Aim of the study
This study aimed to evaluate the effect of BJP-IVb on dopaminergic neurodegeneration in PD and clarified the underlying mechanisms from the aspect of iron overload-mediated ferroptosis. Materials and
Conclusion
BJP-IVb suppressed iron overload-mediated dopaminergic neuron ferroptosis and improved motor dysfunctions in PD, which was achieved by inhibiting IRP2-mediated iron overload. This study provided a potential drug candidate for the treatment of PD.
Methods
One-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models were established in this study. Behavioral tests, cell cytotoxicity assay, tyrosine hydroxylase (TH) and Nissl staining were performed to evaluate the antiparkinsonian effect of BJP-IVb. Cellular ultrastructure, iron content and lipid peroxidation were detected to evaluate iron overload-mediated dopaminergic neuron ferroptosis. Iron regulatory protein 2 (IRP2) and iron transport-related proteins were detected by immunofluorescence and Western blot to evaluated iron transport. Finally, plasmid vector-mediated IRP2 overexpression were performed to further clarify the molecular mechanism.
Results
BJP-IVb alleviated MPP+-induced neurotoxicity in vitro and improved MPTP-induced dopaminergic neuron loss and motor dysfunctions of PD mice, confirming an effect of BJP-IVb against dopaminergic neurodegeneration of PD. Further results revealed that BJP-IVb protected against PD by suppressing iron overload-mediated dopaminergic neuron ferroptosis, as evidenced by the attenuated lipid peroxidation, decreased iron content and changes in cellular ultrastructure. Finally, the decreased iron regulatory protein (IRP2) was confirmed to be responsible for BJP-IVb-mediated ferroptosis suppression by modulating iron transport-related proteins and alleviating iron overload.