Hyperoside Exerts Therapeutic Effects on Parkinson's Disease by Mitigating Oxidative Stress through Activation of Nrf2/HO-1 Pathway.

OBJECTIVE

To investigate whether hyperoside (HYP), the main active ingredients of Wuzi Yanzong Pill, can reduce oxidative stress (OS) damage and treat Parkinson's disease (PD) by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway.

METHODS

MPTP-induced PD mouse model was established and animals were divided into 5 groups by random number table method: control group, MPTP group (15, 20, and 30 mg/kg on days 1, 2 and 3-7, respectively), and MPTP+HYP low-, medium-, and high-dose groups (25, 50, and 100 mg·kg-1·d-1, respectively). Behavioral tests were conducted and protein expression levels of tyrosine hydroxylase (TH), Nrf2, HO-1, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax) were analyzed using Western blot. Glutathione (GSH), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) levels were measured by ELISA. Molecular docking and dynamics simulations were performed on HYP and Nrf2, and neuronal apoptosis was detected by TUNEL assay. Multivariate statistical analysis was used to investigate the correlation between HYP's therapeutic effect on PD and OS via the Nrf2/HO-1 pathway. In the SH-SY5Y cell model (MPP+ and ML385), cell viability and toxicity were assessed with cell counting kit-8 and lactate dehydrogenase assays, and protein expression levels and OS indicatars were also measured.

RESULTS

In animal experiments, HYP intervention improved motor abilities, increased TH, Nrf2, HO-1, and Bcl-2 expressions, and reduced Bax expression compared to the MPTP group (P<0.05 or P<0.01). It also elevated GSH, GSH-Px, SOD, and CAT levels, decreased MDA, and reduced neuronal apoptosis (P<0.05 or P<0.01). Molecular docking and dynamics showed HYP binds effectively to Nrf2. Multivariate analysis revealed a strong correlation between HYP's therapeutic effect on PD and OS via the Nrf2/HO-1 pathway. In cell experiments, ML385 inhibited Nrf2/HO-1 activation by HYP (P<0.05 or P<0.01), diminishing its effect on OS and apoptosis.

CONCLUSION

HYP can reduce OS and apoptosis by activating the Nrf2/HO-1 pathway, thereby exerting a therapeutic effect in PD.