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dc.contributor.authorMcQuade, RM
dc.contributor.authorCarbone, SE
dc.contributor.authorStojanovska, V
dc.contributor.authorRahman, A
dc.contributor.authorGwynne, RM
dc.contributor.authorRobinson, AM
dc.contributor.authorGoodman, CA
dc.contributor.authorBornstein, JC
dc.contributor.authorNurgali, K
dc.date.accessioned2020-12-22T03:02:45Z
dc.date.available2020-12-22T03:02:45Z
dc.date.issued2016-12-01
dc.identifier.citationMcQuade, R. M., Carbone, S. E., Stojanovska, V., Rahman, A., Gwynne, R. M., Robinson, A. M., Goodman, C. A., Bornstein, J. C. & Nurgali, K. (2016). Role of oxidative stress in oxaliplatin-induced enteric neuropathy and colonic dysmotility in mice. BRITISH JOURNAL OF PHARMACOLOGY, 173 (24), pp.3502-3521. https://doi.org/10.1111/bph.13646.
dc.identifier.issn0007-1188
dc.identifier.urihttp://hdl.handle.net/11343/257766
dc.description.abstractBACKGROUND 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.
dc.languageEnglish
dc.publisherWILEY
dc.titleRole of oxidative stress in oxaliplatin-induced enteric neuropathy and colonic dysmotility in mice
dc.typeJournal Article
dc.identifier.doi10.1111/bph.13646
melbourne.affiliation.departmentPhysiology
melbourne.affiliation.departmentMedicine and Radiology
melbourne.source.titleBritish Journal of Pharmacology
melbourne.source.volume173
melbourne.source.issue24
melbourne.source.pages3502-3521
dc.rights.licenseCC BY-NC-ND
melbourne.elementsid1125176
melbourne.contributor.authorBornstein, Joel
melbourne.contributor.authorGwynne, Rachel
melbourne.contributor.authorGoodman, Craig
melbourne.contributor.authorMcQuade, Rachel
dc.identifier.eissn1476-5381
melbourne.accessrightsOpen Access


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