Echinacoside protects against MPTP/MPP+-induced neurotoxicity via regulating autophagy pathway mediated by Sirt1

Parkinson's disease (PD) is a common chronic neurodegenerative disease and greatly affects the quality of PD patients' life. Current symptomatic treatment of PD is limited. There are no effective treatment and drugs that could radically cure PD. Increasing experimental evidence has proven a causal relationship between alpha-synuclein (-synuclein, -syn) and the neuropathology of Parkinson's diseases, although the exact pathophysiological role of -synuclein is not fully clarified. Previous studies showed that monomers and polymers of -synuclein were secreted from damaged nerve cells via exocytosis and occupied healthy nerve cells via endocytosis, which afford evidence for the prion-like role of -synuclein. Autophagy is the known mechanism for eukaryotic cells to degrade protein polymers and damaged organelles that proteasome does not cope with. Therefore, promoting the clearance of -synuclein by enhancing autophagy in neuronal cells could be a promising treatment in the early stage of PD. SIRT1 is a potent regulator of autophagy, because it deacetylates a mass of important transcription factors such as Forkhead Box subgroup O (FoxO) transcription factors family. SIRT1's action relates to FoxO, because FoxO transcription factors are involved in various molecular pathways underlying neuronal protection and autophagy. Moreover, Sirt1 deacetylates proautophagic proteins such as Atg5, Atg7, and Atg8. Echinacoside (ECH) is the main active ingredient of a widely used Chinese herb cistanche, which has been proven to elicit neuroprotective effects in models of neurodegenerative diseases. In this study, we found that ECH could improve PD-like symptoms in MPTP-lesioned mouse model. We further showed that the underlying mechanism of the action of ECH was associated with enhancing autophagy in neurons via bind to Sirt1 directly and affect FoxO expression. Our study demonstrated ECH as a potential therapeutic agent against PD.