Chronic Oxaliplatin Treatment Induces CIPN in Mice via Activation of the TXNIP Pathway

Oxaliplatin is a platinum-based alkylating chemotherapeutic agent primarily used for colorectal cancer treatment. While oxaliplatin is an effective chemotherapeutic agent, it is commonly associated with severe and often long-lasting neurotoxic side effects, including chemotherapy-induced peripheral neuropathy (CIPN). Because neurotoxicity develops with cumulative dosing, oxaliplatin-induced peripheral neuropathy represents a major dose-limiting side effect. The underlying mechanisms of chronic oxaliplatin-induced neuropathy remain poorly understood, and behavioral models of CIPN in mice have been challenging to reproduce. As a result, the precise pathophysiology of CIPN has yet to be elucidated. The aim of this study was to investigate the underlying mechanisms of oxaliplatin-induced peripheral neuropathy using a chronic mouse model treated with a clinically relevant, human-equivalent dose. C57BL/6 male mice were treated with intraperitoneal oxaliplatin (0, 5 mg/kg, and 10 mg/kg) once a week for 8 weeks. During treatments, mice were followed with measurements of spontaneous pain behaviors, induced pain behaviors, and nerve conduction velocity. Electron microscopy of the sciatic nerve and histology and bulk RNA sequencing of the dorsal root ganglia (DRG) were performed post-mortem. Oxaliplatin-treated mice that received 10 mg/kg/weekdose over 8 weeks replicated clinically significant spontaneous and evoked pain behaviors in our mouse model and induced strong changes in redox and inflammatory profile in the DRG. Histological post-mortem evaluation of the sciatic nerves identified strong effects on mitochondria. KEGG analysis, Non-Negative Matrix Factorization, and correlation analysis on the differentially expressed genes in DRG pointed to the potential role of thioredoxin interacting protein (TXNIP) in regulating oxidative stress pathways. Upregulation of Txnip in the DRG was verified through qPCR, western blotting, and immunohistochemistry and connected to the upstream and downstream pathways. Overall, the results provided insights into the pathophysiology and the mechanism of CIPN with oxaliplatin and highlighted potential drug targets for treatments. Oxaliplatin at high accumulative dosage leads to behavioral and physiological symptoms in mice resembling those in cancer patients undergoing chemotherapy. Our findings suggest TXNIP may serve as a central regulator of oxidative stress and inflammation in CIPN caused by oxaliplatin, presenting a potential therapeutic target for alleviating neuropathy.