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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 CMMCs and short contractions. (A) The frequencies of CMMCs quantified in spatiotemporal maps from sham‐treated and oxaliplatin‐treated mice before and after L‐NNA application. (B) Speed of CMMCs in the colons from sham and oxaliplatin‐treated mice in both test conditions. *P < 0.05, significantly different as indicated; n = 10 mice per group. (C) The frequencies of short contractions were quantified in spatiotemporal maps from sham and oxaliplatin‐treated mice before and after L‐NNA application. (D) Speed of all short contractions analysed before and after L‐NNA application. Changes in the frequency of distal anterograde (E) and retrograde (F) short contractions in the colons from sham and oxaliplatin‐treated mice in both test conditions. Data presented as mean ± SEM. *P < 0.05, significantly different as indicated; n = 10 mice per group).
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bph13646-fig-0009: Effects of L‐NNA on CMMCs and short contractions. (A) The frequencies of CMMCs quantified in spatiotemporal maps from sham‐treated and oxaliplatin‐treated mice before and after L‐NNA application. (B) Speed of CMMCs in the colons from sham and oxaliplatin‐treated mice in both test conditions. *P < 0.05, significantly different as indicated; n = 10 mice per group. (C) The frequencies of short contractions were quantified in spatiotemporal maps from sham and oxaliplatin‐treated mice before and after L‐NNA application. (D) Speed of all short contractions analysed before and after L‐NNA application. Changes in the frequency of distal anterograde (E) and retrograde (F) short contractions in the colons from sham and oxaliplatin‐treated mice in both test conditions. Data presented as mean ± SEM. *P < 0.05, significantly different as indicated; n = 10 mice per group).

Mentions: In vivo treatment with oxaliplatin was associated with a lower CMMC frequency than in sham‐treated preparations (P < 0.05). Application of L‐NNA significantly increased the frequency of CMMCs in colons from oxaliplatin‐treated (P < 0.05), but not sham‐treated mice (Figure 9A, Table 1). The rate of rise of CMMCs was comparable between sham‐treated and oxaliplatin‐treated mice, but increased CMMC rate of rise following addition of L‐NNA was noted in the colons from sham (P < 0.05), but not oxaliplatin‐treated animals (Figure 9B, Table 1).


Role of oxidative stress in oxaliplatin ‐ induced enteric neuropathy and colonic dysmotility in mice
Effects of L‐NNA on CMMCs and short contractions. (A) The frequencies of CMMCs quantified in spatiotemporal maps from sham‐treated and oxaliplatin‐treated mice before and after L‐NNA application. (B) Speed of CMMCs in the colons from sham and oxaliplatin‐treated mice in both test conditions. *P < 0.05, significantly different as indicated; n = 10 mice per group. (C) The frequencies of short contractions were quantified in spatiotemporal maps from sham and oxaliplatin‐treated mice before and after L‐NNA application. (D) Speed of all short contractions analysed before and after L‐NNA application. Changes in the frequency of distal anterograde (E) and retrograde (F) short contractions in the colons from sham and oxaliplatin‐treated mice in both test conditions. Data presented as mean ± SEM. *P < 0.05, significantly different as indicated; n = 10 mice per group).
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Related In: Results  -  Collection

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

bph13646-fig-0009: Effects of L‐NNA on CMMCs and short contractions. (A) The frequencies of CMMCs quantified in spatiotemporal maps from sham‐treated and oxaliplatin‐treated mice before and after L‐NNA application. (B) Speed of CMMCs in the colons from sham and oxaliplatin‐treated mice in both test conditions. *P < 0.05, significantly different as indicated; n = 10 mice per group. (C) The frequencies of short contractions were quantified in spatiotemporal maps from sham and oxaliplatin‐treated mice before and after L‐NNA application. (D) Speed of all short contractions analysed before and after L‐NNA application. Changes in the frequency of distal anterograde (E) and retrograde (F) short contractions in the colons from sham and oxaliplatin‐treated mice in both test conditions. Data presented as mean ± SEM. *P < 0.05, significantly different as indicated; n = 10 mice per group).
Mentions: In vivo treatment with oxaliplatin was associated with a lower CMMC frequency than in sham‐treated preparations (P < 0.05). Application of L‐NNA significantly increased the frequency of CMMCs in colons from oxaliplatin‐treated (P < 0.05), but not sham‐treated mice (Figure 9A, Table 1). The rate of rise of CMMCs was comparable between sham‐treated and oxaliplatin‐treated mice, but increased CMMC rate of rise following addition of L‐NNA was noted in the colons from sham (P < 0.05), but not oxaliplatin‐treated animals (Figure 9B, Table 1).

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