SODIUM-CALCIUM EXCHANGER NCX2 ROLE IN OXALIPLATIN-INDUCED PERIPHERAL NEUROTOXICITY DEVELOPMENT

Oxaliplatin (OHP) is the cornerstone drug for colorectal cancer, hampered by OHP-induced peripheral neurotoxicity (OIPN). OIPN is characterised by an acute and chronic syndrome. Acute OIPN mirrors a transient axonal hyperexcitability at each cycle, whereas chronic OIPN corresponds to persistent axonal damage (AxD) causing sensory loss and neuropathic pain, affecting the quality of life of cancer survivors. The putative link between acute and chronic OIPN could be the Na⁺/Ca²⁺ exchanger 2 (NCX2): acute OIPN might lead to increased intraneuronal Na+ levels triggering NCX2 reverse mode; thus, Na+ is exchanged with Ca2+ potentially leading to chronic AxD. We investigated NCX2 contribution to OIPN in an in vitro setting. Primary cultures of mouse dorsal root ganglia neurons were treated with OHP to trigger neurotoxicity. First, NCX2 protein expression was characterised via Western blot, while NCX2 localization via immunofluorescence. Then, as a tentative neuroprotection strategy, NCX2 expression was selectively downregulated via siRNA technology. Neurite elongation and viability were the outcome measures to detect neuroprotection. OHP treatment was associated with changes in NCX2 protein expression compared to control conditions. Immunofluorescence analyses tentatively suggested an alteration in NCX2 distribution in sensory neurons and satellite cells that surround degenerating neurons. Moreover, siRNA-mediated NCX2 silencing significantly reduced neurotoxicity. NCX2 might play a relevant role in preventing OIPN, thus, targeting NCX2 might represent a promising strategy to treat this condition and more: a similar pathogenetic cascade (an upstream event - axonal hyperexcitability - and a downstream event - consequent Ca2+ neurotoxicity) were described in other peripheral neuropathies.