title: Glucocorticoids Suppress the Protective Effect of Cyclooxygenase-2-Related Signaling on Hippocampal Neurogenesis Under Acute Immune Stress.
abstract: Stress and glucocorticoids suppress adult neurogenesis in the hippocampus. However, the molecular mechanisms underlying stress-induced impairment of adult neurogenesis are poorly understood. We previously suggested that cyclooxygenase (COX)-2 is a common mediator of stresses in the brain. Here, using a lipopolysaccharide (LPS)-induced acute infectious stress model, we evaluated the roles of COX-2 and its major downstream product prostaglandin E2 (PGE2) in adult neurogenesis and the influence of glucocorticoids on COX-2-related signaling. Treatment of rats with LPS significantly decreased neurogenesis in the dentate gyrus (DG) of the hippocampus, and this inhibitory effect of LPS on neurogenesis was reversed by the glucocorticoid receptor antagonist RU486. Moreover, RU486 significantly enhanced the increase in messenger RNA (mRNA) levels of COX-2 and microsomal prostaglandin E synthase (mPGES)-1 in the hippocampus following LPS stimulation. Administration of AH6809, a selective antagonist of the PGE2 EP2 receptor, as well as NS398, a COX-2 selective inhibitor, exacerbated the suppression of proliferation of neural progenitor cells (NPCs) in the DG. Gene expression of EP1, EP2, and EP3, but not EP4, receptors was also increased following LPS stimulation. Immunohistochemical studies indicated that NPCs expressed EP2 receptor, whereas the majority of cells expressing COX-2 and mPGES-1 were mature neurons in the DG. These results suggest that acute infectious stress upregulates COX-2-related signaling in neurons in the DG, which plays a protective role in neurogenesis through EP2 receptor at least partially. In addition, LPS-induced glucocorticoids suppress this COX-2-related signaling, resulting in decreased neurogenesis.
authors.affiliation: Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, 113-8657, Japan.
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, 113-8657, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuwaki
authors.affiliation: Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, 113-8657, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Yamanouchi
authors.affiliation: Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, 113-8657, Japan. amnishi@mail.ecc.u-tokyo.ac.jp.
authors.forename: Masugi
authors.initials: M
authors.lastname: Nishihara
mesh_terms: D000208:Acute Disease; D000818:Animals; D003141:Communicable Diseases / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D007111:Immunity, Cellular / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D044004:Xanthones / Q000494:pharmacology
chemical_list: D005938:Glucocorticoids; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D044004:Xanthones; D015735:Mifepristone; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D051546:Cyclooxygenase 2
keywords: COX-2; Glucocorticoids; Hippocampus; Neurogenesis; Stress; mPGES-1