title: Increased Ghrelin but Low Ghrelin-Reactive Immunoglobulins in a Rat Model of Methotrexate Chemotherapy-Induced Anorexia.
abstract: OBJECTIVE
  Cancer chemotherapy is commonly accompanied by mucositis, anorexia, weight loss, and anxiety independently from cancer-induced anorexia-cachexia, further aggravating clinical outcome. Ghrelin is a peptide hormone produced in gastric mucosa that reaches the brain to stimulate appetite. In plasma, ghrelin is protected from degradation by ghrelin-reactive immunoglobulins (Ig). To analyze possible involvement of ghrelin in the chemotherapy-induced anorexia and anxiety, gastric ghrelin expression, plasma levels of ghrelin, and ghrelin-reactive IgG were studied in rats treated with methotrexate (MTX).
  
  
  METHODS
  Rats received MTX (2.5 mg/kg, subcutaneously) for three consecutive days and were killed 3 days later, at the peak of anorexia and weight loss. Control rats received phosphate-buffered saline. Preproghrelin mRNA expression in the stomach was analyzed by in situ hybridization. Plasma levels of ghrelin and ghrelin-reactive IgG were measured by immunoenzymatic assays and IgG affinity kinetics by surface plasmon resonance. Anxiety- and depression-like behaviors in MTX-treated anorectic and in control rats were evaluated in the elevated plus-maze and the forced-swim test, respectively.
  
  
  RESULTS
  In MTX-treated anorectic rats, the number of preproghrelin mRNA-producing cells was found increased (by 51.3%, p < 0.001) as well were plasma concentrations of both ghrelin and des-acyl-ghrelin (by 70.4%, p < 0.05 and 98.3%, p < 0.01, respectively). In contrast, plasma levels of total IgG reactive with ghrelin and des-acyl-ghrelin were drastically decreased (by 87.2 and 88.4%, respectively, both p < 0.001), and affinity kinetics of these IgG were characterized by increased small and big Kd, respectively. MTX-treated rats displayed increased anxiety- but not depression-like behavior.
  
  
  CONCLUSIONS
  MTX-induced anorexia, weight loss, and anxiety are accompanied by increased ghrelin production and by a decrease of ghrelin-reactive IgG levels and affinity binding properties. Such changes of ghrelin-reactive IgG may underlie their decreased ghrelin-transporting capacities compromising ghrelin orexigenic and anxiolytic effects and contributing to chemotherapy-induced loss of appetite.
authors: Nutrition, Gut and Brain Laboratory, INSERM UMR1073, Rouen, France; Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, France.
authors: Marie
authors: M
authors: François
authors: Nutrition, Gut and Brain Laboratory, INSERM UMR1073, Rouen, France; Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, France.
authors: Kuniko
authors: K
authors: Takagi
authors: Nutrition, Gut and Brain Laboratory, INSERM UMR1073, Rouen, France; Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, France.
authors: Romain
authors: R
authors: Legrand
authors: Nutrition, Gut and Brain Laboratory, INSERM UMR1073, Rouen, France; Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, France.
authors: Nicolas
authors: N
authors: Lucas
authors: Nutrition, Gut and Brain Laboratory, INSERM UMR1073, Rouen, France; Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, France.
authors: Stephanie
authors: S
authors: Beutheu
authors: Nutrition, Gut and Brain Laboratory, INSERM UMR1073, Rouen, France; Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, France.
authors: Christine
authors: C
authors: Bôle-Feysot
authors: Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, France; Animal Behavior Platform (SCAC), Rouen, France.
authors: Aurore
authors: A
authors: Cravezic
authors: Nutrition, Gut and Brain Laboratory, INSERM UMR1073, Rouen, France; Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, France.
authors: Naouel
authors: N
authors: Tennoune
authors: Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, France; Animal Behavior Platform (SCAC), Rouen, France.
authors: Jean-Claude
authors: JC
authors: do Rego
authors: Nutrition, Gut and Brain Laboratory, INSERM UMR1073, Rouen, France; Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, France; Department of Nutrition, Rouen University Hospital, CHU Charles Nicolle, Rouen, France.
authors: Moïse
authors: M
authors: Coëffier
authors: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences , Kagoshima , Japan.
authors: Akio
authors: A
authors: Inui
authors: Nutrition, Gut and Brain Laboratory, INSERM UMR1073, Rouen, France; Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, France; Department of Nutrition, Rouen University Hospital, CHU Charles Nicolle, Rouen, France.
authors: Pierre
authors: P
authors: Déchelotte
authors: Nutrition, Gut and Brain Laboratory, INSERM UMR1073, Rouen, France; Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, France.
authors: Sergueï O
authors: SO
authors: Fetissov
keywords: anorexia; autoantibodies; chemotherapy; ghrelin; intestinal inflammation