Inhibition of alpha-synuclein seeded fibril formation and toxicity by herbal medicinal extracts.
Amyloid fibrils
Dihydromyricetin
Parkinson’s disease
Salvianolic acid B
Seeded fibril formation
α-Synuclein
Journal
BMC complementary medicine and therapies
ISSN: 2662-7671
Titre abrégé: BMC Complement Med Ther
Pays: England
ID NLM: 101761232
Informations de publication
Date de publication:
06 Mar 2020
06 Mar 2020
Historique:
received:
18
11
2019
accepted:
11
02
2020
entrez:
8
3
2020
pubmed:
8
3
2020
medline:
5
9
2020
Statut:
epublish
Résumé
Recent studies indicated that seeded fibril formation and toxicity of α-synuclein (α-syn) play a main role in the pathogenesis of certain diseases including Parkinson's disease (PD), multiple system atrophy, and dementia with Lewy bodies. Therefore, examination of compounds that abolish the process of seeding is considered a key step towards therapy of several synucleinopathies. Using biophysical, biochemical and cell-culture-based assays, assessment of eleven compounds, extracted from Chinese medicinal herbs, was performed in this study for their effect on α-syn fibril formation and toxicity caused by the seeding process. Salvianolic acid B and dihydromyricetin were the two compounds that strongly inhibited the fibril growth and neurotoxicity of α-syn. In an in-vitro cell model, these compounds decreased the insoluble phosphorylated α-syn and aggregation. Also, in primary neuronal cells, these compounds showed a reduction in α-syn aggregates. Both compounds inhibited the seeded fibril growth with dihydromyricetin having the ability to disaggregate preformed α-syn fibrils. In order to investigate the inhibitory mechanisms of these two compounds towards fibril formation, we demonstrated that salvianolic acid B binds predominantly to monomers, while dihydromyricetin binds to oligomeric species and to a lower extent to monomers. Remarkably, these two compounds stabilized the soluble non-toxic oligomers lacking β-sheet content after subjecting them to proteinase K digestion. Eleven compounds were tested but only two showed inhibition of α-syn aggregation, seeded fibril formation and toxicity in vitro. These findings highlight an essential beginning for development of new molecules in the field of synucleinopathies treatment.
Sections du résumé
BACKGROUND
BACKGROUND
Recent studies indicated that seeded fibril formation and toxicity of α-synuclein (α-syn) play a main role in the pathogenesis of certain diseases including Parkinson's disease (PD), multiple system atrophy, and dementia with Lewy bodies. Therefore, examination of compounds that abolish the process of seeding is considered a key step towards therapy of several synucleinopathies.
METHODS
METHODS
Using biophysical, biochemical and cell-culture-based assays, assessment of eleven compounds, extracted from Chinese medicinal herbs, was performed in this study for their effect on α-syn fibril formation and toxicity caused by the seeding process.
RESULTS
RESULTS
Salvianolic acid B and dihydromyricetin were the two compounds that strongly inhibited the fibril growth and neurotoxicity of α-syn. In an in-vitro cell model, these compounds decreased the insoluble phosphorylated α-syn and aggregation. Also, in primary neuronal cells, these compounds showed a reduction in α-syn aggregates. Both compounds inhibited the seeded fibril growth with dihydromyricetin having the ability to disaggregate preformed α-syn fibrils. In order to investigate the inhibitory mechanisms of these two compounds towards fibril formation, we demonstrated that salvianolic acid B binds predominantly to monomers, while dihydromyricetin binds to oligomeric species and to a lower extent to monomers. Remarkably, these two compounds stabilized the soluble non-toxic oligomers lacking β-sheet content after subjecting them to proteinase K digestion.
CONCLUSIONS
CONCLUSIONS
Eleven compounds were tested but only two showed inhibition of α-syn aggregation, seeded fibril formation and toxicity in vitro. These findings highlight an essential beginning for development of new molecules in the field of synucleinopathies treatment.
Identifiants
pubmed: 32143619
doi: 10.1186/s12906-020-2849-1
pii: 10.1186/s12906-020-2849-1
pmc: PMC7076823
doi:
Substances chimiques
Benzofurans
0
Drugs, Chinese Herbal
0
Flavonols
0
Plant Extracts
0
alpha-Synuclein
0
salvianolic acid B
C1GQ844199
dihydromyricetin
KD8QND6427
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
73Subventions
Organisme : NIA NIH HHS
ID : R37 AG019391
Pays : United States
Organisme : Qatar National Research Fund
ID : NPRP grant 4-1371-1-223
Organisme : Qatar Foundation
ID : Start-up Fund SF 2017-007
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