title: Peripherally administered orexin improves survival of mice with endotoxin shock.
abstract: Sepsis is a systemic inflammatory response to infection, accounting for the most common cause of death in intensive care units. Here, we report that peripheral administration of the hypothalamic neuropeptide orexin improves the survival of mice with lipopolysaccharide (LPS) induced endotoxin shock, a well-studied septic shock model. The effect is accompanied by a suppression of excessive cytokine production and an increase of catecholamines and corticosterone. We found that peripherally administered orexin penetrates the blood-brain barrier under endotoxin shock, and that central administration of orexin also suppresses the cytokine production and improves the survival, indicating orexin's direct action in the central nervous system (CNS). Orexin helps restore body temperature and potentiates cardiovascular function in LPS-injected mice. Pleiotropic modulation of inflammatory response by orexin through the CNS may constitute a novel therapeutic approach for septic shock.
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Irukayama-Tomobe
authors.affiliation: Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Murakoshi
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Kiyama
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Ishikawa
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Hosokawa
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Tominaga
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Uchida
authors.affiliation: Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Kimura
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Kanuka
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Morita
authors.affiliation: Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Michito
authors.initials: M
authors.lastname: Hamada
authors.affiliation: Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan.|Department of Molecular Genetics and Howard Hughes Medical Institute, Unversity of Texas Southwestern Medical Center, Dallas, United States.
authors.forename: Masashi
authors.identifier: 0000-0002-7358-4022
authors.initials: M
authors.lastname: Yanagisawa
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D001833:Body Temperature Regulation / Q000187:drug effects* / Q000276:immunology; D001919:Bradycardia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D054405:Chemokine CCL3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D054407:Chemokine CCL4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000068797:Orexins / Q000494:pharmacology*; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology
chemical_list: C496534:Ccl3 protein, mouse; C496535:Ccl4 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D020381:Interleukin-17; D008070:Lipopolysaccharides; D000068797:Orexins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: central nervous system; immunology; mouse; neuroscience; orexin; sepsis