Sinomenine Modifies Parkinson's Disease Through Nrf2 Activation.

BACKGROUND

Disease-modifying treatments for Parkinson's disease (PD) are urgently needed, with the Nrf2/ARE pathway a promising target. This study aims to explore the effects of sinomenine on PD and Nrf2/ARE activation.

METHODS

6-OHDA-treated Parkinsonian SH-SY5Y cells and rats were used. Apoptosis and cell viability were measured using flow cytometry and CCK-8 assays. Nrf2 and its downstream proteins were assessed by Western blotting, while ROS levels were detected with fluorescent dyes. Nrf2 silencing via shRNA evaluated sinomenine's dependence on Nrf2 activation. In vivo, behavioral changes, tyrosine hydroxylase (TH) levels and malondialdehyde (MDA) levels were measured. Microglial inflammation was analyzed by measuring TNF-α and IL-1β expression and cytoskeleton analysis. Nrf2 nuclear translocation was verified by Western blotting and molecular docking was performed.

RESULTS

Sinomenine reduced apoptosis and ROS, improved cell viability, upregulated Nrf2 and antioxidant enzyme expression. The protective effects against apoptosis were abolished by Nrf2 silencing. In PD animals, sinomenine improved motor deficits, enhanced Nrf2, GCLC, GCLM, NQO1, and HO-1 expression, decreased MDA levels, increased TH levels in the striatum and maintained count of dopaminergic neurons in substantia nigra. Additionally, it suppressed TNF-α and IL-1β levels in brain tissue and blood, preserving normal microglial morphology and reducing neuroinflammation. Sinomenine promoted Nrf2 nuclear translocation and showed high Keap1 affinity in docking.

CONCLUSIONS

Sinomenine activates the Nrf2/ARE pathway, mitigating oxidative stress and inflammation in PD models, possibly through Keap1 binding and Nrf2 nuclear translocation. These findings suggest sinomenine may serve as a potential disease-modifying therapy for Parkinson's disease, pending further clinical validation.