title: Increased Hypothalamic Levels of Endozepines, Endogenous Ligands of Benzodiazepine Receptors, in a Rat Model of Sepsis.
abstract: The mechanisms involved in septic anorexia are mainly related to the secretion of inflammatory cytokines. The term endozepines designates a family of neuropeptides, including the octadecaneuropeptide (ODN), originally isolated as endogenous ligands of benzodiazepine receptors. Previous data showed that ODN, produced and released by astrocytes, is a potent anorexigenic peptide. We have studied the effect of sepsis by means of a model of cecal ligation and puncture (CLP) on the hypothalamic expression of endozepines (DBI mRNA and protein levels), as well as on the level of neuropeptides controlling energy homeostasis mRNAs: pro-opiomelanocortin, neuropeptide Y, and corticotropin-releasing hormone. In addition, we have investigated the effects of two inflammatory cytokines, TNF-α and IL-1β, on DBI mRNA levels in cultured rat astrocytes.
  
  
  
  Studies were performed on Sprague-Dawley male rats and on cultures of rat cortical astrocytes. Sepsis was induced using the CLP method. Sham-operated control animals underwent the same procedure, but the cecum was neither ligated nor incised.
  
  
  
  Sepsis caused by CLP evoked an increase of DBI mRNA levels in ependymal cells bordering the third ventricle and in tanycytes of the median eminence. CLP-induced sepsis was also associated with stimulated ODN-like immunoreactivity (ODN-LI) in the hypothalamus. In addition, TNF-α, but not IL-1β, induced a dose-dependent increase in DBI mRNA in cultured rat astrocytes. An increase in the mRNA encoding the precursor of the anorexigenic peptide α-melanocyte stimulating hormone, the pro-opiomelanocortin, and the corticotropin-releasing hormone was observed in the hypothalamus.
  
  
  
  These results suggest that during sepsis, hypothalamic mRNA encoding endozepines, anorexigenic peptide as well as stress hormone could play a role in the anorexia/cachexia associated with inflammation due to sepsis and we suggest that this hypothalamic mRNA expression could involve TNF-α.
authors.affiliation: *National Institute for Medical Research (INSERM), U982 †Institute for Research and Innovation in Biomedicine (IRIB), Normandy University ‡Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Rouen University, Mont-Saint-Aignan §Department of Anesthesiology and Critical Care, Rouen University Hospital, Rouen, France ||Institute of Cardiology and Pneumology, Quebec City, Canada ¶Laboratory of Functional Neurophysiology and Pathology, Research Unit UR/11ES09, Tunis, Tunisia #Oncology, Molecular Endocrinology, and Human Genomics Research Center, Quebec, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Clavier
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Besnier
authors.forename: Antoine
authors.initials: A
authors.lastname: Lefevre-Scelles
authors.forename: Damien
authors.initials: D
authors.lastname: Lanfray
authors.forename: Olfa
authors.initials: O
authors.lastname: Masmoudi
authors.forename: Georges
authors.initials: G
authors.lastname: Pelletier
authors.forename: Hélène
authors.initials: H
authors.lastname: Castel
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Tonon
authors.forename: Vincent
authors.initials: V
authors.lastname: Compère
mesh_terms: D000818:Animals; D000855:Anorexia / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000097:blood; D026261:Diazepam Binding Inhibitor / Q000097:blood / Q000378:metabolism*; D004195:Disease Models, Animal; D007031:Hypothalamus / Q000378:metabolism; D066298:In Vitro Techniques; D007249:Inflammation / Q000097:blood / Q000175:diagnosis; D020382:Interleukin-18 / Q000097:blood; D008024:Ligands; D008297:Male; D009478:Neuropeptide Y / Q000097:blood; D009479:Neuropeptides / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D011333:Pro-Opiomelanocortin / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D018805:Sepsis / Q000097:blood* / Q000175:diagnosis* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D026261:Diazepam Binding Inhibitor; D020382:Interleukin-18; D008024:Ligands; D009478:Neuropeptide Y; D009479:Neuropeptides; D010446:Peptide Fragments; D011963:Receptors, GABA-A; D014409:Tumor Necrosis Factor-alpha; C067529:diazepam binding inhibitor (33-50); D011333:Pro-Opiomelanocortin; D003346:Corticotropin-Releasing Hormone