title: Role of oxidative stress in oxaliplatin-induced enteric neuropathy and colonic dysmotility in mice.
abstract: Oxaliplatin is a platinum-based chemotherapeutic drug used as a first-line therapy for colorectal cancer. However, its use is associated with severe gastrointestinal side-effects resulting in dose limitations and/or cessation of treatment. In this study, we tested whether oxidative stress, caused by chronic oxaliplatin treatment, induces enteric neuronal damage and colonic dysmotility.
  
  
  
  Oxaliplatin (3 mg·kg-1per day) was administered in vivo to Balb/c mice intraperitoneally three times a week. The distal colon was collected at day 14 of treatment. Immunohistochemistry was performed in wholemount preparations of submucosal and myenteric ganglia. Neuromuscular transmission was studied by intracellular electrophysiology. Circular muscle tone was studied by force transducers. Colon propulsive activity studied in organ bath experiments and faeces were collected to measure water content.
  
  
  
  Chronic in vivo oxaliplatin treatment resulted in increased formation of reactive oxygen species (O2-), nitration of proteins, mitochondrial membrane depolarisation resulting in the release of cytochrome c, loss of neurons, increased inducible NOS expression and apoptosis in both the submucosal and myenteric plexuses of the colon. Oxaliplatin treatment enhanced NO-mediated inhibitory junction potentials and altered the response of circular muscles to the NO donor, sodium nitroprusside. It also reduced the frequency of colonic migrating motor complexes and decreased circular muscle tone, effects reversed by the NO synthase inhibitor, Nω-Nitro-L-arginine.
  
  
  
  Our study is the first to provide evidence that oxidative stress is a key player in enteric neuropathy and colonic dysmotility leading to symptoms of chronic constipation observed in oxaliplatin-treated mice.
authors.affiliation: Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne, Australia.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: McQuade
authors.affiliation: Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne, Australia.
authors.forename: Simona E
authors.initials: SE
authors.lastname: Carbone
authors.affiliation: Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne, Australia.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Stojanovska
authors.affiliation: Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne, Australia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Rahman
authors.affiliation: Department of Physiology, Melbourne University, Melbourne, Australia.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Gwynne
authors.affiliation: Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne, Australia.
authors.forename: Ainsley M
authors.initials: AM
authors.lastname: Robinson
authors.affiliation: Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne, Australia.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Goodman
authors.affiliation: Department of Physiology, Melbourne University, Melbourne, Australia.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Bornstein
authors.affiliation: Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne, Australia.
authors.forename: Kulmira
authors.initials: K
authors.lastname: Nurgali
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007418:Intestinal Pseudo-Obstruction / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000077150:Oxaliplatin; D018384:Oxidative Stress / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D013481:Superoxides