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

Helen F Galley, Barry McCormick, Kirsten L. Wilson, Damon A. Lowes, Lesley Colvin, Carole Torsney

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Abstract

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 of mitochondrial membrane potential and metabolic rate, independent of concentration (20-100µM). Mitochondrial volume was increased dose-dependently by paclitaxel (200% increase at 100µM). These effects were prevented by co-treatment with 1µM melatonin. Paclitaxel cytotoxicity against cancer cells was not affected by co-exposure to 1µM 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, pre-treatment with oral melatonin (5/10/50mg/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 (10mg/kg/day) was similarly effective when administered continuously in drinking water (39% difference). Melatonin also reduced paclitaxel-induced elevated 8-isoprostane F2 levels in peripheral nerves (by 22% in sciatic; 41% in saphenous) and limited paclitaxel-induced reduction of 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.
Original languageEnglish
Article numbere12444
JournalJournal of Pineal Research
Volume63
Issue number4
Early online date22 Sep 2017
DOIs
Publication statusPublished - Nov 2017

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Neuralgia
Melatonin
Paclitaxel
8-epi-prostaglandin F2alpha
Peripheral Nerves
Hypersensitivity
Therapeutics
Mitochondrial Size
In Vitro Techniques
Drug Therapy
Cell Line
Unmyelinated Nerve Fibers
Mitochondrial Membrane Potential
Peripheral Nervous System Diseases
Drinking Water
Neoplasms
Mitochondria
Oxidative Stress
Antioxidants
Breast Neoplasms

Keywords

  • Neuropathic pain
  • Paclitaxel
  • mitochondria
  • melatonin
  • chemotherapy
  • oxidative stress
  • antioxidant

Cite this

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.

In: Journal of Pineal Research, Vol. 63, No. 4, e12444, 11.2017.

Research output: Contribution to journalArticle

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. In: Journal of Pineal Research. 2017 ; Vol. 63, No. 4.
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note = "Acknowledgements Thank you to Professor Ahmet Hoke (Johns Hopkins, Baltimore, USA) for the gift of DRG cells; and to Professor Patrick M. Dougherty (MD Anderson Cancer Center, Texas, USA) for sharing his expertise in the rat model. Funding The study was funded by the Association of Anaesthetists of Great Britain and Ireland, the British Journal of Anaesthesia/Royal College of Anaesthetists and the Melville Trust.",
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N1 - Acknowledgements Thank you to Professor Ahmet Hoke (Johns Hopkins, Baltimore, USA) for the gift of DRG cells; and to Professor Patrick M. Dougherty (MD Anderson Cancer Center, Texas, USA) for sharing his expertise in the rat model. Funding The study was funded by the Association of Anaesthetists of Great Britain and Ireland, the British Journal of Anaesthesia/Royal College of Anaesthetists and the Melville Trust.

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N2 - 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 of mitochondrial membrane potential and metabolic rate, independent of concentration (20-100µM). Mitochondrial volume was increased dose-dependently by paclitaxel (200% increase at 100µM). These effects were prevented by co-treatment with 1µM melatonin. Paclitaxel cytotoxicity against cancer cells was not affected by co-exposure to 1µM 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, pre-treatment with oral melatonin (5/10/50mg/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 (10mg/kg/day) was similarly effective when administered continuously in drinking water (39% difference). Melatonin also reduced paclitaxel-induced elevated 8-isoprostane F2 levels in peripheral nerves (by 22% in sciatic; 41% in saphenous) and limited paclitaxel-induced reduction of 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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