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Melatonin limits paclitaxel‐induced mitochondrial dysfunction in vitro and protects against paclitaxel‐induced neuropathic pain in the rat

Chemotherapy‐induced neuropathic pain is a debilitating and common side effect of cancer treatment. Mitochondrial dysfunction associated with oxidative stress in peripheral nerves has been implicated in the underlying mechanism. We investigated the potential of melatonin, a potent antioxidant that p...

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Autores principales: Galley, Helen F., McCormick, Barry, Wilson, Kirsten L., Lowes, Damon A., Colvin, Lesley, Torsney, Carole
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656911/
https://www.ncbi.nlm.nih.gov/pubmed/28833461
http://dx.doi.org/10.1111/jpi.12444
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author Galley, Helen F.
McCormick, Barry
Wilson, Kirsten L.
Lowes, Damon A.
Colvin, Lesley
Torsney, Carole
author_facet Galley, Helen F.
McCormick, Barry
Wilson, Kirsten L.
Lowes, Damon A.
Colvin, Lesley
Torsney, Carole
author_sort Galley, Helen F.
collection PubMed
description Chemotherapy‐induced neuropathic pain is a debilitating and common side effect of cancer treatment. Mitochondrial dysfunction associated with oxidative stress in peripheral nerves has been implicated in the underlying mechanism. We investigated the potential of melatonin, a potent antioxidant that preferentially acts within mitochondria, to reduce mitochondrial damage and neuropathic pain resulting from the chemotherapeutic drug paclitaxel. In vitro, paclitaxel caused a 50% reduction in mitochondrial membrane potential and metabolic rate, independent of concentration (20‐100 μmol/L). Mitochondrial volume was increased dose‐dependently by paclitaxel (200% increase at 100 μmol/L). These effects were prevented by co‐treatment with 1 μmol/L melatonin. Paclitaxel cytotoxicity against cancer cells was not affected by co‐exposure to 1 μmol/L melatonin of either the breast cancer cell line MCF‐7 or the ovarian carcinoma cell line A2780. In a rat model of paclitaxel‐induced painful peripheral neuropathy, pretreatment with oral melatonin (5/10/50 mg/kg), given as a daily bolus dose, was protective, dose‐dependently limiting development of mechanical hypersensitivity (19/43/47% difference from paclitaxel control, respectively). Melatonin (10 mg/kg/day) was similarly effective when administered continuously in drinking water (39% difference). Melatonin also reduced paclitaxel‐induced elevated 8‐isoprostane F(2)α levels in peripheral nerves (by 22% in sciatic; 41% in saphenous) and limited paclitaxel‐induced reduction in C‐fibre activity‐dependent slowing (by 64%). Notably, melatonin limited the development of mechanical hypersensitivity in both male and female animals (by 50/41%, respectively), and an additive effect was found when melatonin was given with the current treatment, duloxetine (75/62% difference, respectively). Melatonin is therefore a potential treatment to limit the development of painful neuropathy resulting from chemotherapy treatment.
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spelling pubmed-56569112017-11-01 Melatonin limits paclitaxel‐induced mitochondrial dysfunction in vitro and protects against paclitaxel‐induced neuropathic pain in the rat Galley, Helen F. McCormick, Barry Wilson, Kirsten L. Lowes, Damon A. Colvin, Lesley Torsney, Carole J Pineal Res Original Articles Chemotherapy‐induced neuropathic pain is a debilitating and common side effect of cancer treatment. Mitochondrial dysfunction associated with oxidative stress in peripheral nerves has been implicated in the underlying mechanism. We investigated the potential of melatonin, a potent antioxidant that preferentially acts within mitochondria, to reduce mitochondrial damage and neuropathic pain resulting from the chemotherapeutic drug paclitaxel. In vitro, paclitaxel caused a 50% reduction in mitochondrial membrane potential and metabolic rate, independent of concentration (20‐100 μmol/L). Mitochondrial volume was increased dose‐dependently by paclitaxel (200% increase at 100 μmol/L). These effects were prevented by co‐treatment with 1 μmol/L melatonin. Paclitaxel cytotoxicity against cancer cells was not affected by co‐exposure to 1 μmol/L melatonin of either the breast cancer cell line MCF‐7 or the ovarian carcinoma cell line A2780. In a rat model of paclitaxel‐induced painful peripheral neuropathy, pretreatment with oral melatonin (5/10/50 mg/kg), given as a daily bolus dose, was protective, dose‐dependently limiting development of mechanical hypersensitivity (19/43/47% difference from paclitaxel control, respectively). Melatonin (10 mg/kg/day) was similarly effective when administered continuously in drinking water (39% difference). Melatonin also reduced paclitaxel‐induced elevated 8‐isoprostane F(2)α levels in peripheral nerves (by 22% in sciatic; 41% in saphenous) and limited paclitaxel‐induced reduction in C‐fibre activity‐dependent slowing (by 64%). Notably, melatonin limited the development of mechanical hypersensitivity in both male and female animals (by 50/41%, respectively), and an additive effect was found when melatonin was given with the current treatment, duloxetine (75/62% difference, respectively). Melatonin is therefore a potential treatment to limit the development of painful neuropathy resulting from chemotherapy treatment. John Wiley and Sons Inc. 2017-09-22 2017-11 /pmc/articles/PMC5656911/ /pubmed/28833461 http://dx.doi.org/10.1111/jpi.12444 Text en © 2017 The Authors. Journal of Pineal Research Published by John Wiley & Sons Ltd This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Galley, Helen F.
McCormick, Barry
Wilson, Kirsten L.
Lowes, Damon A.
Colvin, Lesley
Torsney, Carole
Melatonin limits paclitaxel‐induced mitochondrial dysfunction in vitro and protects against paclitaxel‐induced neuropathic pain in the rat
title Melatonin limits paclitaxel‐induced mitochondrial dysfunction in vitro and protects against paclitaxel‐induced neuropathic pain in the rat
title_full Melatonin limits paclitaxel‐induced mitochondrial dysfunction in vitro and protects against paclitaxel‐induced neuropathic pain in the rat
title_fullStr Melatonin limits paclitaxel‐induced mitochondrial dysfunction in vitro and protects against paclitaxel‐induced neuropathic pain in the rat
title_full_unstemmed Melatonin limits paclitaxel‐induced mitochondrial dysfunction in vitro and protects against paclitaxel‐induced neuropathic pain in the rat
title_short Melatonin limits paclitaxel‐induced mitochondrial dysfunction in vitro and protects against paclitaxel‐induced neuropathic pain in the rat
title_sort melatonin limits paclitaxel‐induced mitochondrial dysfunction in vitro and protects against paclitaxel‐induced neuropathic pain in the rat
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656911/
https://www.ncbi.nlm.nih.gov/pubmed/28833461
http://dx.doi.org/10.1111/jpi.12444
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