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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 L‐NNA on fragmented contractions and colonic faecal content. (A) Fragmented contractions were defined as interrupted contractions consisting of period(s) of relaxation (arrow) and simultaneously occurring contractions (arrowheads). The frequency (B) of fragmented contractions in the colon from sham and oxaliplatin‐treated mice before and after L‐NNA application. (C) Wet weight of faecal pellets measured immediately upon pellet expulsion; dry weight of faecal pellets measured after 72 h of dehydration at room temperature. (D) Faecal water content calculated as the difference between the wet weight and dry weight. (E) Total number of faecal pellets along the entire length of the colon counted in freshly excised intact colons. Data presented as mean ± SEM. *P < 0.05, significantly different as indicated; n = 10 mice per group.
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bph13646-fig-0010: Effects of L‐NNA on fragmented contractions and colonic faecal content. (A) Fragmented contractions were defined as interrupted contractions consisting of period(s) of relaxation (arrow) and simultaneously occurring contractions (arrowheads). The frequency (B) of fragmented contractions in the colon from sham and oxaliplatin‐treated mice before and after L‐NNA application. (C) Wet weight of faecal pellets measured immediately upon pellet expulsion; dry weight of faecal pellets measured after 72 h of dehydration at room temperature. (D) Faecal water content calculated as the difference between the wet weight and dry weight. (E) Total number of faecal pellets along the entire length of the colon counted in freshly excised intact colons. Data presented as mean ± SEM. *P < 0.05, significantly different as indicated; n = 10 mice per group.

Mentions: These were defined as incomplete contractions occurring simultaneously rather than propagating over the length of the colon (Figure 10A). The frequency of fragmented contractions was significantly higher in oxaliplatin‐treated than in sham‐treated mice (Figure 10B, Table 1). Application of L‐NNA did not affect the frequency of fragmented contractions in either oxaliplatin‐treated or sham‐treated mice.


Role of oxidative stress in oxaliplatin ‐ induced enteric neuropathy and colonic dysmotility in mice
Effects of L‐NNA on fragmented contractions and colonic faecal content. (A) Fragmented contractions were defined as interrupted contractions consisting of period(s) of relaxation (arrow) and simultaneously occurring contractions (arrowheads). The frequency (B) of fragmented contractions in the colon from sham and oxaliplatin‐treated mice before and after L‐NNA application. (C) Wet weight of faecal pellets measured immediately upon pellet expulsion; dry weight of faecal pellets measured after 72 h of dehydration at room temperature. (D) Faecal water content calculated as the difference between the wet weight and dry weight. (E) Total number of faecal pellets along the entire length of the colon counted in freshly excised intact colons. Data presented as mean ± SEM. *P < 0.05, significantly different as indicated; n = 10 mice per group.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

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

bph13646-fig-0010: Effects of L‐NNA on fragmented contractions and colonic faecal content. (A) Fragmented contractions were defined as interrupted contractions consisting of period(s) of relaxation (arrow) and simultaneously occurring contractions (arrowheads). The frequency (B) of fragmented contractions in the colon from sham and oxaliplatin‐treated mice before and after L‐NNA application. (C) Wet weight of faecal pellets measured immediately upon pellet expulsion; dry weight of faecal pellets measured after 72 h of dehydration at room temperature. (D) Faecal water content calculated as the difference between the wet weight and dry weight. (E) Total number of faecal pellets along the entire length of the colon counted in freshly excised intact colons. Data presented as mean ± SEM. *P < 0.05, significantly different as indicated; n = 10 mice per group.
Mentions: These were defined as incomplete contractions occurring simultaneously rather than propagating over the length of the colon (Figure 10A). The frequency of fragmented contractions was significantly higher in oxaliplatin‐treated than in sham‐treated mice (Figure 10B, Table 1). Application of L‐NNA did not affect the frequency of fragmented contractions in either oxaliplatin‐treated or sham‐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