title: The involvement of mast cells in the irinotecan-induced enteric neurons loss and reactive gliosis.
abstract: The irinotecan (CPT-11) causes intestinal mucositis and diarrhea that may be related to changes in the enteric nervous system (ENS). In inflammatory condition, mast cells release a variety of pro-inflammatory mediators that can interact with the ENS cells. It has not been explored whether CPT-11 is able to alter the enteric glial and neuronal cell, and the role of mast cells in this effect. Therefore, this study was conducted to investigate the effect of CPT-11 on the enteric glial and neuronal cells, as well as to study the role of mast cells in the CPT-11-induced intestinal mucositis.
  
  
  
  Intestinal mucositis was induced in Swiss mice by the injection of CPT-11 (60 mg/kg, i.p.) once a day for 4 days following by euthanasia on the fifth day. To investigate the role of mast cells, the mice were pretreated with compound 48/80 for 4 days (first day, 0.6 mg/kg; second day, 1.0 mg/kg; third day, 1.2 mg/kg; fourth day, 2.4 mg/kg) to induce mast cell degranulation before the CPT-11 treatment.
  
  
  
  Here, we show that CPT-11 increased glial fibrillary acidic protein (GFAP) and S100β gene and S100β protein expressions and decreased HuC/D protein expression in the small intestine segments. Concomitantly, CPT-11 enhanced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels and inducible nitric oxide synthase (iNOS) gene expression, associated with an increase in the total number macrophages (positive cells for ionized calcium-binding adapter molecule, Iba-1) and degranulated mast cells in the small intestine segments and caused significant weight loss. The pretreatment with compound 48/80, an inductor of mast cells degranulation, significantly prevented these CPT-11-induced effects.
  
  
  
  Our data suggests the participation of mast cells on the CPT-11-induced intestinal mucositis, macrophages activation, enteric reactive gliosis, and neuron loss.
authors.affiliation: Department of Morphology, Federal University of Piauí, Teresina, Piauí, Brazil.
authors.forename: Ludmila T
authors.initials: LT
authors.lastname: Nogueira
authors.affiliation: Department of Morphology, Faculty of Medicine, Federal University of Ceará, Farias Delmiro street, Fortaleza, CE, 60430170, Brazil.
authors.forename: Deiziane V S
authors.initials: DV
authors.lastname: Costa
authors.affiliation: Department of Morphology, Faculty of Medicine, Federal University of Ceará, Farias Delmiro street, Fortaleza, CE, 60430170, Brazil.
authors.forename: Antoniella S
authors.initials: AS
authors.lastname: Gomes
authors.affiliation: Department of Morphology, Faculty of Medicine, Federal University of Ceará, Farias Delmiro street, Fortaleza, CE, 60430170, Brazil.
authors.forename: Conceição S
authors.initials: CS
authors.lastname: Martins
authors.affiliation: Department of Morphology, Faculty of Medicine, Federal University of Ceará, Farias Delmiro street, Fortaleza, CE, 60430170, Brazil.
authors.forename: Angeline M H P
authors.initials: AM
authors.lastname: Silva
authors.affiliation: Paulo Niemeyer Brain Institute, Federal University of Rio de Janeiro, UFRJ, Rio de Janeiro, RJ, Brazil.
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Coelho-Aguiar
authors.affiliation: Department of Anatomy, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Castelucci
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Roberto C P
authors.initials: RC
authors.lastname: Lima-Júnior
authors.affiliation: Department of Morphology, Faculty of Medicine, Federal University of Ceará, Farias Delmiro street, Fortaleza, CE, 60430170, Brazil.
authors.forename: Renata F C
authors.initials: RF
authors.lastname: Leitão
authors.affiliation: Paulo Niemeyer Brain Institute, Federal University of Rio de Janeiro, UFRJ, Rio de Janeiro, RJ, Brazil.
authors.forename: Vivaldo
authors.initials: V
authors.lastname: Moura-Neto
authors.affiliation: Department of Morphology, Faculty of Medicine, Federal University of Ceará, Farias Delmiro street, Fortaleza, CE, 60430170, Brazil. gerlybrito@hotmail.com.
authors.forename: Gerly A C
authors.initials: GA
authors.lastname: Brito
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D002452:Cell Count; D017615:Enteric Nervous System / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005911:Gliosis / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077146:Irinotecan; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin
keywords: Enteric nervous system; Glia; Irinotecan; Mast cell; Mucositis; Neuron