Neuropathic pain is a common and dose-limiting adverse effect of several cancer chemotherapeutic agents including paclitaxel. Current treatments for chemotherapy-induced peripheral neuropathy (CIPN) are largely ineffective and the pain can persist long after the cessation of the chemotherapy regimen. Whilst the specific underlying mechanisms are not fully understood, oxidative stress and mitochondrial damage are thought to be involved in the development of CIPN. Antioxidants which protect mitochondria may inhibit oxidative stress and protect mitochondrial function more effectively than antioxidants which do not specifically act within mitochondria, and may attenuate CIPN. The overall aim of the study was therefore to determine the effects of mitochondrial-targeted antioxidants on CIPN. This was addressed in two main parts. Firstly, in vitro studies aimed to determine the effects of paclitaxel alone and in combination with mitochondrial-targeted antioxidants melatonin and MitoVitE, and a non-targeted antioxidant, Trolox, on oxidative stress and mitochondrial function in cells. In vivo studies aimed to determine the effects of melatonin, MitoVitE and Trolox in a preclinical rat model of paclitaxel neuropathic pain. In vitro studies used a dorsal root ganglion (DRG) cell line (50B11). Cells were cultured with a range of concentrations of paclitaxel, with or without the addition of melatonin, MitoVitE or Trolox. Several measures of oxidative stress including free radical production, and glutathione levels, and measures of mitochondrial function, including mitochondrial metabolic rate, membrane potential, mitochondrial pore opening and ATP production were made. In vivo studies used a rat model of paclitaxel-CIPN, and assessed the effects of melatonin, MitoVitE and Trolox on behavioural measures of pain. In vitro studies showed that paclitaxel induced oxidative stress and caused mitochondrial damage in the DRG cell line. Compared to paclitaxel alone, cells co-treated with melatonin and MitoVitE had reduced oxidative stress and mitochondrial damage. Co-treatment of cells with paclitaxel and Trolox did not differ from conditions with paclitaxel only. In vivo studies demonstrated that melatonin and MitoVitE attenuated paclitaxel-induced mechanical hypersensitivity, whilst Trolox did not affect behavioural measures of CIPN. These studies suggest that mitochondrial-targeted antioxidants may be useful as a potential treatment strategy for CIPN.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:685280 |
| Date | January 2015 |
| Creators | McCormick, Barry |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=229728 |
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