Sodium-Calcium Exchanger 2 Role In An In Vitro Oxaliplatin-Induced Peripheral Neurotoxicity Model

Introduction: Oxaliplatin (OHP) induced peripheral neurotoxicity (OIPN) is a common adverse event hampering quality of life in cancer survivors. Sodium-calcium exchanger (NCX2) might play a key role in OIPN. OHP alters sodium (Na+)-voltage operated ion channels kinetics leading to increased Na+ intraneuronal levels, thus potentially activating NCX2 reverse mode: to rebalance Na+ levels, calcium (Ca2+) is exchanged, and these Ca2+ increased levels might lead to axonal damage. The aim of this study was to investigate NCX2 involvement in OIPN. Materials and methods: Primary neuronal dorsal root ganglia cultures were treated with OHP (25uM) for 24 and 48 hours, and compared to corresponding controls (CTRL). Western blot (Wb) was used to quantify NCX2 protein expression, while its localization was observed via immunofluorescence (IF). Results: Wb showed that NCX2 levels were significantly increased in neurons after 24 hour OHP treatment, while they appear decreased after a 48 hours treatment. IF showed a different NCX2 localization in CTRL and OHP-treated neurons: treated neurons showed a localization more pronounced at the level of the plasma membrane, with an even more intense signal in correspondence of the satellite cells, while in CTRL it was distributed in the soma. Conclusions: Wb findings might be in line with an endogenous, despite inefficient, auto-protective mechanisms that neurons exerts to prevent cellular damage: after 24 hours, to compensate Na+ increased levels, NCX2 is overexpressed boosting the reserve mode action; whereas, after 48 hours, the downregulation might be justified as a potential mechanisms to prevent Ca2+ toxicity. NCX2 localization, shifting from a diffuse representation in the soma to a localization more restricted to the plasma membrane after OHP exposure, could mirror the need to exchange ions with the extracellular space and the satellite cells. These results support the potential pivotal role of OIPN-related axonal damage.