inflammatory drugs. However, the specific roles of COX-1 and COX-2 in modulating a neuroinflammatory response are unclear. Recently, we demonstrated that COX-1 deficient mice show decreased neuroinflammatory response and neuronal damage in response to lipopolysaccharide (LPS).MethodsIn this study, we investigated the role of COX-2 in the neuroinflammatory response to intracerebroventricular-injected LPS (5 μg), a model of direct activation of innate immunity, using COX-2 deficient (COX-2-/-) and wild type (COX-2+/+) mice, as well as COX-2+/+ mice pretreated for 6 weeks with celecoxib, a COX-2 selective inhibitor.ResultsTwenty-four hours after LPS injection, COX-2-/- mice showed increased neuronal damage, glial cell activation, mRNA and protein expression of markers of inflammation and oxidative stress, such as cytokines, chemokines, iNOS and NADPH oxidase. Brain protein levels of IL-1β, NADPH oxidase subunit p67phox, and phosphorylated-signal transducer and activator of transcription 3 (STAT3) were higher in COX-2-/- and in celecoxib-treated mice, compared to COX-2+/+ mice. The increased neuroinflammatory response in COX-2-/- mice was likely mediated by the upregulation of STAT3 and suppressor of cytokine signaling 3 (SOCS3).ConclusionThese results show that inhibiting COX-2 activity can exacerbate the inflammatory response to LPS, possibly by increasing glial cells activation and upregulating the STAT3 and SOCS3 pathways in the brain.
Highlights
Prostaglandin endoperoxide synthases or cyclooxygenases (COX-1 and COX-2) play a central role in the inflammatory cascade by converting arachidonic acid (AA), released from membrane phospholipids by a phospholipase A2 (PLA2), into prostaglandin endoperoxide H2, which in turn is converted to bioactive prostanoids by specific terminal synthases
We demonstrate that COX-2-/- mice are more susceptible than COX-2+/+ mice to LPS-induced neuronal injury and exhibit an increase in microglia and astrocyte activation, and increases in the expression of genes and proteins for inflammatory cytokines, chemokines, reactive oxygen species-generating enzymes, such as inducible nitric oxide synthase (iNOS) and NADPH oxidase, and in the expression of signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) signaling molecules
LPS-induced glial cell activation is increased in COX-2-/mice To determine glial cell response, we examined the expression of glial fibrillary acidic protein (GFAP), a specific marker for astrocytes, and scavenger receptor A (SRA), a specific marker for phagocytic microglia [36], 24 h after LPS injection, using quantitative real time PCR and immunohistochemistry
Summary
Prostaglandin endoperoxide synthases or cyclooxygenases (COX-1 and COX-2) play a central role in the inflammatory cascade by converting arachidonic acid (AA), released from membrane phospholipids by a phospholipase A2 (PLA2), into prostaglandin endoperoxide H2, which in turn is converted to bioactive prostanoids by specific terminal synthases. In the CNS, COX-2 has been implicated in important physiological functions such as synaptic transmission, neurotransmitter release, blood flow regulation, and sleep/wake cycle [5,6,7,8,9]. Both COX-1 and COX-2 have been shown to play important roles in an inflammatory response, their contribution being different depending on the type of insult, the time after insult, and the tissue examined [6,10]. Since COX-2 is inducible by inflammatory stimuli, it has been traditionally considered as the most appropriate target for anti-inflammatory drugs. We demonstrated that COX-1 deficient mice show decreased neuroinflammatory response and neuronal damage in response to lipopolysaccharide (LPS)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
