Effect of Metformin Nanoparticle-Mediated Thioredoxin Interacting Protein Expression on Oxaliplatin-Induced...

Oxaliplatin (LOHP) is an approved anti-cancer drug that often accumulates in the peripheral nerves during the treatment of cancer. Metformin is a prescription drug with a wide range of pharmacological effects, which can augment the anti-cancer efficacy of chemotherapy drugs. Recent studies suggest that metformin is a potential drug that can relieve oxaliplatin induced neuralgia, and autophagy plays an important role in it. This study aims at exploring the effect and mechanism of action of metformin on oxaliplatin-induced peripheral neuropathic pain. To explore the underlying mechanism of metformin on peripheral nerves, neuropathic pain model was developed by intraperitoneal injection of oxaliplatin into mice. Metformin nanoparticles encapsulated by PLGA were used to intervene the pain in the model mice. RT-qPCR and immunoblotting were used to detect the effects of metformin on the expression of TXNIP and autophagy associated genes-BECN1 and LC3B in the sciatic nerves of pain model mice. Hematoxylin and eosin staining were used to detect the pathological changes in the sciatic nerve. Flow cytometry and Annexin V-FITC/PI apoptosis detection kit were used to detect the apoptosis of sciatic nerve cells. The effect of metformin on the pain perception of mice was detected by thermal and mechanical stimulation experiments. The results showed that the expression of TXNIP and autophagy related indexes-BECN1 and LC3B in sciatic nerve decreased significantly after oxaliplatin treatment. However, metformin intervention resulted in significant up-regulation of TXNIP and autophagy related indexes, and augmented the threshold of thermal sensitivity and mechanical tingling. Thus, our study has identified TXNIP as a novel target for oxaliplatin induced peripheral nerve pain. We have shown that oxaliplatin inhibits TXNIP expression, regulates autophagy, thereby affecting neuralgia. In contrast, metformin promotes the expression of TXNIP and autophagy of cells thereby inhibiting neural sensitivity and thus results in pain relief.