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

Chang Chen,Lili Tang,Ye Yang,Baomei Xia,Gang Chen,Yang Zhao,Yan Liang,Juanjuan Tang,Zhennian Zhang,Hui Yang,Wei Wu,Yan Lu

doi:10.1007/s11011-018-0330-3

Chang Chen, Lili Tang + Show 10 more

Open Access

https://doi.org/10.1007/s11011-018-0330-3

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Abstract

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 (α-synuclein, α-syn) and the neuropathology of Parkinson’s diseases, although the exact pathophysiological role of α-synuclein is not fully clarified. Previous studies showed that monomers and polymers of α-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 α-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 α-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.

Highlights

Neurodegenerative disorders exert a heavy toll on patients’ quality of life and pose an economic burden for society
This study focuses on MPTP-induced Parkinson’s disease (PD) mouse model and MPP+ induced PC12 cell model to explore how ECH regulates Sirt1 and how it performs neuroprotective effect in PD in vitro and in vivo models
Western blotting detection indicated that the expressions of autophagy proteins such as LC3-II and Beclin-1 and p-PI3K were significantly reduced (p < 0.01, p < 0.01, p < 0.05) while the expression of P62 which is negatively related to autophagy was significantly increased (p < 0.05) in the PC12 cell after being incubated with 1 mM MPP+ for 24 h. 100 μM ECH treatment increased the expression of LC3-II, Beclin-1 and p-PI3K (p < 0.05, p < 0.01, p < 0.05) while reduced the expression of p62 (p < 0.05). (Figure 4e‐j) The result above indicated that ECH reversion of MPP+ induced PC12 cell damage was related to the upregulation of autophagy

Summary

Introduction

Neurodegenerative disorders exert a heavy toll on patients’ quality of life and pose an economic burden for society. It is proved that MPTP could induce obvious neurotoxicity of both pathological and biochemical damage dopaminergic neurons in the nigrostriatal pathway (Abushouk et al 2017). It becomes the most commonly used neurotoxin for the preparation of PD animal model. In addition to its important role of normal brain aging process, SIRT1 has been shown to improve a series of neurodegenerative disorders in animal models including Alzheimer’s, Parkinson’s, and Huntington’s disease. SIRT1 can promote the transcription of heat shock protein 70 and other molecular chaperones by deacetylating heat shock factor 1 Another possible mechanism is that SIRT1 deacetylate PGC1a as overexpressed PGC1a or resveratrol to protect dopaminergic neurons from MPTP-induced cell degeneration. This study focuses on MPTP-induced PD mouse model and MPP+ induced PC12 cell model to explore how ECH regulates Sirt and how it performs neuroprotective effect in PD in vitro and in vivo models

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Compliance with ethical standards