Plantamajoside Promotes NGF/TrkA Pathway to Inhibit Neuronal Apoptosis and Improve Diabetic Peripheral Neuropathy.

The symptoms caused by diabetic peripheral neuropathy (DPN) have severely impacted patients' quality of life. While plantamajoside (PMS) exhibits neuroprotective properties, its efficacy and molecular mechanisms against DPN are unexplored. This study first established a high glucose (HG)-induced in vitro model of DPN and investigated the neuroprotective effects of PMS on RSC96 cells. We next demonstrated the anti-apoptotic effects of PMS and NGF/TrkA pathway mediated neurotrophic effects. Finally, we established a DPN mouse model and confirmed the therapeutic effects of PMS on DPN mice through behavioural tests and pathological staining, while also assessing the impact of PMS on the NGF/TrkA pathway and apoptosis. Our results showed that, in HG-induced DPN models, PMS enhanced cell viability while reducing LDH activity. Transcriptomics results indicated that the Apoptosis and Neurotrophins signalling pathways were key pathways for PMS on DPN. PMS treatment reduced HG-induced RSC96 cell apoptosis while enhancing NGF levels and upregulating NGF/TrkA-related protein expression. However, this protection was abolished by TrkA inhibitor or NGF neutralising antibodies. In vivo experimental results showed that PMS improved the mechanical pain threshold, thermal pain reaction time, and nerve conduction velocity of DPN mice. PMS improved pathological damage to the sciatic nerve, enhanced the number of Nissl bodies, reduced TUNEL-positive expression, and upregulated NGF levels. Furthermore, PMS reduced apoptosis and elevated NGF/TrkA-related protein expression in the sciatic nerve of DPN mice. In conclusion, PMS alleviates DPN through activating the NGF/TrkA pathway and inhibiting apoptosis.