Dingzhen pills inhibit neuronal ferroptosis and neuroinflammation by inhibiting the cGAS-STING pathway for Parkinson's disease mice.

Background: Parkinson's disease (PD) is a neurodegenerative disease whose cause and molecular mechanism remain unclear. Dingzhen pill (DZP), a water extract from crude herbs, is thought to possibly play a neuroprotective role in PD. However, the underlying pharmacological mechanisms of the DZP and its impact on the potential pathways against PD have not been elucidated.

Aim: The aim of this study was to explore the effect and molecular mechanism of DZP treatment on PD by quantitative proteomic and metabolomic analysis.

Methods: The effect of DZP on the behavior of movement disorders in a mouse model of MPTP-induced was first evaluated. Secondary metabolomics for TCM resolved the components of DZP and its metabolites distributed in the serum of PD mice. Proteomics was used to resolve the effects of DZP on proteins in brain tissue in mice with PD. Network pharmacology and molecular docking analysis were used to screen and validate the binding relationships of components and targets. Immunofluorescence and western blot analysis verified the pathway affected by DZP.

Results: Our study showed that DZP improved the movement disorder of PD mice and promoted the recovery of dopaminergic neurons in substantia nigra. Secondary metabolomics showed that 460 kinds of secondary metabolites existed in serum of PD mice after DZP treatment. Proteomics analysis showed that DZP affected the expression of 9393 proteins, 87 of which were up-regulated and 120 down-regulated. Through target prediction and molecular docking, a total of 8 compounds were found to interact with 8 pathological PD targets, playing a significant role in neuronal protection. In addition, DZP inhibits neuronal ferroptosis and neuroinflammation by inhibiting the cGAS-STING pathway.

Conclusion: This study is helpful to understand the molecular mechanism of the multi-component, multi-target neuroprotective effect of DZ, and may contribute to the development of DZP as a new therapeutic strategy for clinical application in PD.