[Xiaoyao San alleviates abnormal α‑syn aggregation and neuronal injury in a Caenorhabditis elegans model of Parkinson disease via the SKN-1 antioxidative pathway].

OBJECTIVES

To investigate the neuroprotective effects of XiaoyaoSan (XYS) in a Caenorhabditis elegans (C. elegans) model of Parkinson disease (PD) and explore its molecular mechanism.

METHODS

A PD model was established in C. elegans using 6-hydroxydopamine (6-OHDA) and validated using a transgenic strain overexpressing α‑synuclein (α‑syn) (NL5901). The worms were treated with 25, 50 or 100 μg/mL XYS, and their lifespan was recorded. Their motor function and food-related behaviors were evaluated by counting body bends within 20 s and observing the basal slowing response. Dopaminergic neuron degeneration and α‑syn aggregation were observed in GFP-labeled transgenic worms. Intracellular ROS levels were measured using a DHE fluorescent probe, and the mRNA expressions of dat-1, cat-2, ced-9, gst-4, and sod-3 were analyzed using RT-qPCR. RNA interference (RNAi) was employed to knock down skn-1 expression to determine whether the effects of XYS depend on the SKN-1/Nrf2 signaling pathway.

RESULTS

XYS significantly prolonged the lifespan of PD model worms, increased their body bends within 20 s on day 5 and day 10, and improved the basal slowing response. XYS obviously alleviated 6-OHDA-induced dopaminergic neuronal damage, upregulated the expression of dat-1, cat-2, and ced-9, and reduced α‑syn accumulation. Treatment with XYS decreased reactive oxygen species (ROS) levels and upregulated the antioxidant-related genes including sod-3 and gst-4. Mechanistic studies showed that XYS significantly enhanced skn-1::GFP and sod-3::GFP fluorescence signals. Knocking down skn-1 resulted in decreased lipid content in the worms, and XYS failed to significantly reverse this change; skn-1 knockdown also abolished the restorative effect of XYS on sod-3::GFP fluorescence reduction.

CONCLUSIONS

XYS improves neurological function in Caenorhabditis elegans PD model by alleviating oxidative stress and suppressing abnormal α‑syn aggregation, and its neuroprotective effect is mediated probably by the SKN-1/Nrf2-related antioxidant pathway.