Investigation into mitochondrial DNA, mitochondrial function and nerve activity in oxaliplatin-induced peripheral neuropathy

Student thesis: Doctoral ThesisDoctor of Philosophy


Chemotherapy-induced peripheral neuropathy (CIPN) is the major dose-limiting side effect of several first-line chemotherapeutic agents, including oxaliplatin. Symptoms can be very detrimental to the patients’ quality of life. They can occur at any time during and after treatment and can endure for months or years after treatment cessation. No treatment is currently available to prevent or reverse CIPN and there is no tool to identify those at risk. Moreover, the causal mechanisms of CIPN are still under investigation. This thesis aimed to explore the feasibility of a blood biomarker for oxaliplatin-induced peripheral neuropathy (OIPN) and to get a deeper understanding of the mechanisms involved in its development and maintenance. Mitochondrial DNA (MtDNA) content in blood and other bodily fluid has already been used as biomarker for several diseases. Here, we recruited > 50 colorectal cancer patients undergoing an oxaliplatin treatment. Blood was collected prior to, during and after treatment completion, and MtDNA content in whole blood was measured using real-time quantitative PCR. We found that MtDNA content varied among patients and time points. By comparing MtDNA content in patients who developed OIPN to that of patients who did not, we will understand whether MtDNA is a feasible predictive biomarker for OIPN. A rat model of OIPN was generated by the systemic (intraperitoneal) administration of 2 mg/kg clinically formulated oxaliplatin on four alternate days. The model displayed a persistent mechanical hypersensitivity, but other symptoms observed in the clinic, including cold allodynia, numbness and spontaneous pain, could not be replicated. Studies focused on two key time points: day 7, 24 hours after treatment cessation, when animals did not display symptoms of pain-like behaviour, and peak pain, when the nociceptive behaviour reached its maximal severity. The electric properties of the saphenous nerve were evaluated in terms of compound action potentials (CAPs) of A- and C-fibres. In oxaliplatin-treated animals, CAPs were altered at day 7, but not at peak pain. Mitochondrial dysfunction is a key factor in the development and the maintenance of OIPN. Systemic exposure to oxaliplatin did not affect parameters of mitochondrial respiration or glycolytic function in DRG neurons at day 7. Similarly, in vitro exposure to oxaliplatin for an hour did not affect the bioenergetic status of DRG neurons. The expression levels of mitochondrial Ca2+ channels were evaluated in the DRG, sciatic and saphenous nerves. In particular, the expression of the Na+/Ca2+/Li+ exchanger (NCLX) and of the mitochondrial calcium uniporter (MCU) was altered after oxaliplatin administration, thus potentially affecting mitochondrial functionality. These studies provided a further insight on mitochondrial dysfunction and altered nerve conduction in the pathophysiology of OIPN.
Date of Award2021
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorSarah Flatters (Supervisor), Stuart Bevan (Supervisor) & Nicola Hamilton-Whitaker (Supervisor)

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