Cistanche tubulosa improves peripheral neuropathy in MPTP‐induced PD mice based on regulation of m6A methylation

Abstract Background This study aimed to discover whether Cistanche tubulosa affects the AKT/CASP3 pathway by regulating m6A methylation, to exert a protective effect against peripheral nerve injury in a Parkinson's Disease (PD) mouse model. Methods In this study, network pharmacology analysis and the molecular docking virtual screening technique was used to filter Acteoside (Act), a potential neuroprotective agent of active components in Cistanche tubulosa . A PD‐related peripheral neuropathy mouse model was established by MPTP induction, followed by 21 days treatment of oral Act (25, 50, and 100 mg kg −1 ). Pole climbing, automatic avoidance ability and hot plate sensory tests were evaluated to determine behavioral changes caused by central and peripheral nerve injury. The pathological alterations of dorsal root ganglion tissue and the protein levels of IL‐6, AKT, and CASP3 under Act intervention, as well as the dynamic changes of FTO, METTL3, and YTHDF2 which are closely related to m6A methylation, were comprehensively analyzed to observe the peripheral nerve protective efficacy of Act. Results The results showed that peripheral neuropathy occurring with PD in the mouse model, which could be verified by behavioral tests and pathological histological changes. In addition to the previously established protective effect of Act on dopaminergic neurons in substantia nigra (SN), extensive follow‐up studies demonstrated that Act effectively induced m6A methylation, which could further regulate the AKT/CASP3 pathway to play a therapeutic role. In this study, medium and high doses of Act played more obvious therapeutic roles. Conclusion These findings suggest that Act may regulate the severity of peripheral nerve injury under the activation of the AKT/CASP3 signaling pathway by balancing the methylation level of m6A. These results provide a theoretical basis and experimental evidence for further research on the protective effect of Cistanche tubulosa on both the central and peripheral nerves in the treatment of PD.