Paeoniflorin Upregulates Mitochondrial Thioredoxin of Schwann Cells to Improve Diabetic Peripheral Neuropathy Indicated by 4D Label‐Free Quantitative Proteomics

Diabetic peripheral neuropathy (DPN) is a diabetic complication characterized by demyelination. The pathogenesis of DPN has not been fully elucidated, thus lacking therapies. In the current study, we aimed to confirm whether paeoniflorin (PF) could improve DPN by upregulating mitochondrial thioredoxin (Trx2) based on 4D Label‐free proteomic experiments of Schwann cells (SCs) mitochondria. Firstly, PF increased the expression of mitochondrial processing peptidase α (Pmpca) and small ubiquitin‐related modifier 1 (Sumo1) to increase mitochondrial protein processing of Trx2. Then, PF increased the protein expression of Trx reductase 2 (TrxR2) and peroxiredoxin 3 (Prx3), which belong to mitochondrial Trx systems. Accordingly, PF decreased mitochondrial reactive oxygen species (ROS) while increasing mtDNA and mitochondrial membrane potential to improve mitochondria function under high glucose environment. Furthermore, total glucosides of paeony capsules (TGP), containing more than 90% PF, increased the Trx2, TrxR2, and Prx3 levels in sciatic nerve of DPN rats, thus reducing demyelination as well as improving mechanical pain threshold, thermal pain threshold, motor nerve conduction velocity (MNCV), and sensor nerve conduction velocity (SNCV). Overall, these results suggest that PF could provide protection for DPN by upregulating Trx2.