Deen, Fahm; (2023) Novel mechanisms underlying chemotherapy induced peripheral neuropathy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent, progressive and often irreversible syndrome which causes chronic pain and poor quality of life in patients undergoing therapy with neurotoxic yet life-saving anti-cancer compounds. Using a battery of functional assays in tandem with optical and electrophysiological techniques, this study sought to investigate the role of mitochondrial impairment, metabolic insufficiency, and altered neuronal excitability in the pathogenesis of CIPN. In particular, the involvement of functionally distinct subpopulations of predominantly nociceptive (cholera toxin B subunit-negative; CTB−) and non-nociceptive (cholera toxin B subunit-positive; CTB+) sensory neurons was explored in phenotypically unique models of CIPN. In an in vitro model of acute oxaliplatin (platinum)-induced neuropathy, electrophysiological evaluation revealed increased spontaneous and evoked firing of CTB+ neurons at initial stages, followed by a significant decline in neuronal excitability. During periods of reduced neuronal activity, mitochondrial respiration and glycolysis were substantially reduced in CTB+ neurons. This was accompanied by decreased glucose uptake and cytosolic acidification, specifically in medium-large CTB+ neurons. Notably, mitochondrial calcium homeostasis was significantly dysregulated in these neurons, rendering the organelles susceptible to calcium overload with reduced ability to maintain mitochondrial membrane potential. Conversely, the proteasome inhibitor, bortezomib, induced neuronal silencing in both CTB+ and CTB− neurons. At a subcellular level, CTB+ neurons underwent bioenergetic reprogramming, where glycolysis was upregulated to compensate for impaired mitochondrial respiration. Conversely, mitochondrial respiratory inhibition was observed in CTB− neurons, alongside a concomitant reduction in glycolytic capacity. In addition, morphometric analysis revealed cytosolic vacuolation and mitochondrial rearrangement in small-diameter (nociceptive) sensory neurons, indicating a drug-induced stress response. In conclusion, this study significantly advances our mechanistic understanding of CIPN and unravels several neuronal subtype-specific pathways involving bioenergetic impairment and mitochondrial dysfunction that lead to energy deficits and altered excitability in sensory neurons. The novel cellular and sub-cellular targets identified here could be leveraged to develop effective therapies for this debilitating condition.

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