Starts:
Tuesday, September 20th
4:30pm-6:00pm EDT
Category:
Topical Workshop
Tracks:
Basic Science
Room
717 A/B
Chemotherapy-induced Peripheral Neuropathy: Pathophysiology and Mechanism-based Treatment
CIPN is common following chemotherapy and is clinically poorly managed, thus understanding the underlying mechanisms could lead to more effective treatment. Nav1.6 but not Nav1.7 is important for the maintenance of vincristine-induced pain (VIP) in mice, while live imaging shows that paclitaxel increases trafficking of Nav1.7 to distal ends of sensory neuron axons, which is significantly increased by the concomitant treatment with inflammatory mediators. VIP in mice is driven by activation of the NLRP3 inflammasome and subsequent release of interleukin-1β from macrophages, and is significantly reduced in mice lacking NLRP3 signaling pathway components, or after treatment with the NLRP3 inhibitor MCC950. Additionally, the IL-1 receptor antagonist anakinra prevented the development of VIP without adversely affecting chemotherapy efficacy in patient-derived medulloblastoma xenograph models. Chronic treatment of Drosophila larvae with paclitaxel caused altered branching and degeneration of nociceptive neurons, reduced thermal nociceptive responses, and activated resident macrophage-like cells, suggesting a conserved neuron-immune interaction contributing to the CIPN pathology Live imaging and superresolution approaches show alterations in endosome-mediated trafficking of integrins, and nociceptive neuron-specific overexpression of integrins conferred a protective effect. This workshop will discuss the interplay between chemotherapy-induced peripheral neuropathy and pain (CIPN) and inflammation using innovative conceptual and methodological approaches.