Chronic Oxaliplatin Treatment Resembles Human CIPN Behavior in Mice and Leads to Activation of TXNIP Pathway

Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. Long-term neurotoxicity with oxaliplatin is one of the most devastating adverse effects in patients treated with oxaliplatin. At the high accumulative dosage, the negative effect of oxaliplatin on the becomes evident and is linked to a growing number of clinical reports. The aim of this study was to determine the potential mechanisms of chronic oxaliplatin treatment. C57BL/6 male mice were treated with intraperitoneal oxaliplatin (0 and 10 mg/kg) once a week for eight weeks which is the human equivalent dosage. During the treatment, mice were followed with the measurement of physiological parameters, electron microscopy of the sciatic nerve, NCV, histology and RNA sequencing of the DRG. Oxaliplatin replicated clinically significant spontaneous and evoked pain behaviors in our mouse model and induced strong changes in redox and inflammatory profile in 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 (DEGs) in DRG pointed to the potential role of thioredoxin interacting protein (TXNIP) in regulating oxidative stress pathways. Up-regulation of TXNIP in 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. After 8 weeks of oxaliplatin treatment, mice DRGs were collected and total RNA was extracted. There were 10 RNA samples, 5 from control and 5 from oxaliplatin group passed the integrity threshold (larger than 8) and were used for RNA sequencing. Differentially expressed genes between control and oxaliplatin-treated mice were identified with Partek software to study the effects of oxaliplatin on gene expression profile in mice DRG.