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The Journal of Neuroscience, October 14, 2009, 29(41):12970-12981; doi:10.1523/JNEUROSCI.2373-09.2009

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Behavioral/Systems/Cognitive
Cerebrovascular Cyclooxygenase-1 Expression, Regulation, and Role in Hypothalamic-Pituitary-Adrenal Axis Activation by Inflammatory Stimuli

Borja García-Bueno,^1,2 * Jordi Serrats,^1 * and Paul E. Sawchenko¹

¹Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies and Clayton Medical Research Foundation, La Jolla, California 92037, and ²Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain

Correspondence should be addressed to Dr. Paul E. Sawchenko, Laboratory of Neuronal Structure and Function, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037. Email: sawchenko{at}salk.edu

Systemic injection of lipopolysaccharide (LPS) is a widely used model of immune/inflammatory challenge, which can invoke a host of CNS responses, including activation of the hypothalamic-pituitary-adrenal (HPA) axis. Inducible vascular prostaglandin E₂ (PGE₂) synthesis by endothelial (ECs) and/or perivascular cells (PVCs) (a macrophage-derived vascular cell type) is implicated in the engagement of HPA and other CNS responses, by virtue of their capacity to express cyclooxygenase-2 (COX-2) and microsomal PGE₂ synthase-1. Evidence from genetic and pharmacologic studies also supports a role for the constitutively expressed COX-1 in inflammation-induced activation of the HPA axis, although histochemical evidence to support relevant localization(s) and regulation of COX-1 expression is lacking. The present experiments fill this void in showing that COX-1 immunoreactivity (IR) and mRNA are detectable in identified PVCs and parenchymal microglia under basal conditions and is robustly expressed in these and ECs 1–3 h after intravenous injection of LPS (2 µg/kg). Confocal and electron microscopic analyses indicate distinct cellular/subcellular localizations of COX-1-IR in the three cell types. Interestingly, COX-1 expression is enhanced in ECs of brain PVC-depleted rats, supporting an anti-inflammatory role of the latter cell type. Functional involvement of COX-1 is indicated by the observation that central, but not systemic, pretreatment with the selective COX-1 inhibitor SC-560 attenuated the early phase of LPS-induced increases in adrenocorticotropin and corticosterone secretion. These findings support an involvement of COX-1 in bidirectional interplay between ECs and PVCs in initiating vascular PGE₂ and downstream HPA response to proinflammatory challenges.

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Received May 20, 2009; revised Aug. 20, 2009; accepted Sept. 4, 2009.

Correspondence should be addressed to Dr. Paul E. Sawchenko, Laboratory of Neuronal Structure and Function, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037. Email: sawchenko{at}salk.edu

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