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

Whole‐mount preparations of myenteric neurons in the proximal and distal colon following 14 days of in vivo oxaliplatin treatment. Myenteric neurons labelled with anti‐β‐tubulin III antibody (Tub III, red) counterstained with DAPI (blue) that labels neuronal nuclei within the ganglion (arrow) and smooth muscle cell nuclei outside the ganglion (arrowhead) (CI). nNOS‐IR neurons (green). Scale bar = 20 μm.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

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

bph13646-fig-0001: Whole‐mount preparations of myenteric neurons in the proximal and distal colon following 14 days of in vivo oxaliplatin treatment. Myenteric neurons labelled with anti‐β‐tubulin III antibody (Tub III, red) counterstained with DAPI (blue) that labels neuronal nuclei within the ganglion (arrow) and smooth muscle cell nuclei outside the ganglion (arrowhead) (CI). nNOS‐IR neurons (green). Scale bar = 20 μm.

Mentions: To investigate changes to the total number of myenteric neurons, whole‐mount preparations of the distal and proximal colon were labelled with β‐tubulin antibody to count neurons within a 2 mm2 area (Figure 1). Repeated in vivo administration of oxaliplatin caused myenteric neuronal loss in both the proximal and distal colon when compared to sham (Figure 2A). Significant neuronal loss was also observed in the submucosal plexus in the distal colon from oxaliplatin‐treated mice, compared to sham (Figure 2AI).


Role of oxidative stress in oxaliplatin ‐ induced enteric neuropathy and colonic dysmotility in mice
Whole‐mount preparations of myenteric neurons in the proximal and distal colon following 14 days of in vivo oxaliplatin treatment. Myenteric neurons labelled with anti‐β‐tubulin III antibody (Tub III, red) counterstained with DAPI (blue) that labels neuronal nuclei within the ganglion (arrow) and smooth muscle cell nuclei outside the ganglion (arrowhead) (CI). nNOS‐IR neurons (green). Scale bar = 20 μm.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

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

bph13646-fig-0001: Whole‐mount preparations of myenteric neurons in the proximal and distal colon following 14 days of in vivo oxaliplatin treatment. Myenteric neurons labelled with anti‐β‐tubulin III antibody (Tub III, red) counterstained with DAPI (blue) that labels neuronal nuclei within the ganglion (arrow) and smooth muscle cell nuclei outside the ganglion (arrowhead) (CI). nNOS‐IR neurons (green). Scale bar = 20 μm.
Mentions: To investigate changes to the total number of myenteric neurons, whole‐mount preparations of the distal and proximal colon were labelled with β‐tubulin antibody to count neurons within a 2 mm2 area (Figure 1). Repeated in vivo administration of oxaliplatin caused myenteric neuronal loss in both the proximal and distal colon when compared to sham (Figure 2A). Significant neuronal loss was also observed in the submucosal plexus in the distal colon from oxaliplatin‐treated mice, compared to sham (Figure 2AI).

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