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.
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.
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.
- Neuropathic pain
- oxidative stress