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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

Effects of oxaliplatin treatment on colonic smooth muscles. (A,AI) Smooth muscle relaxation following application of the NO donor, SNP (10 μM) to the colon from day 14 sham (A) and oxaliplatin‐treated (AI) mice. (B) Comparison of the maximum relaxation produced by circular muscles in response to SNP in colonic preparations from sham and oxaliplatin‐treated mice quantified as an absolute change in the force transduction from the basal values. *P < 0.05, significantly different as indicated; n = 6 mice per group. (C) Resting diameter of the distal colon from sham and oxaliplatin‐treated mice. *P = 0.05, significantly different as indicated; n = 7 mice per group. (D) Gross morphological changes in the colon following repeated in vivo oxaliplatin administration. Colonic crypt length was shorter in oxaliplatin‐treated mice and muscle thickness was reduced in comparison to the sham‐treated animals. (DI) Statistical analysis of the muscle layer thickness in the colon preparations from sham and oxaliplatin‐treated mice. Data presented as mean ± SEM. *P < 0.05, significantly different as indicated; n = 6 mice per group, 10 sections per preparation from each animal.
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bph13646-fig-0007: Effects of oxaliplatin treatment on colonic smooth muscles. (A,AI) Smooth muscle relaxation following application of the NO donor, SNP (10 μM) to the colon from day 14 sham (A) and oxaliplatin‐treated (AI) mice. (B) Comparison of the maximum relaxation produced by circular muscles in response to SNP in colonic preparations from sham and oxaliplatin‐treated mice quantified as an absolute change in the force transduction from the basal values. *P < 0.05, significantly different as indicated; n = 6 mice per group. (C) Resting diameter of the distal colon from sham and oxaliplatin‐treated mice. *P = 0.05, significantly different as indicated; n = 7 mice per group. (D) Gross morphological changes in the colon following repeated in vivo oxaliplatin administration. Colonic crypt length was shorter in oxaliplatin‐treated mice and muscle thickness was reduced in comparison to the sham‐treated animals. (DI) Statistical analysis of the muscle layer thickness in the colon preparations from sham and oxaliplatin‐treated mice. Data presented as mean ± SEM. *P < 0.05, significantly different as indicated; n = 6 mice per group, 10 sections per preparation from each animal.

Mentions: Smooth muscle tone of the distal colon was studied in organ bath experiments using force transducers. We measured the force produced by 3 mm wide circular muscle rings. Application of SNP (10 μM) to organ baths containing distal colon segments resulted in a decrease in circular muscle tone, that is relaxation, in tissues from both sham (Figure 7A) and oxaliplatin‐treated (Figure 7AI) mice. The reduction in tension produced by SNP was greater in the colon segments from sham‐treated mice than in segments from oxaliplatin‐treated mice (Figure 7B). Thus, the relaxation force in response to SNP was reduced in colonic circular muscles from oxaliplatin‐treated mice.


Role of oxidative stress in oxaliplatin ‐ induced enteric neuropathy and colonic dysmotility in mice
Effects of oxaliplatin treatment on colonic smooth muscles. (A,AI) Smooth muscle relaxation following application of the NO donor, SNP (10 μM) to the colon from day 14 sham (A) and oxaliplatin‐treated (AI) mice. (B) Comparison of the maximum relaxation produced by circular muscles in response to SNP in colonic preparations from sham and oxaliplatin‐treated mice quantified as an absolute change in the force transduction from the basal values. *P < 0.05, significantly different as indicated; n = 6 mice per group. (C) Resting diameter of the distal colon from sham and oxaliplatin‐treated mice. *P = 0.05, significantly different as indicated; n = 7 mice per group. (D) Gross morphological changes in the colon following repeated in vivo oxaliplatin administration. Colonic crypt length was shorter in oxaliplatin‐treated mice and muscle thickness was reduced in comparison to the sham‐treated animals. (DI) Statistical analysis of the muscle layer thickness in the colon preparations from sham and oxaliplatin‐treated mice. Data presented as mean ± SEM. *P < 0.05, significantly different as indicated; n = 6 mice per group, 10 sections per preparation from each animal.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5120153&req=5

bph13646-fig-0007: Effects of oxaliplatin treatment on colonic smooth muscles. (A,AI) Smooth muscle relaxation following application of the NO donor, SNP (10 μM) to the colon from day 14 sham (A) and oxaliplatin‐treated (AI) mice. (B) Comparison of the maximum relaxation produced by circular muscles in response to SNP in colonic preparations from sham and oxaliplatin‐treated mice quantified as an absolute change in the force transduction from the basal values. *P < 0.05, significantly different as indicated; n = 6 mice per group. (C) Resting diameter of the distal colon from sham and oxaliplatin‐treated mice. *P = 0.05, significantly different as indicated; n = 7 mice per group. (D) Gross morphological changes in the colon following repeated in vivo oxaliplatin administration. Colonic crypt length was shorter in oxaliplatin‐treated mice and muscle thickness was reduced in comparison to the sham‐treated animals. (DI) Statistical analysis of the muscle layer thickness in the colon preparations from sham and oxaliplatin‐treated mice. Data presented as mean ± SEM. *P < 0.05, significantly different as indicated; n = 6 mice per group, 10 sections per preparation from each animal.
Mentions: Smooth muscle tone of the distal colon was studied in organ bath experiments using force transducers. We measured the force produced by 3 mm wide circular muscle rings. Application of SNP (10 μM) to organ baths containing distal colon segments resulted in a decrease in circular muscle tone, that is relaxation, in tissues from both sham (Figure 7A) and oxaliplatin‐treated (Figure 7AI) mice. The reduction in tension produced by SNP was greater in the colon segments from sham‐treated mice than in segments from oxaliplatin‐treated mice (Figure 7B). Thus, the relaxation force in response to SNP was reduced in colonic circular muscles from oxaliplatin‐treated mice.

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