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

View Article: PubMed Central - PubMed

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 (O2ˉ), 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.

No MeSH data available.


Related in: MedlinePlus

Translocation of nitrotyrosine to the nuclei of submucosal and myenteric neurons. Whole‐mount preparations of colonic submucosal ganglia from day 14 sham (A–AII) and oxaliplatin‐treated (B–BII) mice and myenteric ganglia from sham (C–CII) and oxaliplatin‐treated (D–DII) mice. Scale bar = 50 μm. Neurons and ganglia were labelled with anti‐β‐tubulin III antibody (Tub III, red). Nitrotyrosine within the ganglia was labelled with anti‐nitrotyrosine antibody (NT, green). *P < 0.05, significantly different as indicated; n = 6 mice per group.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5120153&req=5

bph13646-fig-0004: Translocation of nitrotyrosine to the nuclei of submucosal and myenteric neurons. Whole‐mount preparations of colonic submucosal ganglia from day 14 sham (A–AII) and oxaliplatin‐treated (B–BII) mice and myenteric ganglia from sham (C–CII) and oxaliplatin‐treated (D–DII) mice. Scale bar = 50 μm. Neurons and ganglia were labelled with anti‐β‐tubulin III antibody (Tub III, red). Nitrotyrosine within the ganglia was labelled with anti‐nitrotyrosine antibody (NT, green). *P < 0.05, significantly different as indicated; n = 6 mice per group.

Mentions: An antibody against nitrotyrosine was used to label nitrated proteins within the submucosal (Figure 4A–AII and B–BII) and myenteric (Figure 4C–CII and D–DII) plexuses. The number of neurons per 2 mm2 displaying translocation of nitrated proteins to the nuclei was higher in both the submucosal and myenteric plexuses of the colon from oxaliplatin‐treated ,compared with sham‐treated (Figure 4E).


Role of oxidative stress in oxaliplatin ‐ induced enteric neuropathy and colonic dysmotility in mice
Translocation of nitrotyrosine to the nuclei of submucosal and myenteric neurons. Whole‐mount preparations of colonic submucosal ganglia from day 14 sham (A–AII) and oxaliplatin‐treated (B–BII) mice and myenteric ganglia from sham (C–CII) and oxaliplatin‐treated (D–DII) mice. Scale bar = 50 μm. Neurons and ganglia were labelled with anti‐β‐tubulin III antibody (Tub III, red). Nitrotyrosine within the ganglia was labelled with anti‐nitrotyrosine antibody (NT, green). *P < 0.05, significantly different as indicated; n = 6 mice per group.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120153&req=5

bph13646-fig-0004: Translocation of nitrotyrosine to the nuclei of submucosal and myenteric neurons. Whole‐mount preparations of colonic submucosal ganglia from day 14 sham (A–AII) and oxaliplatin‐treated (B–BII) mice and myenteric ganglia from sham (C–CII) and oxaliplatin‐treated (D–DII) mice. Scale bar = 50 μm. Neurons and ganglia were labelled with anti‐β‐tubulin III antibody (Tub III, red). Nitrotyrosine within the ganglia was labelled with anti‐nitrotyrosine antibody (NT, green). *P < 0.05, significantly different as indicated; n = 6 mice per group.
Mentions: An antibody against nitrotyrosine was used to label nitrated proteins within the submucosal (Figure 4A–AII and B–BII) and myenteric (Figure 4C–CII and D–DII) plexuses. The number of neurons per 2 mm2 displaying translocation of nitrated proteins to the nuclei was higher in both the submucosal and myenteric plexuses of the colon from oxaliplatin‐treated ,compared with sham‐treated (Figure 4E).

View Article: PubMed Central - PubMed

ABSTRACT

Background and purpose: Oxaliplatin is a platinum&#8208;based chemotherapeutic drug used as a first&#8208;line therapy for colorectal cancer. However, its use is associated with severe gastrointestinal side&#8208;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&nbsp;mg&middot;kg&minus;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&#713;), 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&#8208;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, N&omega;&#8208;Nitro&#8208;L&#8208;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&#8208;treated mice.

No MeSH data available.


Related in: MedlinePlus