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Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy

Paclitaxel is a first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Previous preclinical studies indicate mitochondrial dysfunction and oxidative stress are associated with this disorder; however no direct assessment of reactive oxygen species (ROS) levels and...

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Autores principales: Duggett, Natalie A., Griffiths, Lisa A., McKenna, Olivia E., de Santis, Vittorio, Yongsanguanchai, Nutcha, Mokori, Esther B., Flatters, Sarah J.L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996646/
https://www.ncbi.nlm.nih.gov/pubmed/27393249
http://dx.doi.org/10.1016/j.neuroscience.2016.06.050
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author Duggett, Natalie A.
Griffiths, Lisa A.
McKenna, Olivia E.
de Santis, Vittorio
Yongsanguanchai, Nutcha
Mokori, Esther B.
Flatters, Sarah J.L.
author_facet Duggett, Natalie A.
Griffiths, Lisa A.
McKenna, Olivia E.
de Santis, Vittorio
Yongsanguanchai, Nutcha
Mokori, Esther B.
Flatters, Sarah J.L.
author_sort Duggett, Natalie A.
collection PubMed
description Paclitaxel is a first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Previous preclinical studies indicate mitochondrial dysfunction and oxidative stress are associated with this disorder; however no direct assessment of reactive oxygen species (ROS) levels and antioxidant enzyme activity in sensory neurons following paclitaxel has been undertaken. As expected, repeated low doses of systemic paclitaxel in rats induced long-lasting pain behaviour with a delayed onset, akin to the clinical scenario. To elucidate the role of ROS in the development and maintenance of paclitaxel-induced painful neuropathy, we have assessed ROS and antioxidant enzyme activity levels in the nociceptive system in vivo at three key behavioural time-points; prior to pain onset (day 7), peak pain severity and pain resolution. In isolated dorsal root ganglia (DRG) neurons, ROS levels were unchanged following paclitaxel-exposure in vitro or in vivo. ROS levels were further assessed in DRG and spinal cord in vivo following intrathecal MitoTracker®RedCM-H(2)XRos administration in paclitaxel-/vehicle-treated rats. ROS levels were increased at day 7, specifically in non-peptidergic DRG neurons. In the spinal cord, neuronally-derived ROS was increased at day 7, yet ROS levels in microglia and astrocytes were unaltered. In DRG, CuZnSOD and glutathione peroxidase (GPx) activity were increased at day 7 and peak pain time-points, respectively. In peripheral sensory nerves, CuZnSOD activity was increased at day 7, and at peak pain, MnSOD, CuZnSOD and GPx activity were increased. Catalase activity was unaltered in DRG and saphenous nerves. These data suggest that neuronally-derived mitochondrial ROS, accompanied with an inadequate endogenous antioxidant enzyme response, are contributory factors in paclitaxel-induced painful neuropathy.
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spelling pubmed-49966462016-10-01 Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy Duggett, Natalie A. Griffiths, Lisa A. McKenna, Olivia E. de Santis, Vittorio Yongsanguanchai, Nutcha Mokori, Esther B. Flatters, Sarah J.L. Neuroscience Article Paclitaxel is a first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Previous preclinical studies indicate mitochondrial dysfunction and oxidative stress are associated with this disorder; however no direct assessment of reactive oxygen species (ROS) levels and antioxidant enzyme activity in sensory neurons following paclitaxel has been undertaken. As expected, repeated low doses of systemic paclitaxel in rats induced long-lasting pain behaviour with a delayed onset, akin to the clinical scenario. To elucidate the role of ROS in the development and maintenance of paclitaxel-induced painful neuropathy, we have assessed ROS and antioxidant enzyme activity levels in the nociceptive system in vivo at three key behavioural time-points; prior to pain onset (day 7), peak pain severity and pain resolution. In isolated dorsal root ganglia (DRG) neurons, ROS levels were unchanged following paclitaxel-exposure in vitro or in vivo. ROS levels were further assessed in DRG and spinal cord in vivo following intrathecal MitoTracker®RedCM-H(2)XRos administration in paclitaxel-/vehicle-treated rats. ROS levels were increased at day 7, specifically in non-peptidergic DRG neurons. In the spinal cord, neuronally-derived ROS was increased at day 7, yet ROS levels in microglia and astrocytes were unaltered. In DRG, CuZnSOD and glutathione peroxidase (GPx) activity were increased at day 7 and peak pain time-points, respectively. In peripheral sensory nerves, CuZnSOD activity was increased at day 7, and at peak pain, MnSOD, CuZnSOD and GPx activity were increased. Catalase activity was unaltered in DRG and saphenous nerves. These data suggest that neuronally-derived mitochondrial ROS, accompanied with an inadequate endogenous antioxidant enzyme response, are contributory factors in paclitaxel-induced painful neuropathy. Elsevier Science 2016-10-01 /pmc/articles/PMC4996646/ /pubmed/27393249 http://dx.doi.org/10.1016/j.neuroscience.2016.06.050 Text en © 2016 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Duggett, Natalie A.
Griffiths, Lisa A.
McKenna, Olivia E.
de Santis, Vittorio
Yongsanguanchai, Nutcha
Mokori, Esther B.
Flatters, Sarah J.L.
Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy
title Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy
title_full Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy
title_fullStr Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy
title_full_unstemmed Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy
title_short Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy
title_sort oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996646/
https://www.ncbi.nlm.nih.gov/pubmed/27393249
http://dx.doi.org/10.1016/j.neuroscience.2016.06.050
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