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Role of oxidative stress in oxaliplatin-induced enteric neuropathy and colonic dysmotility in mice.

Abstract：

BACKGROUND AND PURPOSE: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. EXPERIMENTAL APPROACH:Oxaliplatin (3 mg·kg-1 per 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. KEY RESULTS: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. CONCLUSION AND IMPLICATIONS: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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

McQuade RM,Carbone SE,Stojanovska V,Rahman A,Gwynne RM,Robinson AM,Goodman CA,Bornstein JC,Nurgali K

doi

10.1111/bph.13646

subject

Has Abstract

pub_date

2016-12-01 00:00:00

pages

3502-3521

issue

eissn

0007-1188

issn

1476-5381

journal_volume

173

pub_type

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Role of oxidative stress in oxaliplatin-induced enteric neuropathy and colonic dysmotility in mice.