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 F2 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.

中文翻译：

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褪黑素可在体外限制紫杉醇引起的线粒体功能障碍，并防止紫杉醇引起的大鼠神经性疼痛。

化学疗法引起的神经性疼痛是癌症治疗中令人衰弱的常见副作用。与周围神经氧化应激相关的线粒体功能障碍与潜在的机制有关。我们研究了褪黑激素（一种优先在线粒体内发挥作用的有效抗氧化剂）减少由化疗药物紫杉醇引起的线粒体损伤和神经性疼痛的潜力。在体外，紫杉醇导致线粒体膜电位和代谢率降低50％，而与浓度（20-100μmol/ L）无关。紫杉醇以剂量依赖性方式增加线粒体体积（100μmol/ L时增加200％）。通过与1μmol/ L褪黑激素共同治疗可防止这些影响。紫杉醇对癌细胞的细胞毒性不受乳腺癌细胞系MCF-7或卵巢癌细胞系A2780共同暴露于1μmol/ L褪黑素的影响。在紫杉醇诱发的疼痛性周围神经病变的大鼠模型中，口服每日剂量推定的褪黑激素（5/10/50 mg / kg）预处理具有保护性，且剂量依赖性地限制了机械性超敏反应的发生（19/43 /与紫杉醇对照分别有47％的差异）。当在饮用水中连续给药时，褪黑激素（10 mg / kg /天）同样有效（相差39％）。褪黑素还降低了紫杉醇引起的周围神经中8-异前列腺素F2α水平升高（坐骨神经减少了22％；大隐隐神经减少了41％），紫杉醇引起的C纤维活性依赖性减慢作用的减少也有限（减少了64％）。尤其，褪黑素限制了雄性和雌性动物机械性超敏反应的发生（分别降低了50/41％），并且在目前的治疗方案度洛西汀中给予褪黑素时，发现了加合效应（分别相差75/62％）。因此，褪黑激素是一种潜在的治疗方法，可以限制化学疗法治疗引起的疼痛性神经病的发展。