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Free Content Cyclooxygenase-1 mediates prostaglandin E2 elevation and contextual memory impairment in a model of sustained hippocampal interleukin-1β expression

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J. Neurochem. (2010) 114, 247–258. Abstract

Interleukin (IL)-1β is a proinflammatory cytokine implicated in several neurodegenerative disorders. Downstream actions of IL-1β include production of prostaglandin (PG) E2 by increasing expression of cyclooxygenase (COX) enzymes and prostaglandin E synthase (PGES) isoforms. We recently developed a transgenic mouse carrying a dormant human IL-1β eXcisional Activation Transgene (XAT) for conditional and chronic up-regulation of IL-1β in selected brain regions. This model is characterized by regionally specific glial activation, immune cell recruitment, and induction of cytokines and chemokines. Here, we aimed to elucidate the effects of long-term IL-1β expression on the PGE2 synthetic pathway and to determine the effects of PGs on inflammation and memory in our model. As expected, PGE2 levels were significantly elevated after IL-1β up-regulation. Quantitative real-time PCR analysis indicated significant induction of mRNAs for COX-1 and membranous PGES-1, but not COX-2 or other PGES isoforms. Immunohistochemistry revealed elevation of COX-1 but no change in COX-2 following sustained IL-1β production. Furthermore, pharmacological inhibition of COX-1 and use of COX-1 knockout mice abrogated IL-1β-mediated PGE2 increases. Although COX-1 deficient mice did not present a dramatically altered neuroinflammatory phenotype, they did exhibit improved contextual fear memory. This data suggests a unique role for COX-1 in mediating chronic neuroinflammatory effects through PGE2 production.
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Keywords: cyclooxygenase-1; hippocampus; interleukin-1; neuroinflammation; prostaglandin E2

Document Type: Research Article

Affiliations: 1: Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA 2: Department of Orthodontics and Pediatric Dentistry, Stony Brook University Medical Center, Stony Brook, New York, USA

Publication date: 01 July 2010

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