The role of acute excitation of sensory neurons in the development of paclitaxel-induced peripheral neuropathy

Paclitaxel-induced peripheral neuropathy (PIPN) and associated neuropathic pain is a significant adverse effect experienced by cancer patients who received paclitaxel infusion. It can adversely affect daily activities and quality of life, and sometimes forces the suspension of treatment, which can negatively impact survival. However, the mechanisms underlying the pathogenesis of PIPN are uncertain, hindering the development of effective therapies for this comorbidity. The proposed studies aim to identify molecular/cellular mechanisms initiating PIPN. Patients with acute pain during paclitaxel infusion have a higher risk of developing PIPN, suggesting acute excitation of sensory neurons is linked to the development of PIPN. Our recent study indicates that paclitaxel excites sensory neurons by inhibiting KCNQ channels that are abundant in sensory neurons and axons. Neuronal over-excitation results in quick ATP depletion. Transportation of molecules towards and away from the soma is an ATP-dependent process critical for mitochondrial assembly and clearance. We hypothesize that the acute over-excitation of primary sensory neurons induced by paclitaxel leads to ATP-dependent transport impairment (including of mitochondria and mitophagosomes) in the axon, resulting in the pathological alteration to the extremities in a “stocking and glove” distribution. In the proposed study, we will first detect whether early over-excitation of DRG neurons induces PIPN-like alterations. Genetic tools will be used to stimulate sensory neurons and monitor PIPN-like changes. Simultaneously, we will also use genetic tools to inhibit sensory neurons and determine if it can prevent the development of PIPN. The relationship between ATP level and mitochondria movement in the axon will be observed by live-cell imaging. The spatiotemporal distribution of abnormal mitochondria and mitophagy activity along peripheral fibers after paclitaxel exposure will be observed in vivo to evaluate the role of neuronal hyperexcitability in the pathogenesis of mitochondrial dysfunction, which is critical for the development of PIPN, and its relationship to the “stocking and glove” distribution of sensory dysfunction. The effect of creatine, an ATP buffer, on mitochondria and mitophagy will also be observed. Finally, the efficacy of the creatine and retigabine regime in the PIPN animal model will be determined in the context of metastatic tumor burden. Therefore, this study may lead to a better understanding of the mechanism underlying PIPN as well as delineate novel targets for the treatment of PIPN.