Ursolic acid inhibits autophagy-dependent neuronal cell death by reducing oxidative stress levels in an in vitro model of Parkinson’s disease

Background

Parkinson’s disease (PD) is a common neurodegenerative disease in middle-aged and older adults. Autophagy defect is related to the pathogenesis of Parkinson’s disease. Ursolic acid (UA), a naturally occurring triterpene carboxylic acid compound, has recently gained attention for its strong antioxidant properties. However, little is known about the effect of UA on the level of apoptosis of nerve cells.

Objective

This study aims to investigate whether UA could regulate autophagy-dependent apoptosis by reducing the level of cellular oxidative stress.

Results

Here, we found that Rotenone led to a reduction in ATG5/LC3-II levels and autophagosome formation in PC12 cells and primary neurons, accompanied by an increase in p62 level, indicating inhibition of autophagy. However, interestingly, knocking down ATG5 enhanced the inhibition of autophagy and increased neuronal apoptosis by Rotenone. The effects of Rotenone on autophagy and apoptosis were related to the enhancement of oxidative stress and the activation of AMP-activated protein kinase (AMPK). UA decreased the oxidative stress level of nerve cells, inhibited the activity of AMPK, increased the autophagosome formation and ATG5/LC3-II levels, and decreased the p62 level, promoting autophagy and thereby suppressing apoptosis. Furthermore, dominant-negative AMPKα, or inhibition of AMPK with compound C alleviated Rotenone-induced decrease in ATG5/LC3-II levels and autophagosome formation, and increases in phosphorylated AMPK and p62 levels, and cell apoptosis. The effect of Rotenone on autophagy and apoptosis is associated with the production of excess oxygen radicals in cells, as evidenced using UA.

Conclusion

These results suggest that UA can alleviate AMPK activation, inhibition of autophagy, and neuronal apoptosis induced by Rotenone by reducing oxidative stress level. Our findings highlight that UA has great potential in the prevention and treatment of Parkinson’s disease.