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

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 α 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. This article is protected by copyright. All rights reserved.

Original languageEnglish
Article number12444
Number of pages14
JournalJournal of pineal research
Volume63
Issue number4
Early online date22 Aug 2017
DOIs
Publication statusPublished - Nov 2017

Keywords / Materials (for Non-textual outputs)

  • antioxidant
  • chemotherapy
  • melatonin
  • mitochondria
  • neuropathic pain
  • oxidative stress
  • Paclitaxel
  • INDUCED PERIPHERAL NEUROPATHY
  • TEMPORAL-LOBE EPILEPSY
  • ACETYL-L-CARNITINE
  • OXIDATIVE STRESS
  • C-FIBERS
  • CONDUCTION-VELOCITY
  • NEURONAL DAMAGE
  • SEX-DIFFERENCES
  • KAINATE MODEL
  • BREAST-CANCER

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