Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Neuroprotective Effect of Astersaponin I against Parkinson's Disease through Autophagy Induction

  • Zhang, Lijun (Natural Product Research Center, Korea Institute of Science and Technology) ;
  • Park, Jeoung Yun (Natural Product Research Center, Korea Institute of Science and Technology) ;
  • Zhao, Dong (Natural Product Research Center, Korea Institute of Science and Technology) ;
  • Kwon, Hak Cheol (Natural Product Informatics Research Center, Korea Institute of Science and Technology) ;
  • Yang, Hyun Ok (Natural Product Research Center, Korea Institute of Science and Technology)
  • Received : 2021.01.06
  • Accepted : 2021.06.07
  • Published : 2021.11.01
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Abstract

An active compound, triterpene saponin, astersaponin I (AKNS-2) was isolated from Aster koraiensis Nakai (AKNS) and the autophagy activation and neuroprotective effect was investigated on in vitro and in vivo Parkinson's disease (PD) models. The autophagy-regulating effect of AKNS-2 was monitored by analyzing the expression of autophagy-related protein markers in SH-SY5Y cells using Western blot and fluorescent protein quenching assays. The neuroprotection of AKNS-2 was tested by using a 1-methyl-4-phenyl-2,3-dihydropyridium ion (MPP+)-induced in vitro PD model in SH-SY5Y cells and an MPTP-induced in vivo PD model in mice. The compound-treated SH-SY5Y cells not only showed enhanced microtubule-associated protein 1A/1B-light chain 3-II (LC3-II) and decreased sequestosome 1 (p62) expression but also showed increased phosphorylated extracellular signal-regulated kinases (p-Erk), phosphorylated AMP-activated protein kinase (p-AMPK) and phosphorylated unc-51-like kinase (p-ULK) and decreased phosphorylated mammalian target of rapamycin (p-mTOR) expression. AKNS-2-activated autophagy could be inhibited by the Erk inhibitor U0126 and by AMPK siRNA. In the MPP+-induced in vitro PD model, AKNS-2 reversed the reduced cell viability and tyrosine hydroxylase (TH) levels and reduced the induced α-synuclein level. In an MPTP-induced in vivo PD model, AKNS-2 improved mice behavioral performance, and it restored dopamine synthesis and TH and α-synuclein expression in mouse brain tissues. Consistently, AKNS-2 also modulated the expressions of autophagy related markers in mouse brain tissue. Thus, AKNS-2 upregulates autophagy by activating the Erk/mTOR and AMPK/mTOR pathways. AKNS-2 exerts its neuroprotective effect through autophagy activation and may serve as a potential candidate for PD therapy.

Keywords

Acknowledgement

This work was funded and supported by the Bio-Synergy Research Project (NRF-2012M3A9C4048793) and the Bio & Medical Technology Development Program (NRF-2015M3A9A5030735) of the Ministry of Science, ICT, and Future Planning through the National Research Foundation of the Republic of Korea to HOY. This work also was supported by Korea Institute of Science and Technology (KIST) Institutional Program (2Z05640).

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