Protective Effects of Imeglimin Against Oxaliplatin-Induced Peripheral Neurotoxicity: Evidence From In Vitro and...

Oxaliplatin is a platinum-based anticancer agent widely used for gastrointestinal malignancies; however, it is known to cause dose-dependent peripheral neuropathy (OIPN), a characteristic adverse effect. OIPN results in a reduced quality of life and often necessitates dose reduction or discontinuation of oxaliplatin; however, effective preventive strategies for OIPN have yet to be established. Imeglimin, an oral antidiabetic agent belonging to the glimin class, has been suggested to influence key aspects of cellular energy metabolism. Because metformin, which shares structural and mechanistic features with imeglimin, prevents OIPN and exhibits unique pharmacological actions, we investigated whether imeglimin also prevents OIPN using both in vitro and in vivo models. In vitro, imeglimin attenuated oxaliplatin-induced cell death, axonal shortening, and oxidative stress in F11 neuronal cells. In vivo, imeglimin prevented reductions in withdrawal thresholds to mechanical stimulation and mitigated sciatic nerve axonal injury in a rat OIPN model. Importantly, imeglimin did not diminish the cytotoxicity of oxaliplatin in several cancer cell lines or its antitumor efficacy in tumor-bearing mice. These findings suggest that imeglimin may prevent OIPN without compromising the antitumor activity of oxaliplatin.