Journal
BRAIN BEHAVIOR AND IMMUNITY
Volume 62, Issue -, Pages 53-63Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2017.02.003
Keywords
Clodronate liposomes; Cyclooxygenase; Hypothalamo-pituitary-adrenal axis; Paraventricular nucleus; Perivascular macrophage; Prostaglandin E2; Restraint; Stress
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Funding
- NIH [NS-21182]
- Spanish Ministry of Education and Science
- German Research Foundation (DFG) [GR4370]
- National Council for Science and Technology (CONACYT), Mexico
- Bruce Ford and Ann Smith Bundy Foundation
- Carlos III Health Institute
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Activation of the hypothalamo-pituitary-adrenal (HPA) axis by inflammatory stressors (e.g., bacterial lipopolysaccharide) is thought to involve vascular transduction of circulating cytokines, with perivascular macrophages (PVMs) along with endothelia, effecting activation of HPA control circuitry via inducible (cyclooxygenase-2- or COX-2-dependent) prostaglandin synthesis. To test the stressor-specificity of this mechanism, we examined whether ablation of PVMs or pharmacologic blockade of COX activity affected HPA responses to a representative emotional stressor, restraint. Exposing rats to a single 30 min acute restraint episode provoked increased plasma levels of at least one proinflammatory cytokine, IL-6, microglial activation and multiple indices of cerebrovascular activation, including COX-2 expression and increased brain prostaglandin E-2 levels at 0-2 h after stress. Pretreatment with the nonselective COX inhibitor, indomethacin, either icy (10 Kg in 5 I) or iv (1mg/kg) significantly reduced restraint induced Fos expression in the paraventricular hypothalamic nucleus (PVH) by 45%, relative to vehicle injected controls. A 75% reduction of the PVH activational response was seen in rats exposed to acute restraint 5-7 days after ablation of brain PVMs by icy injection of liposomes encapsulating the bisphosphonate drug, clodronate. Basal plasma levels of ACTH and corticosterone were not altered in clodronate liposome-injected rats, but the peak magnitude of restraint-induced HPA secretory responses was substantially reduced, relative to animals pretreated with saline-filled liposomes. These findings support an unexpectedly prominent role for inducible prostaglandin synthesis by PVMs in HPA responses to acute restraint, a prototypic emotional stressor. (C) 2017 Elsevier Inc. All rights reserved.
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