Investigating the elemental composition of peripheral sensory nerves and their function in paclitaxel-induced peripheral neuropathy

Student thesis: Doctoral ThesisDoctor of Philosophy


By 2030, 4 million people are estimated to survive cancer in the UK. Increased survival rates are the result of effective anti-cancer treatments such as chemotherapy. A range of chemotherapeutic agents are known to cause the debilitating condition, chemotherapy-induced peripheral neuropathy. Paclitaxel is an anti-mitotic agent that is used to treat a range of cancers including breast, ovarian and small-cell lung cancer. Paclitaxel administration generates a profound peripheral neuropathy, with patients reporting sensory symptoms such as mechanical hypersensitivity, tingling, numbness and burning sensations throughout their extremities. These symptoms can arise after the cessation of paclitaxel administration and often last for many months to years, having an extremely detrimental effect on a patient’s quality of life. The mechanism behind the development and maintenance of paclitaxel-induced peripheral neuropathy is currently unclear, with no prevention or cure.
The research outlined in this thesis aims to explore the mechanisms or causal effects of paclitaxel using a rat model of paclitaxel-induced peripheral neuropathy, which displays similar sensory symptoms to patients over a comparable time-course. Tissues were examined before the onset and at the peak of mechanical hypersensitivity behaviours. Analgesics with proven efficacy in the alleviation of PIPN symptoms in animal models were assessed. Additionally, the expression of voltage-gated sodium and potassium channels was assessed using western blot techniques. NaV1.7 and KV7.3 protein channels were not detected in peripheral tissues using this technique. The KV7.5 channel was identified in DRG tissue and did not have altered expression following paclitaxel administration.
The electrical activity of the saphenous nerve was assessed using compound action potential recordings. Paclitaxel did not evoke changes in any of the measured compound action potential parameters, suggesting that the sensory conduction is not altered in the saphenous nerve following paclitaxel administration. Sodium and potassium play a major role in sensory processing due to their contribution to action potentials. Sodium and potassium levels were measured in axons of the saphenous nerve using energy-dispersive x-ray spectroscopy, coupled with advanced sample preparation techniques. Overall, paclitaxel administration decreased Na/K ratios within the lumen of axons before the onset of mechanical hypersensitivity, however this observation was not significant at the peak of mechanical hypersensitivity behaviour. This may be due to the accumulation of potassium ions within the lumen, contributing to the development of hypersensitivity and neuronal excitability, resulting in patient symptoms.
Date of Award1 Apr 2021
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorSarah Flatters (Supervisor), Stephen McMahon (Supervisor) & Roland Fleck (Supervisor)

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