NCX2 Targeting as a Neuroprotective Strategy Against Oxaliplatin-Induced Peripheral Neurotoxicity

Background/Objectives: Oxaliplatin (OHP) is a key component of colorectal cancer chemotherapy, but OHP-induced peripheral neurotoxicity (OIPN) is a major dose-limiting adverse effect. OHP-related sodium-channel dysfunction could increase intracellular Na⁺ and sustain depolarization, conditions that may theoretically favor reverse-mode NCX activity, in which the exchanger promotes Ca²⁺ entry rather than Ca²⁺ extrusion. This study evaluated whether NCX2 targeting could reduce OHP-induced sensory neuron injury. Methods: Primary mouse dorsal root ganglion neurons were exposed to OHP, with or without SEA0400 (NCX modulator) pretreatment or siRNA-mediated NCX2 knockdown. Neuronal viability, neurite elongation, live-cell morphology, NCX2 fluorescence, and lipid droplet accumulation were quantified. Results: OHP reduced neuronal survival and neurite elongation and induced stress-related morphological changes and lipid droplet accumulation. NCX2-associated fluorescence varied by neuronal subtype, dose, and time. SEA0400 and partial NCX2 knockdown attenuated selected injury endpoints, mainly under low-dose conditions. Conclusions: These findings suggest that NCX2 may be involved in selected OHP-induced sensory neuron injury endpoints and support further investigation of NCX2 as a potential preventive target. However, reverse-mode NCX activity, Na⁺/Ca²⁺ fluxes, NCX2 directionality, and translational relevance require direct validation.