Inhibition of alpha-synuclein seeded fibril formation and toxicity by herbal medicinal extracts

Abstract

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: 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: 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 αsyn 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: 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.

Baicalein Ameliorates Aβ-Induced Memory Deficits and Neuronal Atrophy via Inhibition of PDE2 and PDE4

“…In this study, we found that chronic treatment with baicalein reversed Aβ-induced decreases in the dendric length, number of dendrites and spine density in the CA1 of hippocampus, suggesting that baicalein could rescue Aβ-induced deleterious effects. These findings consistent with the previous studies, which suggested that flavonoids protect neurons against neurotoxic substance induced neuronal atrophy and cell death ( Rajput et al, 2017 ; Ardah et al, 2020 ). Moreover, our study found that the expression of presynaptic and postsynaptic proteins, i.e., synaptophysin and PSD95, was decreased in the Aβ-treated group.…”

α-Synuclein phosphorylation at serine 129 occurs after initial protein deposition and inhibits seeded fibril formation and toxicity

“…WT HEK293 cells were grown in Dulbecco’s MEM-high glucose (Gibco) supplemented by 15% FBS (Gibco) and 1% penicillin-streptomycin (Gibco) and incubated at 37 °C in a 5% CO 2 /95% air humidified incubator. After plating HEK cells overnight in six-well plates, cells were transfected with 2 µg of WT–α-syn plasmid DNA by lipofectamine 3,000 reagent (Invitrogen) ( 58 ). One group of α-syn expressing HEK cells was similarly transfected again with 4 µg of mutant serine 129 to alanine (S129A) PFFs the following day.…”

Acetylcholinesterase Inhibitors in the Treatment of Neurodegenerative Diseases and the Role of Acetylcholinesterase in their Pathogenesis

“…Salvianolic Acid B inhibited the formation of α-synuclein fibrils. In addition, it had a cytoprotective effect on cells by protecting against the toxic effects of α-synuclein aggregates [424]. This compound is non-toxic and had no effect on cell viability and demonstrated a concentration-dependent effect.…”