title: Enteric neuropathy evoked by repeated cisplatin in the rat.
abstract: BACKGROUND
  Acute administration of the antitumoral drug cisplatin can induce nausea/emesis and diarrhea. The long-term effects of cisplatin on gastrointestinal motility, particularly after repeated administration, are not well known. Because cisplatin is highly neurotoxic, myenteric neurons can be affected. Our aim was to study the prolonged effects of repeated cisplatin administration in a rat model, focusing on gastrointestinal motor function and myenteric neurons.
  
  
  METHODS
  Rats received saline or cisplatin (1 or 3 mg kg(-1), i.p.) once weekly for 5 weeks. One week after treatment, both upper gastrointestinal transit and colonic activity were evaluated, and tissue samples from ileum, colon and rectum were processed for histological analysis. Intestinal transit was measured invasively (charcoal method). Colonic activity was determined electromyographically. The gut wall structure was evaluated in sections using conventional histology and immunohistochemistry. Whole-mount preparations from the distal colon were labeled for different markers, including nitric oxide synthase (NOS) and calcitonin-gene related peptide (CGRP) to determine relative proportions of myenteric neurons vs the total neuronal population labeled with HuC/D.
  
  
  RESULTS
  One week after repeated cisplatin exposure, the upper gastrointestinal transit rate and colonic activity were dose-dependently reduced. The number of NSE- or HuC/D-immunoreactive myenteric neurons per ganglion was decreased; the proportion of CGRP-immunoreactive neurons was decreased, whereas that of NOS-immunoreactive cells was increased.
  
  
  CONCLUSIONS
  Chronic cisplatin may induce an enteric neuropathy characterized by changes in myenteric neurons associated with marked gastrointestinal motor dysfunction.
authors.affiliation: Department of Pharmacology and Nutrition, Rey Juan Carlos University, Alcorcón, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Vera
authors.forename: M
authors.initials: M
authors.lastname: Castillo
authors.forename: P A
authors.initials: PA
authors.lastname: Cabezos
authors.forename: A
authors.initials: A
authors.lastname: Chiarlone
authors.forename: M I
authors.initials: MI
authors.lastname: Martín
authors.forename: A
authors.initials: A
authors.lastname: Gori
authors.forename: G
authors.initials: G
authors.lastname: Pasquinelli
authors.forename: G
authors.initials: G
authors.lastname: Barbara
authors.forename: V
authors.initials: V
authors.lastname: Stanghellini
authors.forename: R
authors.initials: R
authors.lastname: Corinaldesi
authors.forename: R
authors.initials: R
authors.lastname: De Giorgio
authors.forename: R
authors.initials: R
authors.lastname: Abalo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002945:Cisplatin / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D017615:Enteric Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D008297:Male; D009197:Myenteric Plexus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000970:Antineoplastic Agents; D019001:Nitric Oxide Synthase; D015740:Calcitonin Gene-Related Peptide; D002945:Cisplatin